Textbook of Pediatric Rheumatology 5th Edition

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TEXTBOOK OF PEDIATRIC RHEUMATOLOGY Copyright © 2005, Elsevier Inc.

ISBN 1-4160-0246-4

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

Library of Congress Cataloging-in-Publication Data Textbook of pediatric rheumatology / [edited by] James T. Cassidy, Ross E. Petty–5th ed / associate editors, Ronald M. Laxer, Carol B. Lindsley p.; cm. Includes bibliographical references and index ISBN 1-4160-0246-4 1. Pediatric rheumatology 2. Rheumatism in children. I. Cassidy, James T. II Petty, Ross E. [DNLM: 1. Rheumatic Disease–Child 2. Arthritis–Child 3. Connective Tissue Diseases–Child 4. Vasculitis–Child. WE 544 T355 2006] RJ482.R48.C37 2006 618.922723-dc22

Publishing Director: Kim Murphy Developmental Editor: Janine Kusza Project Manager: David Saltzberg Marketing Manager: Megan Carr

Printed in the United States Last digit is the print number: 9

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To Nan, Beryl, Edda and Bart

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CONTRIBUTING AUTHORS

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KhaIed Alsaeld, MD Chief of Pediatric Rheumatology, Department of Pediatrics, Kuwait University, Faculty Medicine, Safat, Kuwait

Frank Dressler, MD Lecturer, Department of Pediatrics, Hannover Medical School, Assistentzarzt, Kinderklinik der Medizinischen, Hochschule Hannover, Hannover, Germany

Balu H. Athreya, MD Division of Rheumatology, Alfred 1. duPont Hospital for Children, Wilmington, Department of Pediatrics, Wilmington, Delaware, USA

Oaran M. Duffy, MB, BCH, M5c Associate Professor of Paediatrics and Director, Division of Paediatric Rheumatology, Montreal Children's Hospital, and McGill University, Montreal, Quebec, Canada

Ella M. Ayoub, MD (deceased) Distinguished Service Professor, Department of Pediatrics, University of Florida, College of Medicine, Gainesville, Florida, USA

Fernanda Faldnl, MD Department of Pediatrics, University of Florence and Oespedale Meyer, Florence, Italy

Susannah Brydges, PHD Fellow, Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

Ruben Burgos-Vargas, MD Professor of Medicine, Universidad Nacional, Auton6ma de Mexico, Mexico DF James T. Cassidy, MD Professor Emeritus of Child Health and Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, and Professor Emeritus of Pediatrics and Communicable Diseases and Internal Medicine, University of Michigan, Medical School, Ann Arbor, Michigan, USA Rolando Omaz, MD Dirigente Medico, Department of Pediatrics, Fondazione Policlinico Mangiagalli, University of Milan, Milan, Italy Robert A. Colbert, MD, PHD Associate Professor of Pediatrics, Associate Director, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Marco Gattorno, MD Department of Pediatrics, University of Genoa, Genoa, Italy Edward H. Giannini, MSc DR PH Professor of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA David N. Glass, MD Professor of Pediatrics, Director, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Judith G. Hall, OC, MD Professor Emeritus, Medical Genetics and Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada Robert M. Hamilton, MD Professor, Department of Paediatrics, University of Toronto; and Section Head, Electrophysiology, Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada Hans-Iko Huppertz, MD Professor of Pediatrics, Head, and Director, Children's Hospital CProfessor-Hess-Kinderklinik), Bremen, Germany

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CONTRIBUTING AUTHORS

Daniel L. Kastner, MD, PHD Chief, Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA Wletse Kuls, MD, PhD Professor of Pediatrics, University of Utrecht and Department of Pediatrics, University Medical Center, Utrecht, The Netherlands Ronald M. Laxer, MD, FRCPC Professor of Paediatrics and Medicine, University of Toronto; and Vice President, Clinical and Academic Affairs and Staff Rheumatologist, The Hospital for Sick Children, Toronto, Ontario, Canada Carol B. Lindsley, MD Professor, Department of Pediatrics, Chief, Pediatric Rheumatology, University of Kansas Medical Center, Kansas City, Kansas, USA Daniel J. Lovell, MD, MPH Professor of Pediatrics, University of Cincinnati College of Medicine; Associate Director, William G. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio, USA Peter N. Malleson, MBBS Professor of Pediatrics, Division of Pediatric Rheumatology, University of British Columbia, British Columbia Children's Hospital, Vancouver, British Columbia, Canada Alberto Martini, MD Professor and Head, Department of Pediatrics, Gaslini Children's Hospital, University of Genoa, Genoa, Italy Audrey M. Nelson, MD Emeritus Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Anne-Marie Prieur, MD Hopital Necker Enfants Malades, Paris, France L1eke A.M. Sanders, MD, PhD Associate Professor of Pediatric Immunology, University of Utrecht and Department of Pediatrics, University Medical Center, Utrecht, The Netherlands David D. Sherry, MD Professor of Pediatrics, University of Pennsylvania, Director, Clinical Rheumatology, Attending, Pain Management, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Earl D. Silverman, MD, FRCPC Professor of Pediatrics and Immunology, University of Toronto, Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada Taunton R. Southwood, MD, BM, BS Professor of Paediatric Rheumatology, Department of Rheumatology, University of Birmingham Medical School, Birmingham Children's Hospital, Birmingham, United Kingdom Dawn Spence, RN, MSN, PNP Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada Robert P. Sundel, MD Assistant Professor of Pediatrics, Harvard Medical School, Director of Rheumatology, Children's Hospital Boston, Boston, Massachusetts, USA Janltzla V6zquez-Mellado, MD, PhD Professor of Medicine, Universidad Nacional Aut6noma de Mexico; Senior Investigator, Rheumatology Service, Hospital General de Mexico, Mexico City, Mexico

Benedlcte Neven Unite d'Immunologie-Hematologie et Rhumatologie, Hopital Necker Enfants Malades, Paris, France

Nlco M. Wulffraat, MD, PhD Associate Professor in Pediatric Immunology, University of Utrecht and Department of Pediatrics, University Medical Center, Utrecht, The Netherlands

Seza Ozen, MD Professor, Department of Pediatrics, Hacettepe University 02, Faculty of Medicine, Ankara, Turkey

Francesco Zullan, MD Professor, Chief, Division of Pediatric Rheumatology, Universita di Padova, Padua, Italy

Ross E. Petty, MD, PHD Professor of Pediatrics, University of British Columbia, Division of Rheumatology, Department of Pediatrics, Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada

FOREWORD

In the beginning, we were a handful of naive but eager and explorative young physicians of disparate training, background, and temperament. We joined together with a vision of doing whatever was necessary to find better ways to study the rheumatic diseases of childhood and adolescence, and to treat our patients more effectively in a comprehensive continuum of care. Our successes resulted from consistent and collegial cooperation in pursuit of these common goals. With the first pediatric rheumatology centers in the u.s. in Ann Arbor, Boston, Dallas, Houston, Los Angeles, New York City, and Seattle, expansion had occurred to 27 by 1976 at the time of the First Park City Meeting, to 77 today, with a similar development of centers of excellence in clinical care and research in pediatric rheumatology around the globe on every continent. Over the years, the acquisition of spe-

cific knowledge in this field has developed at an astounding, accelerated pace. To a major extent the scientific and clinical progress of these decades and its publication has been organized and codified in this Textbook ofPediatric Rheumatology, beginning with the first edition in 1982. It is therefore our distinct privilege to join together to dedicate this fifth edition not only to that early small group of clinics and to their expansion in numbers and effectiveness, but even more to the children with rheumatic diseases, to their families, and to the now thousands of healthcare professionals endeavoring to ameliorate or cure these diseases and to improve the lifestyles and career opportunities of their patients. EARL

J.

BREWER,

JOSEPH

E.

MD, FAAP, MACR MD, MACR

LEVINSON,

xIII

PREFACE

The first edition of the Textbook of Pediatric Rheumatology was published in 1982. The intervening years have encompassed an enormous increase in our understanding of the pathophysiologic mechanisms operative in the genesis of pediatric rheumatic diseases, much of which is specific for the discipline. It was not so many years ago that the rheumatologic literature reflected data primarily from studies of adults. These recent and gratifying developments in scientific studies specific to the younger age groups have afforded us opportunities for better diagnosis and treatment of children with rheumatic disorders. Yet much remains to be accomplished. The present edition continues the tradition of incremental reassessment of authorship established by its predecessors, and represents a complete revision of the original text. We trust it will be a testament to the clinical scope and science of pediatric rheumatology, its codification as a distinct specialty, and the gratifying maturity that it has achieved. It is our belief that the advances in the practice and science of pediatric rheumatology described herein are increasingly recognized as an integral and essential element of the clinical, investigative, and educational programs of academic institutions of medical training and research. This edition was reorganized in order to provide a comprehensive source of information regarding the rheumatic diseases of childhood during the last five years for specialists concerned with the care of these children, and for those in primary fields of medicine in order to facilitate early diagnosis and treatment through timely referral. Significant advances in practice and knowledge have been incorporated including exhaustive reviews of the major clinical syndromes resulting in the rheumatic and inflammatory diseases of childhood and investigative efforts directed toward validation of their classification. The chapters on health care assessment, the conduct of clinical trials, and the design and statistical analysis of therapeutic investigations have been carefully revised. Most importantly, the text continues to reflect the ongoing therapeutic revolution in rheumatology involving biologic modification of the cytokine network which reqUired a reworking and considerable enlargement of the chapter on pharmacology. Chapters on the periodic

fever syndromes and the genetic profiles of related neonatal inflammatory disorders have been added. In the process of documenting these innumerable additions to our knowledge, the cited references have been extensively updated, retaining only those regarded as "classics" or having historic importance, and incorporating recent publications that specifically contribute to understanding the pathophysiology and clinical presentation of the over 100 rheumatic "diseases" that afflict children. The majority of these publications are now specific to children, in contrast to the first edition where much had to be assumed from adult studies. In fact, publications in this field are now so extensive that one can only suggest the depth of the investigations. To give due credit to all would require substantial additional text. It should be noted that much of the material summarized in previous editions has been deleted by acknowledging duplicative studies and tenets now universally accepted. Reviews where appropriate have been emphasized. Thirty-four of our colleagues have been enlisted in these efforts in what is now an international, multiauthored text. The contributions of these authors represent expert appraisals of specific fields of clinical concentration. We are incredibly grateful for their enthusiastic cooperation in this endeavor. Their efforts have clarified areas of immunogenetics that emphasize the extensive advancement in knowledge that will ultimately result from sequencing the human genome, immunologic mechanisms of inflammatory disease, neuroendocrine dysregulation, and developmental defects contributing to the inflammatory arthropathies. Much revision has also resulted from careful and exhaustive reviews of previous editions by John Bohnsack, Hermine Brunner, Edward Giannini, Carol Lindsley, David Sherry, and Carol Wallace. In addition to our colleagues, we are deeply indebted to our families and spousal support throughout this process of revision spanning more than three years, without whose patience and understanding this new edition would not have been possible. A transition in editorial direction, with the appointment of two associate editors who have been contributors to this and previous editions, has been of enormous aid in the preparation of this

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PREFACE

text, and in assuring the continuation of the contributions that it has brought to the specialty. We have also given our last farewells to two former contributors and dear friends who have now left us: Carol G. Ragsdale and Elia M. Ayoub. We trust that the fifth edition of the Textbook ofPediatric Rheumatology will aid physicians caring for children with rheumatic diseases to interpret the complex web of symptoms, signs, and laboratory abnormalities that are characteristic of these disorders, and their often inherent ambiguity; will inspire students of medicine to recognize

the challenges and excitement of this pediatric discipline; and ultimately will ensure the provision of prompt and optimal care to the hundreds of thousands of children and their families around the world who endure the pain and limitations imposed by these disorders. T. CASSIDY, MD PEITY, MD, PHD

JAMES

Ross E.

RONALD CAROL

B.

M. LAxER, MD LINDSLEY, MD

C HAP T E R

1

INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN Ja.s T. Cassidy and Ross E. Petty

~

The rheumatic diseases are chronic multisystem disorders that represent clinical manifestations of acute and chronic inflammation of the connective tissues of the musculoskeletal system, blood vessels, and skin. They range from arthritis limited to one joint, to widespread inflammation of joints, muscles, skin, blood vessels, and organs as diverse as the eye, lung, brain, and bone marrow. Homo sapiens has been afflicted with a variety of these disorders for thousands of years. Chronic arthritis-like changes have been identified in the spines of prehistoric Egyptian mummies circa 8000 BC,I and ankylosing spondylitis may be the most ancient of the defined rheumatic diseases, having been documented in skeletal remains from medieval Europe. 2 However, rheumatoid arthritis may be a more recent development, at least in Europe, where it was first described clinically in the 19th century, although it may have originated much earlier among aboriginals of North America. 3 Rheumatic diseases are worldwide in distribution, although there are notable differences in the frequency of some diseases in different racial groups. Considering the early age at onset of many rheumatic diseases of childhood, as well as their chronicity, they constitute an important burden for society.

EVOLUTION OF TERMINOLOGY In 1883, Barlow introduced a discussion on "Rheumatism and its allies in childhood" as follows: "The fundamental difficulty in discussing rheumatism consists in defining what we mean by it.,,4 The term rheumatism is derived from the Greek rheumatismos: a flux. The first use of this term has been ascribed to Galen, 5 to describe inflammatory or degenerative diseases of the joints, bones, muscles, or bursae. Baillou 0558-1616) first employed the word rheumatism to distinguish acute arthritis from gout. 6 The noun "rheumatism" currently has no precise meaning and has generally fallen into disuse. The adjective rheumatic originally referred to acute rheumatic fever and today has the connotation of "inflammatory."

2

Rheumatic fever per se was distinguished from acute gouty arthritis only in the 17th century by Sydenham in England7 ; he later described chorea. The word arthritis is derived from the Greek arthron, meaning joint. It entered the English language about 1544, when it was used to refer only to gout with the suffix -itis, meaning inflammation (-ites, originally an adjectival inflection, gradually evolved to -itis as a suffix to imply an inflammatory disorder). The term arthralgia indicates joint pain without objective evidence of inflammation. Garrod first proposed the designation rheumatoid arthritis to differentiate this disorder from gout and rheumatism. 8 However, it is likely that Hippocrates recognized these diseases in his innumerable observations on the origin of disease from natural phenomena, separate from sacred or philosophical causation or superstition. 9 In the absence of specific knowledge of etiology or pathogenesis, it is not surprising that the terminology used to describe and classify rheumatic diseases, including those of childhood, continues to evolve. Discrepancies between the American College of Rheumatology criteria for classification of juvenile rheumatoid arthritis (JRA)1O and those of the European League Against Rheumatism for juvenile chronic arthritis (JCA)ll exemplify this point. The problem of definition and classification has been a persistent one and is addressed again in the proposed criteria for juvenile idiopathic arthritis (JIA) of the International League of Associations for Rheumatology (see Chapter 9).12 Terminology for the other rheumatic diseases affecting children has been less controversial; however, validated classification criteria are often lacking. In large part, terms used to describe similar diseases in adults have been adopted without consideration for age-related differences in disorders such as systemic lupus erythematosus (SLE), scleroderma, dermatomyositis, and some of the vasculitides. Proposed criteria for the first three of these are now being validated by international studies. Diagnostic or classification criteria have been developed for "new" diseases such as Kawasaki disease, Lyme disease, and parvovirus Bl9-associated arthritis. Recent

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INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN

genetic discoveries, as in the periodic febrile syndromes, have led to a reclassification of these disorders. In recent decades, chronic noninflammatory pain syndromes have become major clinical components of the field of rheumatology in its broadest sense in both children and adults; criteria for these disorders in children and adolescents have been adopted or modified from those used in adults.

THE RHEUMATIC DISEASES OF CHILDHOOD Pediatric rheumatology is a clinical discipline that embraces the study of inflammatory and noninflammatory disorders of the connective tissues and joints in children. Its boundaries continue to expand, and although inflammatory disorders of joints, muscles, and connective tissues constitute the core of the discipline, the differential diagnosis of these diseases necessitates a broad knowledge of potentially confusing disorders, the majority of which are included in chapters of this textbook. A summary of the history of arthritis in children has been published by Hayem. 13 The first book on pediatrics written by an Englishman, which contains the first English-language reference to rheumatism in children, is the 1545 text by Phaire, 1be Regiment ofLife Whereunto Is Added a Treatise of the Pestilence, with 1be Boke of Chytdren. In this work, the author refers to the "stifnes or starckenes of the limmes" resulting from exposure of a child to cold,14.15 a complaint that may not represent any specific rheumatic disease, and also says, "Here to doo them good that haue most nede, that is to saye children." In 1864, Cornil described a woman in whom polyarthritis had developed when she was 12 years 01d. 16 The disease pursued a chronic relapsing course and terminated in her death from uremic coma at the age of 28 years. Necropsy documented myocardial degeneration, nephrotic syndrome, and ankylosis of some joints, with synovial proliferation and marked destruction of cartilage in others. This girl may have had amyloidosis complicating chronic polyarticular arthritis. In 1873, Bouchut described chronic rheumatism in six children,17 and in 1870 .Moncorvo l8 diagnosed childhood arthritis in one of his own patients in Brazil and in eight patients from the literature. West's 1881 Lectures on the Diseases ofInfancy and Childhood!9 noted that "chronic rheumatic arthritis in children is a rare occurrence." In 1883, Barlow, a mentor to Still at the Hospital for Sick Children, Great Ormond Street, London, chaired a discussion on rheumatism in childhood. 4 In the report of this meeting, the term rheumatism was used to describe poststreptococcal disease, including acute rheumatic fever. Barlow recognized clearly the extent and complexity of these disorders: "For there are in children many affections of joints, and of structures around joints, which do not suppurate, and yet are not rheumatic; and there is much rheumatism in children which does not affect joints." What we would today call toxic synovitis of the hip, acute pyogenic arthritis, syphilitic arthritis, hemophiliac arthropathy, Henoch-Schonlein purpura, poststreptococcal arthritis, and acute rheumatic fever,

3

including carditis, arthritis, nodules, erythema marginatum, and chorea, are all identifiable in this paper. This physician was careful to exclude rickets and scurvy because he considered that the joint itself was not primarily involved in these conditions. In 1891, Diamant-Berger published a detailed account of chronic arthritis in 38 children whom he had seen or whose cases had been documented in the literature. 2o He noted the heterogeneity of onset, its predominance in girls, and involvement of the cervical spine and temporomandibular joints as well as ocular inflammation. He also stated that the prognosis in children was generally better than for chronic arthritis in adults. Five years later, Still described 22 cases of acute and chronic arthritis in children, almost all of whom were observed at the Hospital for Sick Children. 21 This treatise, written under the mentorship of Barlow,22 documented the clinical characteristics and the differing modes of onset in these children. Still was the first English physician to confine his practice to diseases of children and the first Professor of Paediatrics at King's College Hospital Medical School, London. Unfortunately, after his classic study, he rarely returned to the field of pediatric rheumatology, although his scholarly work comprised 108 papers and five books, including the History of Paediatrics (931) and Common Diseases in Children. Also in 1896, Koplick 23 described the first American child with chronic arthritis. Although these descriptions of arthritis in childhood rank as the most important milestones in the early development of pediatric rheumatology, other rheumatic diseases began to be identified in children in the 19th century. The clinical characteristics of leukocytoclastic vasculitis were described by Schonlein24 and Henoch25 in the mid-1800s. Juvenile dermatomyositis was identified by Unvericht in 1877,26 although it was not until the 1960s that significant experience with this disease was reported. SLE has been recognized in children at least since 1904. 27 The original description of scleroderma was in a 17-year-old girl,28 but the disease was rarely diagnosed thereafter in a child until the early 1960s. Ankylosing spondylitis was also perhaps first identified in a child 29 ; it was certainly known to occur in childhood in the 19505,30 but specific studies of the disorder in children did not emerge until the late 1960s. 31.32 More recent additions to the family of pediatric rheumatic diseases include Kawasaki disease, which was reported in some detail in 1967,33 although its clinical characteristics (in infants dying of "polyarteritis nodosa") were described by Munro-Faure in 1959. 34 Other rheumatic diseases, such as neonatal-onset multisystem inflammatory disease or NOMID (also called chronic infantile neurologic, cutaneous, and articular [CINCA] syndrome), neonatal lupus, and Lyme disease, have recently been identified. Noninflammatory musculoskeletal pain syndromes are more recent additions to the expanding list of disorders that cause musculoskeletal pain and dysfunction in children and adolescents. Very little further information about these rheumatic diseases was published until the last half of the 20th century. This development coincided with the availability of penicillin and the retreat of acute rheumatic fever in

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INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN

Europe and North America. Until the mid-1940s this disease was the major rheumatic disease, and it still is in many areas of the developing world. With its control, however, attention was shifted to the chronic nonstreptococcal rheumatic diseases, principally chronic arthritis. Today, the specialty of pediatric rheumatology is concerned with a diverse group of disorders (Table 1-1), most of which are manifestations of systemic disorders and require the greatest expertise for prompt diagnosis and optimal management. Of all of the specialties, rheumatology, one of the most stimulating and challenging areas in all of medicine, may deal with the broadest spectrum of disease, both organ-specific and systemic. It is sometimes considered a "gray area" of medicine because there are few useful diagnostic tests, pathognomonic clinical signs are sparse, and therapy often lacks specificity. This specialty requires a diagnostic and therapeutic approach that embraces the "whole" child and family unit, patience, careful observation over long periods, and a heightened ability to tolerate ambiguity and uncertainty. Sometimes only the passage of time makes a diagnosis evident.

EMERGENCE OF THE SPECIALTY OF PEDIATRIC RHEUMATOLOGY The roots of contemporary pediatric rheumatology are found in pediatrics, internal medicine, immunology, and orthopedics; however, as experience with rheumatic diseases in children accumulates, it is apparent that many aspects of these disorders demand a uniquely pediatric approach. Furthermore, many of the diseases, or their complications, are confined to the childhood and adolescent population but have lasting effects on health and socioeconomic well-being or cause disability well into adulthood. These considerations first emerged in the United Kingdom in particular, where the study of rheumatic disease in children was established in earnest after World War II by the founding in 1947 of the Rheumatism Research Unit at the Canadian Red Cross Memorial Hospital in Taplow, Berkshire, England. 3S .36 Initially the Taplow unit dealt almost exclusively with rheumatic fever. As the frequency of this disease declined in England during the mid-20th century, its focus shifted to

I!:.

TABlE I-I

the other chronic rheumatic diseases and laid the foundation for the specialty of pediatric rheumatology. Pediatric rheumatology began to develop in the United States in the early 1940s. Hospitals for the treatment and rehabilitation of children with rheumatic fever were established after World War II in Chicago (La Rabida) and New York City (Irvington House) that were later expanded in scope to care for children with other rheumatic diseases and chronic illnesses. Establishment of clinical and academic centers of pediatric rheumatology in the United States and subsequently in many other countries marked the "coming of age" of the specialty. The American College of Rheumatology established the Pediatric Council in 1975; its first Conference on the Rheumatic Diseases of Children was held in Park City, Utah, in 1976. The first edition of this textbook was published in 1982. Reminiscences of six of the pioneers of pediatric rheumatology (Stillman, Hanson, Levinson, Ansell, Brewer, and Stoeber) are recommended to the interested reader. 37--42

FACTORS THAT MAY MODIFY RHEUMATIC DISEASES IN CHILDREN One of the fundamental questions that has pervaded research in pediatric rheumatology is the extent to which the rheumatic diseases of childhood are the same as, or different from, rheumatic diseases in adults. It is important to differentiate semantic from biologic similarities: The fact that two diseases bear the same name or share some physical findings, abnormalities in laboratory markers, or even treatments (e.g., JRA and adult rheumatoid arthritis) does not necessarily imply that they are the same disorder biologically. Historically, the pediatric diseases were usually named in ignorance of epidemiology, genetics, or biology. Any distinction based on age at onset alone is arbitrary and unlikely to represent biologic truth. There is no age at which these rheumatic diseases abruptly change from one to the other, yet age-related associations are often evident. For example, there are characteristic age-atonset distributions for the individual chronic arthritides. 43 The spectrum of int1ammatory myositis is very different in the child or adolescent than in the adult. Morphea is a common form of scleroderma in the child, whereas in the

Frequt'll(y ollhe Major Pedialri( (onnedive Tisslle Ubeases in 11,300 Children

Disease Juvenile rheumatoid arthritis Connective tissue diseases Spondyloarthropathy and reactive arthritis Psoriatic arthropathy Infectious arthritis and osteomyelitis Malignancy/hematologic Chronic pain syndromes Hypermobility and overuse syndromes Other diseases

Number of eases 7,368 3,861 2,973 173 1.620 290 4,483 2,745 34,216

%

12.8 6.7

5.1 0.3 2.8 0.5 7.8 4.8 59.3

57,729 diagnoses from 48.934 consecutive patients with definite diagnoses entered into the Pediatric Rheumatic. Disease Registry of the Pediatric Rheumatology Database Research Group. 1992-2002. Courtesy of Suzanne Bowyer. M.D., Pediatric Rheumatology Database Research Group.

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INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN

adult, systemic scleroderma predominates. There is little doubt that some rheumatic diseases occur only in young children (e.g., oligoarthritis with uveitis, Kawasaki disease), and others affect almost exclusively adults (e.g., gout, osteoarthritis). Neonatal lupus, and rarely other rheumatic diseases, represent the effect of maternal autoimmunity on the fetus. In diseases such as SLE and the vasculitides, clinical and laboratory characteristics in children and adults are very similar, if not identical in many cases. However, the reasons that one individual has childhood onset of disease, whereas another has onset in adulthood, are not known. More commonly, however, diseases with similar names and similar biologic characteristics occur in both pediatric and adult populations (e.g., scleroderma, ankylosing spondylitis, SLE). Age-related manifestations of these diseases are well recognized. Some of the prominent differences between children and adults that may modify the clinical expression of a rheumatic disease are presented in Table 1-2. Most, if not all, rheumatic diseases are characterized by disordered immunity, and often there is a genetic predisposition that is expressed clinically early in life. This is particularly true for the inherited dysplasias of bone and cartilage and for biochemical disorders such as mucopolysaccharidoses, hemophilia, and the periodic febrHe syndromes. The influence of age on expression of diseases associated with specific histocompatibility antigens is becoming better understood44 ; however, the strongest major histocompatibility-complex disease association remains that of human leukocyte antigen B27 with ankylosing spondylitis, a disease that begins in childhood in only about 10% of cases. The fact that this genetic predisposition does not more frequently result in childhood onset may reflect yet other factors that differentiate the child from the adult, such as the extent of environmental antigenic experience and the ability of the immune system to respond to its accumulating impact year after year. One argument in support of the significance of antigenic memory and immune reactivity might be exemplified by oligoarthritis. This disease has a narrow age-at-onset distribution: In the majority of children, onset occurs between the ages of 1 and 4 years. 38 Another striking age restriction is apparent in Kawasaki disease, which in North America affects most frequently the 1- to 3-year-old age group.45 One might speculate that these diseases reflect the effect of age at initial exposure to an environmental pathogen such as a virus or bacterium, together with the absence of specific protective immunity, in a genetically predisposed individual.

,1 • TABLE 1-2 Factors rlMt Potentially Modify Expression of Rheumati< Diseases in Childhood

Early expression of genetically determined abnormalities Immaturity and relative inexperience of the immune system Limited antigenic exposure Immaturity of the skeleton and the potential for growth and development Imn:laturity of the gonads and variable hormonal intluences

5

The degree and manner in which skeletal maturity influences the expression of rheumatic diseases is poorly understood. It seems probable, however, that physical and biochemical differences between younger and older cartilage and bone influence the effect of an inflammatory process involving these structures. Because physes are not fused in the growing child with arthritis, local growth abnormalities (e.g., leg-length inequality) may occur. Short stature is a frequent result of widespread arthritis in the child, but it is not an expected development in the skeletally mature adult with arthritis. The anatomy of the blood supply to the physis and epiphysis in the infant is reflected in this age group's predisposition to septic arthritis as a complication of osteomyelitis. The impact of gonadal immaturity on the expression of rheumatic diseases is unclear. SLE occurs predominantly in the pubertal and postpubertal age range. In some studies of SLE,46 girls and boys were affected with equal frequency in early childhood, but in adulthood, women developed this disorder 8 to 9 times more frequently than men. That these observations may reflect the role of reproductive hormones in pathogenesis is supported by studies of adult men with Klinefelter's syndrome cLe., males with two X chromosomes and one Y chromosome), in whom the frequency of SLE is high,47,48 and by studies of lupus-like disease in mice. 49 In contrast, men are much more likely than women to develop ankylosing spondylitis, a characteristic that does not appear to be significantly affected by age.

CHILDHOOD RHEUMATIC DISEASES: EXTENT OF THE PROBLEM It has been difficult to establish the extent of childhood

rheumatic diseases in defined populations with any accuracy. 50 In many of the most densely populated areas of the world, incidence and prevalence data for these disorders do not exist. In the developed world, inconsistencies of definition and classification, the rarity of occurrence for many of these diseases, and brevity of follow-up, have prevented accumulation of any substantial body of epidemiologic data. Two fundamental questions require answers: (1) How many children and adolescents have each of the identifiable rheumatic diseases; and (2) What is the functional outcome for these children? Estimates of the relative frequencies of adult-onset and childhood-onset rheumatic diseases are in Table 1-3. Three national registries from 1996 provided some comparative insights concerning the relative prevalence of the rheumatic diseases of childhood in the United States? Canada,52 and the United Kingdom53 (Table 1-4). Conspicuously under-represented are children with acute rheumatic fever, which is the major rheumatic disease of childhood in much of the world. A study by Manners and Diepeveen54 in Western Australia documented that many cases of chronic arthritis in children went undiagnosed and untreated. If this is the reality of identification in a developed area of the world with readily available expert medical care, the proportion of such children in geographic areas where medical care is less accessible may be even higher. In Finland, Kunnamo and colleagues55

6

C HAP T E R

II

TABLE. I 3

I

INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN

FIl'clueiKY ollhe Rheullldtic [)isedses in Adults dnd Iheir Onset in Childhood

No, Affected

Sex RaUo

Rheumatic Disease In Adults

(xl()5)

(F:M)

Ethnic RaUo (Whlte:Black)

Peak Age at Onset (yr)

Qlldhood Onset (0/0)

Ankylosing spondylitis Rheumatoid arthritis Systemic lupus erythematosus Dermatomyositis/polymyositis Scleroderma Polyarteritis

SOD-WOO 800 50

1:5 3:1 10:6 11:8 4:1 1:1

White> Black Equal 1:4 1:3 Black> White Equal

Young adult Increases with age (20-30) 15-40 45-60 Increases with age 00-50) 40-60

5 18 20 3 Rare'

1.~3.s

24-29 6,3

10

'Except for Kawasaki disease, Modified from data in ref. SO and Chaplers 9-24.

surveyed all children younger than 16 years of age who had swelling or limitation of motion of a joint, walked with a limp, or had hip pain as determined by a primary care physician, pediatrician, or orthopedic surgeon. All of these patients were subsequently examined by a single group of pediatric rheumatologists. Overall, the incidence of arthritis was estimated to be 109 per 100,000 children per year. Transient synovitis of the hip accounted for 48%; other acute transient arthritis CHenoch-Schbnlein purpura, serum sickness) 24%; chronic arthritis, 17%; septic arthritis, 6%; and reactive arthritis, 5%. Connective tissue diseases such as SLE were not identified in this survey. Determination of outcome and the lifelong burden of a pediatric rheumatic disease requires much more precise and comprehensive data than those currently available. The impact of childhood rheumatic diseases on life expectancy, their contribution to morbidity and costs of medical care, and their effect on quality of life are all prognostic parameters of importance about which there is little information even in North Amer:ica and Europe, and no information whatsoever on the global scene. Nevertheless, there can be little doubt that a child who, for example, has arthritis beginning at the age of 2 or 3 years will carry a lifelong burden in one or more of these areas. The expense and inconvenience for other members of the family are also significant.

ADVANCES IN PEDIATRIC RHEUMATOLOGY In the last half century, there have been dramatic advances in understanding the nature of inflammation, the cells and molecules that mediate it, and the therapeutic pOSSibility of specifically regulating the aberrant

I.

TABLE 1-4

immunoinflammatory response. The genetics of rheumatic diseases and, more recently, of the polymorphisms of inflammatory mediators, are pointing the way to therapeutic manipulations at an even more fundamental level, that of the gene. Although this approach is still only a hope for the future, it has been successful experimentally in animal models of arthritis. Currently, specific therapeutic modulation of certain mediators of inflammation is possible, and in particular blockade of tumor necrosis factor-a CTNF-a) has demonstrated great benefit in children with chronic arthritis. It may be premature to consider further advances in understanding of the childhood rheumatic diseases, because so much more must be illuminated. Nevertheless, it is evident that mortality from diseases such as chronic arthritis complicated by amyloidosis, dermatomyositis, and SLE has been dramatically reduced since the 1970s. Disability associated with many rheumatic diseases has been minimized: Wheelchair dependence is now rare, the need for aids to ambulation uncommon, and significant leg-length inequalities increasingly infrequent. Visual outcome in children with uveitis is improved. But much more progress is necessary and should be demanded and expected. Morbidity and mortality, although diminished, still remain serious threats to the child with SLE, vasculitis, or scleroderma, among other disorders. Although there have been major improvements in short- and medium-term outcomes of these and other rheumatic diseases, long-term outcomes are still often disappointing. For example, half of the children with chronic arthritis have active disease 10 years after onset, and children with SLE accumulate visceral damage with the passage of time, with an enduring impact on quality of life, despite much better control of acute lifethreatening events.

Reldtive Frequencies 01 Rheullldtic Disedses in I)edidtrl< Rhellllidtoloyy Clinic s in North Alllericd dnd the United KlIlydolll

U.S.A.S1 Juvenile rheumatoid arthritis/juvenile chronic arthritis Mechanical!orthopedic Vasculitis Systemic lupus erythematosus Juvenile dermatomyositis Systemic scleroderma Rheumatic fever/poststreptococcal arthritis Total

33.1 34.9 10.2 7,1 5,2 0,9 8.6 100.0

CANADASZ 50.0 40,6 3.0 3,9 1.6 0,2 0,7 100,0

U.K." 61.7 32.6 1.9 1.3

2,3 0,2

o 100.0

C HAP T E R

I

INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN

The reasons for these improvements in outcomes are multiple; chief among them are the establishment of a body of knowledge and expertise and involvement of a multidisciplinary team of health professionals in diagnosis and care. Improved application of old techniques and the development of new approaches have been important contributors to improved prognosis. Therapeutic landmarks of importance to the child with a rheumatic disease must include the introduction of cortisone for treatment of rheumatoid arthritis: Its influence on pediatric rheumatology has been profound. Intra-articular steroid use has improved management of oligoarthritis in children, just as methotrexate has radically improved the course and outcome of childhood polyarthritis. More judicious use of glucocorticoids and cytotoxic drugs has minimized toxicity and maximized effectiveness in diseases such as SLE and dermatomyositis. Biologic agents acting against TNF-lX and interleukin1 count among the major advances of the last decade. Although not curative, these agents and their successors promise to revolutionize management of the severe rheumatic diseases of childhood. Identification of the cause of Lyme disease and the pathogenesis of neonatal lupus, and the aggressive treatment of Kawasaki disease with intravenous immunoglobulin, represent landmarks of progress. Collaborative clinical trials led by the Pediatric Rheumatology Collaborative Study Group (PRCSG) and, more recently, the Pediatric Rheumatology International Trials Organisation (PRINTO) and the Childhood Arthritis and Rheumatology Research Alliance (CAARA), have facili~ted the study of therapeutic interventions in chronic arthritis as well as in the rarer connective tissue diseases. Recognition of the appropriateness of patient and family involvement at all stages of decision-making and care has enabled individualized treatment options and improved compliance. Family support organizations such as the American Juvenile Arthritis Organization in the United States and similar groups abroad have helped to promote education and research and to provide psychosocial support for patients and families.

REFERENCES 1. Ruffer MA. Rietti A: On osseous lesions in ancient Egyptians. J Pathol Bacterial 16: 439. 1912. 2. Kramer C: A case of ankylosing spondylitc, in mediaeval Geneva. Ossa 8: 115, 1982. 3, Rothschild BM. Woods RJ: Symmetrical erosive disease in Archaic Indians: the origin of rheumatoid arthritis in the New World? Semin Arthritis Rheum 19: 27~284, 1990. 4. Barlow T: 51st Annual Meeting of the British Medical Association; Section of Diseases of Children. BM] 2: 509-519, 1883. 5. Dieppe P: Did Galen describe rheumatoid arthritis? Ann Rheum Dis 47: 84-85, 1988. 6. Baillou G: De Liber de Arthritede. Paris, 1591. Quoted by Delpeuch G: La Goulle et Ie Rhumatisme, Paris. 1900. 7. Sydenham T: A Treatise of the Gout and Dropsy. London, 1683. 8. Garrod AB: The Nature and Treatment of Gout and Rheumatic Gout. London. Walton and Maberly, 1859. (Cited by Baethge BA.] Rheumatol19: 185, 1992.) 9. Adams F: The Genuine Works of Hippocrates. Translated from the Greek. London, The Sydenham Society, 1849. (Published as the Loeb Classical Libraty translation of the works of Hippocrates, Harvard University Press. Cambridge. MA. reprinred in 1967-68; also reprinted by The Classics of Medicine Library. Gryphon Editions, Ltd. Birmingham, AL. 1985.) 10. Brewer E] ]r, Bass ]C, Cassidy]T, et al: Criteria for the classification of juvenile rheumatoid arthritis. Bull Rheum Dis 23: 712-719, 1972. II. European League Against Rheumatism: EULAR Bulletin No.4: Nomenclature and Classification of Arthritis in Children. Basel, National Zeitung AG, 1977.

7

12. Petty RE, Southwood TR, Manners p. et al: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 31: 390-392, 2004. 13. Hayem F: The history of chronic joint diseases in children. Rev Rhum Engl Ed 66: 499-504, 1999. 14. Phaire T: The Regiment of Life, Whereunto is Added a Treatise of the Pestilence, with The Boke of Chyldren. Newly Corrected and Enlarged. London, Edw. Whitechurch, 1545. (Reprinted 1955 by E. & S. Livingston Ltd., London, p. 31.) 15. Bywaters EG: The history of pediatric rheumatology. Arthritis Rheum 20: 145-152. 1977. 16. Cornil MV: Memoire sur des coincidences pathologiques du rhumatisme articulaire chronique. C R Soc Bioi (Paris) Series 4, 3: 3, 1864, 17. Bouchut E: Traite pratique des Malades des Enfanrs. Ed. 6. Paris. 1875. 18. Moncorvo: Du Rhumatisme Chronique Noueux Des EnI'ants, Paris, 1880. 19. West C: Lectures on the Diseases of Infancy and Childhood. Ed. 7, Philadelphia, 1881. 20. Diamant-Berger M-S: Du Rhumatisme Noueux (Polyarthrite Deformante) Chez les Enfants. Paris, Lecrosnier et Babe. Libraires -Editeurs, 1891. (Reprinted by Editions Louis Pariente, Paris, 1988,) 21. Still GF: On a form of chronic joint disease in children. Med-Chirurg Trans 80: 47-59, 1897, (Reprinted in Arch Dis Child 132: 195, 1978.) 22. Keen ]H: George Frederic Still-Registrar. Great Ormond Street Children's Hospital. Br] Rheumatol 37: 1247, 1998. 23. Koplick H: Arthritis deformans in a child seven years old. Arch Pediatr 13: 161, 1896. 24, Schonlein ]L: Allgemeine und specielle Pathologie und Therapie. Nach dessen Vorlesungen niedergeschrieben und hrsg. von einigen seiner Zuhi'lrer. ed. 3. Ellinger, Herisau Lit Compt. Wurzburg, 1837. 25, Henoch EHH: Ober eine eigenthumliche Form von Purpura. Berl Klin Worchschr 11: 641, lR74. (Translated and reprinted in Am] Dis Child 128: 78. 1974,) 26. Unvericht H: Uber cine eigenrumliche Form von acuter Muskelentzundung mit einem der Trichinose ahnelnden Krankheitsbilde. Munch Med Wochenschr 34: 488, 1887. 27, Osler W: On the visceral manifestations of the erythema group of skin diseases, Am] Med Sci 127: I, 1904. 28. Watson R: An account of an extraordinary disease of the skin. and its cure. Extracted from the Italian of Carlo Crusio: accompanied by a letter of the Abbe Nollet, F.R.S. to Mr. William Watson, F.R.S, Philos Trans R Soc Lond 48: 579, 1754. (Cited by Rodnan GP, Benedeck GT: An historical account of the study of progressive systemic sclerosis [diffuse scleroderma). Ann Intern Med 57: 305, 1968.1 29, Travers B: Curious case of anchylosis of a great part of the vertebral column, probably produced by an ossification of the intervertebral substance. Lancet 5: 254, 1814, (Cited by Bywaters EGL. In Moll ]MH: Ankylosing Spondylitis. Edinburgh. Churchill Livingstone, 1980. p. 14.1 30, Hart FD, Maclagan NF: Ankylosing spondylitis: a review of 184 cases. Ann Rheum Dis 14: 77-83, 1955. 31. Schaller ], Bitnum S, Wedgwood R]: Ankylosing spondylitis with childhood onset.] Pediatr 74: 505-516, 1969. 32. Ladd ]R. Cassidy JT. Martel W: Juvenile ankylosing spondylitis. Arthritis Rheum 14: 579-590, 1971. 33, Kawasaki T: [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children!. Arerugi 16: 178-222, 1967, 34, Munro-Faure H: Necrotising arteritis of the coronary vessels in infancy; case report and review of the literature. Pediatrics 23: 914-926, 1959. 35, Ansell BM, Bywaters EGL, Spencer PE, et al: Ansell BM: Looking back 1947-1985. The Canadian Red Cross Memorial Hospital. Taplow, United Kingdom, 1997, 36, Smythe HA: Historical vignette. Professor Eric Bywaters, 1910-2003. Memories of Taplow.] Rheumatol 31: 601-604, 2004, 37. Stillman ]S: The history of pediatric rheumatology in the United States, Rheum Dis Clin North Am 13: 143-147, 1987. 38, Hanson V: Pediatric rheumatology: A personal perspective. Rheum Dis Clin North Am 13: 155-159. 1987. 39. Levinson JE: Rellections of a pediatric rheumatologist. Rheum Dis Clin North Am 13: 149-154, 1987, 40. Ansell BM: Taplow reminiscences.] Rheumatol 19 (Suppl 33): 105-107, 1992, 41. Brewer E] .Ir: The last thirty and the next ten years.] Rheumatol19 (SuppI33): 108, 1992. 42. Stoeber E: Zur Geschichte Der Kinderklinik und Rheumakinderklinik in Garmisch-Partenkirchen: 1952-1986: Garmisch-Partenkirchen, Umschloggestalrung Christa J. Burges, 1986. 43, Sullivan DB, Cassidy]T, Petty RE: Pathogenic implications of age of onset in juvenile rheumatoid arthritis. Arthritis Rheum 18: 251-255, 1975. 44. Murray K], Moroldo MB, Donnelly P, et al: Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles, Arthritis Rheum 42: 1843-1853. 1999. 45, Wortmann OW, Nelson AM: Kawasaki syndrome. Rheum Dis Clin North Am 16: 363-375, 1990. 46. Cassidy JT, Sullivan DB, Perty RE, et al: Lupus nephritis and encephalopathy: prognosis in 58 children. Arthritis Rheum 20: 315-322, 1977, 47, Ortiz-Neu C, LeRoy EC: The coincidence of Klinefelter's syndrome and systemic lupus erythematosus. Arthritis Rheum 12: 241-246. 1969.

8

CHAPTER

I

INTRODUCTION TO THE STUDY OF RHEUMATIC DISEASES IN CHILDREN

48. Jimenez-Balderas r], Tapia-Serrano R, Fonseca ME, et al: High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction. Arthritis Res 3: 362-367, 2001. 49. Roubinian J. Talal N, SHteri PK, et al: Sex hormone modulation of autoimmunity in NZBINZW mice. Arthritis Rheum 22: 1162-1169, 1979. 50. Lawrence RC, Helmick CG, Arnett FC, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 41: 778-799, 1998. 51. Bowyer S, Roettcher P: Pediatric rheumatology clinic populations in the United States: results of a 3 year survey. Pediatric Rheumatology Database Research Group. J Rheumatol 23: 1968-1974, 1996.

52. Malleson PN, Fung MY, Rosenberg AM: The incidence of pediatric rheumatic dbeases: results from the Canadian Pediatric Rheumatology Association Disease Registry. J Rheumatol 23: 1981-1987, 1996. 53. Symmons DPM, Jones M, Osborne J, et al: Pediatric rheumatology in the United Kingdom: data from the Britbh Pediatric Rheumatology Group National Diagnostic Register. J Rheumatol 23: 1975-1980, 1996. 54. Manners PJ, Diepeveen DA: Prevalence of juvenile chronic arthritis in a population of 12-year-old children in urban Australia. Pediatrics 98: 84--90, 1996. 55. Kunnamo 1, Kallio P, Pelkonen P: Incidence of arthritis in urban Finnish children: A prospective study. Arthritis Rheum 29: 1232-1238, 1986.

2

C HAP T E R

STRUCTURE AND FUNCTION Ross E. Petty and James T. Cassidy

~

Rheumatic diseases frequently affect many different organ systems, but inflammation of the structures of the musculoskeletal system-particularly joints, connective tissues, and muscles-is common to almost all. 1 An appreciation of some of the fundamental aspects of the development, structure, and biochemistry of the connective tissues and the components of the musculoskeletal system is important to the study of pediatric rheumatology. This chapter is intended as an overview of selected aspects of the anatomy and biochemistry of tissues that are particularly important to the study of rheumatic diseases of childhood and as a stimulus for further study.

JOINTS Oassltlcatlon of Joints Joints may be classified as ji'brous, cartilaginous, or synovial (Table 2-1).2 Fibrous joints (synarthroses) are those in which little or no motion occurs and in which the bones are separated by fibrous connective tissue. Cartilaginous joints (amphiarthroses) are those in which little or no motion occurs but the bones are separated by cartilage. Synovial joints (diarthroses) are those in which considerable motion occurs and a joint space lined with a synovial membrane is present between the bones. It is the synovial joint that is the site of inflammation in most of the chronic arthritides of childhood.

the "cavity" regresses and becomes filled with fibrous tissue. 7 The synOVial lining forms subsequent to cavitation, and the development of other structures, such as bursae, intra-articular fat, tendons, muscle, and capsule, quickly ensues. The whole process takes place between the fourth and seventh weeks of gestation, except for the temporomandibular joint, which develops much later. 8

Anatomy of Synovial Joints The anatomy of a typical synovial joint is illustrated in Figure 2-1. The bones of such joints are almost always covered by hyaline cartilage. 9 The synovial membrane attaches at the cartilage-bone junction so that the entire joint "space" is covered by either hyaline cartilage or synovium. The temporomandibular joint is unusual in that the articular surface of the condyle is covered by fibrocartilage rather than by hyaline cartilage. In some synovial joints, intra-articular fibrocartilaginous structures are present. For example, a disk (or meniscus) separates the temporomandibular joint into two spaces; the knee joint contains two menisci that separate the articular surfaces of the tibia and femur; and the triangular fibrocartilage of the wrist joins the distal radioulnar surfaces. Other intra-articular structures include the anterior and posterior cruciate ligaments of the knee, the interosseous ligaments of the talocalcaneal joint, and the triangular ligament of the femoral head. These structures are actually extrasynovial, although they cross through the joint space.

Development of Dlarthrocllal Joints In the fetus, diarthrodial joints develop by the differentiation of a noncartilaginous interzone within the cartilage core of the limb bud. Subsequently, cavitation occurs in this location, resulting in the formation of a joint "space. "3 The most important signals for joint morphogenesis are provided by the cartilage-derived morphogenetic protein 1 (CDMPl) and the bone mOl'phogenetic proteins (BMPs).4,5 The joint "cavity" is occupied at first by hyaluronic acid-rich joint fluid secreted by fibroblast-like cells lining the synovial membrane. Continued development of the diarthrodial joint depends on fetal movement, 6 which induces formation of cartilage and synovial membrane, and without which

ARTICULAR CARTILAGE The hyaline cartilage, which covers subchondral bone, facilitates relatively frictionless motion and absorbs the compressive forces generated by weight-bearing.9--15 The cartilage is firmly fixed to subchondral bone, and its margins blend with the synovial membrane and the periosteum of the metaphysis of the bone. In children, hyaline cartilage is white or slightly blue and is somewhat compressible. It is composed of chondrocytes within an extracellular matrix (ECM) and becomes progressively less cellular throughout the period of growth; the cell volume in adult articular cartilage is less than 2%.16 The

9

10

1'111

C HAP T E R

lABlE

2-)

2

STRUCTURE AND FUNCTION

(Iassifi
Type

Motion

Charaderlstlcs

Examples

Disease Target

Fibrous Cartilaginous Synovial

No No Yes

Bones separated by flbrous connection tissue Bones separated by cartilage Bones separated by joint space lined with synovial membrane

Sutures of skull Symphysis pubis Joints of extremities

None Ankylosing spondylitis Juvenile rheumatoid arthritis

matrix consists of collagen fibers, which contribute tensile strength, and ground substance composed of water and proteoglycan, which contributes resistance to compression. 17-20

Cartilage Zones Articular cartilage is organized into four zones (Fig. 2-2).9 Zones 1, 2, and 3 represent a continuum from the most superficial area of zone 1, in which the long axes of the chondrocytes and collagen fibers are parallel to the surface; through zone 2, where the chondrocytes become rounder and the collagen fibers are oblique; to zone 3, in which the chondrocytes tend to be arranged in columns perpendicular to the surface. The tidemark, a line that stains blue with hematoxylin and eosin, separates zone 3

Quadriceps femoris m.

"

from zone 4 and represents the level at which calcification of the matrix occurs. Chondrocytes in each of the cartilage zones differ not only in appearance but in metabolic activity, gene expression, and response to stimuli. 21 In the child, end-capillaries proliferate in zone 4, eventually leading to replacement of this area by bone. This is probably the manner in which the chondrocytes are nourished, although in the adult, constituent replacement (through the exchange of synovial fluid with cartilage matrix) may play the predominant role.

Chondrocytes Chondrocytes are the sole cellular constituents of cartilage. Their terminal differentiation determines the character of the cartilage (hyaline, fibrous, or elastic). This

",

......

Patellar tendon'''''

... ,

.

Hyaline cartilage'..

• Figure Z-l Sagittal section of the knee. The distinguishing features of the diarthrodial joint are shown, including bone, hyaline cartilage, synovial space, fibrocartilage, capsule, bursae, ligaments, tendons, muscles, and the vascular and nervous supply.The rheumatic diseases affect all these structures individually or in concert.

C HAP T E R

CE:>

CD

~

<:» t::E:> ~

CD CD CD CD
<0

CD

<0

CJ)

~ CD <:?)
C!)

~

Q:>

c:Et ez:o CD CD C2> CI> <:il c::J)


G)G>

(0

IZone 1

e> (;') <::>

G<;)

e•

G> C!)Q)~ e ~ GO €> 1;"\ Qle G> G C!) 'U E:l ~ (!) €> ~
e

0

e

11

superficial zone protein Oubricin) which is important in maintaining relatively frictionless joint motion. Synthesis of this protein is defective in the camptodactyl-arthropathycoxa vara-pericarditis syndrome 24 (see Chapter 40).

Extracellular Matrix Zone 3

0

III'I~I ~~~i1~'I~

STRUCTURE AND FUNCTION

Zone 2


2

Zone 4

~~"trr~~iI~ ~~~~~~~~YII~~»J

The ECM consists of collagen fibers, which contribute tensile strength, water, diverse structural and regulatory proteins, and proteoglycans (mainly aggrecan), which together contribute resistance to compressiony-20 The ECM is heterogeneous and can be subdivided into three compartments. A thin inner rim of aggrecan-rich matrix surrounds the chondroeytes and lacks crosslinked collagen. An outer rim contains fine collagen fibrils. The remainder of the ECM consists primarily of aggrecan, which binds via the link protein to hyaluronan (Fig. 2_3).21 The endoskeleton of hyaline cartilage consists of a network of collagen fibrils, 90% of which are type II collagen, with minor components of collagen types IX and X. 16

. .....re

Proteoglycans

complex process has been recently reviewed. 22 Chondroeytes in articular cartilage persist and do not ordinarily divide after skeletal maturity is attained. 23 Those in the epiphyseal growth plate differentiate to facilitate endochondral ossification, after which they may undergo apoptosis or become osteoblasts. 23 Chondrocytes are responsible for the synthesis of the two major constituents of the matrix, collagen and proteoglycan, as well as enzymes that degrade matrix components (collagenase, neutral proteinases, and cathepsins).23 This dual function places the chondrocyte in the role of regulating cartilage synthesis and degradation. Immediately surrounding the chondrocyte is the pericellular region, which contains type VI collagen and the proteoglycans decorin and aggrecan. 16 Chondrocytes in zone 1 produce

Proteoglycans are macromolecules consisting of a protein core to which are attached 50 to 100 unbranched glycosaminoglycans (chondroitin sulfate and O-linked keratan sulfate).25-27 At least five different protein cores have been defined. The principal proteoglycan of hyaline cartilage is called aggrecan. Its attachment to hyaluronan is stabilized by link protein to form large proteoglycan aggregates with molecular weights of several million (see Figure 2_3).16,17,19 With increasing age, the size of the proteoglycan aggregates increases, the protein and keratan sulfate content increases, and the chondroitin sulfate content decreases. 2R ,29 Chondroitin sulfate chains also become shorter with increasing age, and the position of the sulfated moiety changes, from a combination of 4sulfated and 6-sulfated N-acetylgalactosamine at birth to mainly 6-sulfated N-acetylgalactosamine in the adult,3lH2 Dermatan sulfate and chondroitin-4-sulfate are the principal mucopolysaccharides in skin, tendon, and aorta; heparan sulfate is present in basal lamina.

Z-Z Organization of articular cartilage. In zone 1, adjacent to the joint space, the chondroc.ytes are flattened. In zone 2. the chondrocytes are more roun~d, and in zone 3 they are arranged in perpendicular columns. The tide mark separates zone 3 from zone 4, which is impregnated with calcium salts. Bone is beneath zone 4. (Courtesy of J. R. Petty.)

• f1ture Z-3

The structure of the proteoglycan aggregate of cartilage. The proteoglycan monomer consists of a core protein (a) of variable length that contains three globular domains: G1 (located at the aminoterminus and containing the hyaluronate binding region) G2, and G3. Link protein (e) stabilizes the aggregate by binding simultaneously to the hyaluronate chain (d) and Gl. Glycosaminoglycan molecules are attached to the core protein in specific regions: keratan sulfate (b) and chondroitin sulfate (c).

12

C HAP T E R

2

STRUCTURE AND FUNCTION

Collagens Collagens, the most abundant structural proteins of connective tissues, are glycoproteins with high proline and hydroxyproline content.33--35 Many are tough, fibrous proteins that provide structural strength to the tissues of the hody.36 There are at least 21 different types of collagen divided into seven subclasses (Table 2_2).37-39 Types I, II, and III are among the most common proteins in humans. Type II collagen, the principal constituent that accounts for more than half the dry weight of cartilage, is a trimer of three identical a-helical chains. Collagen types III, VI, IX through XII, and XIV are all present in minute quantities in the mature cartilage matrix. 33 The content of types IX and XI collagen is greater in young animals (20%) than in mature animals (3%).33 Collagen synthesis is minimal in the mature animal. The degree of stable cross-linking of collagen fibers increases with advancing age up to the fourth decade of life. 40 This results in increased resistance to pepsin degradation and may contribute to the increased rigidity and decreased tensile strength of old cartilage. 41 Collagen undergoes extensive changes in primary and tertiary structure after it is secreted from the fibroblast into the extracellular space as a triple-helical procollagen (Fig. 2-4),42 Specific peptidases cleave the amino and carhoxyl extension peptides, yielding collagen molecules

u: II

TABI E l l

that in some types form cross-links and fibrils via lysyl and hydroxylysyl residues. Glycosylation also occurs at this post-translational stage. Collagen genes are named for the type of collagen (e.g., COLI) and the fibril (e.g., Al) and encode the large triple-helical domain common to human collagens. Mutations in the collagen genes 43--46 account for human diseases such as Ehlers-Danlos syndrome and osteogenesis imperfecta (see Chapter 40):j7--49

Other Connective Tissue Constituents In addition to collagens, a number of specialized tissues derived from embryonic mesoderm contribute to connective tissue structures other than cartilage. Elastin occurs in association with collagen in many tissues, especially in the walls of blood vessels and in certain ligaments.50 Fibers of elastin lack the tensile strength of collagens but can stretch and then return to their original length. Elastin is produced by fibroblasts and smooth muscle cells. Fibronectin is a dimeric glycoprotein with a molecular weight of 450,000 that acts as an attachment protein in the ECM. 51 It is produced by many different cell types, including macrophages, dedifferentiated chondrocytes, and fibroblasts, and has the ability to bind to collagens, proteoglycans, fibrinogen, and actin, as well as to cell surfaces and bacteria. Fibronectin

IYI'es 01 (oUdl/en

Subclass and Type

Composition

Duue Distribution

Fibril-forming collagens Type I Type II Type III Type V Type XI

0.1(0, 0.2(0 o.10I) 0.1 (III) 0.1 (V) , o.2CY), o.3(V) 0.1 (XI) , o.2(XI), o.3(XI)

Most connective tissues; abundant in bone, skin, and tendon Cartilage, intervertebral disk, vitreous humor Most connective tissues, particularly skin, lung, blood vessels Tissues containing type I collagen, quantitatively minor component Cartilage, intervertebral disk, vitreous humor

Network-forming collagens o.ICIV), o.20V) , o.30V), o.40V) , Type IV o.5(N), o.60V) 0.1 (VIII), o.2(VIJI) Type VIII 0.1 (X) Type X

Several tissues, especially endothelium Hypertrophic cartilage

FACIT collagens Type IX Type XII Type XIV Type XVI Type XIX Type XX Type XXI

Cartilage, intervertebral disk, vitreous humor Tissues containing type I collagen Tissues containing type I collagen Several tissues Rhabdomyosarcoma cells Corneal epithelium Fetal blood vessel walls

a. ICIX), o.2CIX) , o.3CIX) 0.1 (XII) 0.1 (XIV) 0.1 (XVI) o.1(XIX) o.1(XX) 0.1 (XXI)

Basement membranes

Beaded filament-forming collagen Type VI o.1CYI), o.2(VI), o.3(Vn

Most connective tissues

Collagen of anchoring fibrils Type VII o.1(VIJ)

Skin, oral mucosa, cervix, cornea

Collagens with a transmembrane domain Type XIII 0.1 (XIII) Type XVII a. 1(XVII)

Endomysium, perichondrium, placenta, mucosa of the intestine, meninges Skin, cornea

Collagen types XV and xvm Type XV 0.1 (XV) Type XVIII 0.1 (XVIII)

Many tissues, especially skeletal and heart muscle, placenta Many tissues, especially kidney, liver, lung

FAClT, fihril-associated collagens with interrupted triple-helices. From Ala-Kakko L, Prockop OJ: Collagen and elastin. In Harris ED Jr, et al (eds): Kelley's Textbook of Rheumatology, 7th ed. Philadelphia, Elsevier, 2005. pp. 35--47.

C HAP T E R

mRNA for specific procollagen chains

~

Translation on RER

~

Hydroxylation by 3-proline hydroxylase, 4-proline hydroxylase, and Iysyl hydroxylase

~

Glycosylation of hydoxylysine by galactosyl transferase and addition of glucose by glucosyltransferase

~

Removal of N-terminal signal peptide

~

Release of completed chains from ribosomes

~

Formation of disulfide crosslinks between chains

~

Formation of triple helix procollagen

~

2

STRUCTURE AND FUNCTION

13

alytic groupS'4: the metalloproteinases and serine proteinases, which are active at neutral to slightly alkaline pH, and the cysteine and aspartic proteinases, which are most active at acid pH (Table 2-3). The metalloproteinases, which are activated by calcium and stabilized by zinc ions, consist of at least 10 well-characterized enzymes. 55 They are active in the degradation or remodeling of collagens and are known to be synthesized by rheumatoid synovium. Collagenases are inhibited naturally by a?-macroglobulin and by the tissue inhibitor of metalloprot'i!inase (77MP). Strome(vsin is a neutral proteinase synthesized by cultured fibroblasts and synovium. Other members of this family, the gelatinases, are secreted by many cells in culture and are active in the remodeling of collagen-containing tissues. The serine proteinases are a family of endopeptidases that participate in matrix degradation either directly or by activating precursors of the metalloproteinases. They include many of the enzymes of pathways involving coagulation, fibrinolysis, complement activation, and kinin generation: plasmin, plasminogen activator, kallikrein, and elastase. Serine proteinase inhibitors constitute 10% of the plasma proteins. The cysteine proteinases that degrade ECM include cathepsins Band L, which are lysosomal enzymes associated with inflammatory reactions. The aspartic proteinases are primarily lysosomal proteinases active at acid pH. Cathepsin D is the major representative of this family that degrades proteoglycans and is present in the lysosomes of most cells.

Packaging of procollagen into vesicles

~

Fusion of vesicles with cell membrane, removal of C-terminal nonhelical extensions and part of N-terminal nonhelical regions

~

Collagen

• ,.... 2-4 Schematic representation of collagen biosynthesis.Triplehelical procollagen is secreted from the fibroblast. Specific procollagenases produce collagen by deaving the ends of the molecules.The collagen molecules (except for type IV collagen) then form fibrils that undergo cross-linking to form collagen fibers. (Adapted from Nimni ME: Collagen: structure, function, and metabolism in normal and fibrotic tissues. Semin Arthritis Rheum 13: 1, 1983.)

is present in plasma and as an insoluble matrix throughout loose connective tissues, especially between basement membranes and cells, Laminin is a major constituent of the basement membrane together with type IV collagen.'2 Reticulin may be an embryonic form of type III collagen. It is present as a fine branching network of fibers widespread in spleen, liver, bone marrow, and lymph nodes,

Protelnases for Collagen and Cartilage The proteinases (endopeptidases) are proteolytic enzymes that are active in homeostatic remodeling of the ECM during health and in its degradation during inflammatlon.,3 These enzymes occur both intracellularly and extrllcellularly in tissue fluids and plasma and have been clasfified into four categories based on functional cat-

SYNOVIUM Synovial Membrane The synovial membrane is a vascular connective tissue structure that lines the capsules of all diarthrodial joints and has important intra-articular regulatory functions. 56,57 The synovium consists of specialized fibroblasts,'8 one to three cells in depth, overlying a loose meshwork of type I collagen fibers containing blood vessels, lymphatics, fat pads, unmyelinated nerves, and isolated cells such as mast cells. 59,60 There is no basement membrane separating the joint space from the subsynovial tissues, The synovial membrane is discontinuous, and within the joint space there are so-called bare areas between the edge of the cartilage and the attachment of the synovial membrane to the periosteum of the metaphysis. 6! These bare areas are especially vulnerable to damage (erosion) by inflamed synovium (pannus) in inflammatory joint diseases, Folds, or villi, of synovium provide for unrestricted motion of the joint and for augmented absorptive area. The synoviocytes are of two predominant types, a subdivision that may reflect different functional states rather than different origins. SynOVial A cells are capable of phagocytosis and pinocytosis, have numerous microfilopodia and a prominent Golgi apparatus, and synthesize hyaluronic acid. Synovial B cells are more fibroblast-like, have a prominent rough endoplasmic reticulum, and synthesize fibronectin, laminin, and types I and III collagen as well as enzymes (collagenase, neutral proteinases) and catabolin.

14

C HAP T E R

2

[ . fABLE 2- 3

STRUCTURE AND FUNCTION

Proteinas('s and Inhibitors for (ollagen and (a,tildge Substrdtes

Enzyme

Substrate

Inhibitor

Metalloproteinases Collagenase Gelatinase Stromelysin

Various collagens and GAGs Denatured collagens Fibronectin, GAG, elastin, collagens

TIMP TIMP TIMP

Serine proteinases Plasmin Elastase Cathepsin G Plasminogen activator

Metalloproteinases Various collagens and GAGs GAGs, type II collagen, elastin, TIMP Proplasminogen

a 2-Antiplasmin 0. 1- Plasminogen inactivator aI-Plasminogen inactivator

Cysteine proteinases Cathepsin B Cathepsin L

Type II collagen, GAGs, link protein Type I collagen, GAGs, link protein, elastin

Cystatins Cystatins

Aspartic proteinases Cathepsin D

GAGs, type II collagen

0.2-Macroglobulin

GAGs, glycosaminoglycans; TIMP, tissue inhibitor of metalloproteinase.

Synovial Fluid

VASCULAR SUPPLY

SynOVial fluid, present in very small quantities in normal synovial joints, has two functions: lubrication and nutrition. 62 ,63 Synovial fluid is a combination of a filtrate of plasma that enters the joint space from the subsynovial capillaries and hyaluronic acid, which is secreted by the synoviocytes. Hyaluronic acid provides the high viscosity of synovial fluid and, with water, its lubricating properties. 64 Concentrations of small molecules (electrolytes, glucose) are similar to those in plasma, but larger molecules (e.g., complement components) are present in low concentrations relative to plasma unless an inflammatory state alters vasopermeability. Notably absent from synovial fluid are elements of the coagulation pathway (fibrinogen, prothrombin, factors V and VlI, tissue thromboplastin, and antithrombin).65 As a result, normal synovial fluid is resistant to clotting. There appears to be free exchange of small molecules between synovial fluid of the joint space and water bound to collagen and proteoglycan of cartilage, Characteristics of normal synovial fluid are listed in Table 2-4. 66-74

The arterial supply to the diaphysis and metaphysis of a long bone arises from a nutrient artery that penetrates the diaphysis and terminates in the child in end-arteries at the epiphyseal plate.75 The epiphyseal blood supply arises from juxta-articular arteries that also supply the synovium via a complex network of arterial and alteriovenous anastomoses and capillary beds, which William Harvey called the circulus articularis vasculosus. Not until growth has ceased and the epiphyseal plate has ossified is there arte-

Synovial Strudures Synovium lines bursae and tendon sheaths as well as joints,9 Bursae facilitate frictionless movement between surfaces, such as subcutaneous tissue and bone, or between two tendons. Bursae located near synovial joints frequently communicate with the joint space. This is particularly evident at the shoulder, where the subscapular bursa or recess communicates with the glenohumeral joint; and around the knee, where the suprapatellar pouch, the posterior femoral recess, and occasionally other bursae communicate with the knee joint. Tendon sheaths lined with synovial cells are prominent around tendons as they pass under the extensor retinaculum at the wrist and at the ankle. Although they are closely associated with joints, tendon sheaths do not communicate with the synovial space.

"' ..'

TABLE 2-4

Charaderlstlc Volume pH Retiltive viscosity CI,HCO, Na, K, Ca, Mg Glucose Total protein Albumin

Normal Synovial Fluid

Reference Mean or Representative Value· No.

0.13-3.5 mL (adult knee) 7,3-7.4 235 Slightly higher than serum Slightly lower than serum Serum value ± 10% 1.7-2,1 g/dL 1.2 g/dL 0,17 g/elL 0.1 0,15 g/elL 0.2 0,23 g/dL ~ 0,38 g/dL Y Immunoglobulin G 13% of serum value Immunoglobulin M 5% of serum value Immunoglobulin E 220/0 of serum value 3% of serum value a.,-Macroglobulin 24% of semm vallie Transferrin Ceruloplasmin 16% of serum value 30-50% of plasma value CH,,, 300 mg/dL Hyaluronic acid 7,1 mg/dL Cholesterol Phospholipid 13.8 mg/dL

66 70 66 66 66 67 73 74

71 72

71 69 68 74 74

CH,o' total hemolytic complement assay. 'These values were obtained from various adult synovial lluid studie". Similar data are not available for cbildren.
C HAP T E R

rial communication between the metaphyseal and epiphyseal-synovial circulations, a phenomenon of importance in explaining the predisposition of the immature diaphysis to infection and aseptic necrosis after trauma (Fig. 2-5).

CONNECTIVE TISSUE STRUCTURES Connective tissues proVide the supporting structures of the body (bone, periosteum, cartilage); permit the action of muscles through tendons, ligaments and fasciae; support internal organs (dermis, capsules, serosal membranes, basement membranes); and provide support for blood vessels, lymphatics, and the bronchopulmonary tree.

2

STRUCTURE AND FUNCTION

15

Entheses An enthesis is the site of attachment of tendon, ligament, fascia, or capsule to bone. Unlike tendon or ligament, the enthesis is an active metabolic site, particularly in the child. It includes the peritenon, which is continuous with the periosteum; collagen fibers of the tendon or ligament which insert into the bone (Sharpey 's fibers); the adjoining cartilage; and bone not covered by periosteum. 77 In 1998, a highly informative commentary was published on the strongest tendon in the body, the Achilles tendon, and its enthesis. 78 Entheses have been the subject of a recent extensive review. 79

SKELETAL MUSCLE

Tendons Tendons are specialized connective tissue structures that, via the enthesis, attach muscle to bone. 76 They contain, in addition to water, type I collagen and small amounts of elastin and type III collagen, the latter forming the epitenon and endotenon. The type III collagen fibers are densely packed in a parallel configuration in a proteoglycan matrix containing elongated fibroblasts.

Upments and Fasciae Ligaments and fasciae join bone to bone and, like tendons, are composed of type I collagen. So-called elastic ligalllents, such as the ligamenta flava and ligamentum nuchae, predominantly contain elastin.

b

Anatomy Skeletal muscle makes up approximately 40% of the adult body mass and consists of about 640 separate muscles that support the skeleton and permit movement and locomotion. Skeletal muscle is formed during embryogenesis from mesodermal stem cells that differentiate into the various types of muscle, bone, and connective tissue. A skeletal muscle is surrounded by the connective tissue epimysium. Within the muscle, fascicles are covered by connective tissue perimysium. 8o Each fascicle contains many individual muscle fibers, which are the basic structural units of skeletal muscle (Fig. 2-6). Muscle fibers are elongated, multinucleated cells surrounded by connective tissue endomysium (reticulin, collagen) that is richly supplied with capillaries. Within each fiber are a large number of myofibrils, consisting of highly organized interdigitated myofilaments of actin and myosin: 81 Each myofilament has approximately 180 myosin molecules with a molecular weight of 500,000, a long tail, and a double head. The myofilament is composed of the myosin tails; the myosin heads project in a spiral arrangement. Lying parallel to the myosin molecules are actin filaments (F-actin) composed of globular subunits of G-actin with a molecular weight of 42,000. Two actin filaments are coiled around each other as a helix, with a second protein, tropomyosin E, lying in the groove. A regulatory protein, troponin, is located at intervals along this structure. This complex structure is demonstrable by light or electron microscopy as striations. Creatine kinase is bound to the myosin filaments at regular intervals. 82

Muscle Contraction

:r • ~re Z-5 Blood supply to the epiphysis and metaphysis. End-arteries (a) at the epiphyseal plate arise from the medullary arteries. Juxta-articular arteries (b) supply epiphysis and synovium. (Courtesy of lR. Petty.)

The functional ability of muscle to produce coordinated movements is governed by the conversion of chemical to mechanical energy by actomyosin. 83 ,B4 Calcium diffusion in the myoplasm and binding to thin-filament regulatory proteins are stimulated by the action potential of the a-motor neuron. Variation in the properties of the various types of motor fibers and motor units, and recruitment of motor units, result in the specific patterns of movement. The properties of the motor unit are influenced by the genetic makeup of the individual, muscular conditioning, and the presence

16

C HAP T E R

2

STRUCTURE AND FUNCTION

of any disease that results in joint pain or immobilization, or metabolic, hormonal, or nutritional disturbances. 85 A

Types of Muscle Fibers Muscle fibers constitute 85% of muscle tissue. There are two major types of fibers, which differ in structure and biochemistry (Table 2_5).86-89 Most muscles contain both types. Type I (slow) fibers are narrower, have poorly defined myofibrils, are irregular in size, have thick Z bands, and are rich in mitochondria and oxidative enzymes but poor in phosphorylases. Type II (fastJfibers have fewer mitochondria and are poor in oxidative enzymes but rich in phosphorylases and glycogen. Type I and II muscle fibers can be differentiated histochemically (Fig. 2-7). Muscles differ in the proportions of each

B

c

D

--

--

• •

•

E

F

Troponin

Actin

t

Tropomyosin 8

• Figure 2-6 Schematic representation of the anatomy of skeletal muscle: a, fascicle; b, fiber; c, myofibrils; d, actin and myosin; eand f, enlargement of actin and myosin filaments showing the actin filaments coiled around each other and associated with tropomyosin Blying in the groove. (Courtesy of I.R. Petty.)

II.

TABLE 2-5

• Figure 2-7 Frozen section of normal skeletal muscle stained with adenosine triphosphatase, pH 9.2. Type I fibers are pale, and type II fibers are dark. Magnification x 800. (Courtesy of Dr. M. Norman.)

Classifhalioll of Muscle Fiber Types

Characteristic

Type I

Type IIA

be liB

TYPe lie

Size Color Myoglobin content Mitochondria Blood supply ATPase (pH 4.4) ATPase (pH 10.6) Lipid Glycogen Metabolic characteristics Oxidative (aerobic) Glycolytic (anaerobic) Function Contraction time Resistance to fatigue

Moderate Red High Many

Small White Medium Intermediate

Large White Low Few

Small White High Intermediate

+++

+

+

+

High Low High Low

Low High Low High

Low High Low High

Variable

High Moderate

Intermediate High

Low High

High High

Slow and sustained High

Fast twitch Moderate

Fast twitch Low

Moderate twitch Moderate

ATPase. adenosine triphosphatase.

C HAP T E R

fiber type, For example, the diaphragm contains predominantly "slow" fibers, and small muscles contain predominantly "fast" fibers, Muscle conditioning leads to adaptations in the contractile and structural proteins and fiber species within the genetic potential of the individual. Strength training results in hypertrophy of type IIB fibers, and endurance training leads to metabolic alterations in type I and type IrA fibers. B5 .90-92

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31. RougWey PJ, White RJ: Age-related changes in the structure of the proteoglycan subunits from human articular cartilage. .1 Bioi Chern 255: 217-224, 1980. 32. Roughley PJ: Age-associated changes in cartilage matrix. Clin Orthop 391S: S153- S160, 2001. 33. Eyre 0, Articular cartilage and changes in arthritis: collagen of articular cartilage. Arthritis Res 4: 30-35, 2002, Available at: http:// arthritis-research.com/content/4/1/030 (accessed November 21, 2004). 34. Nimni ME: Collagen: structure, function, and metabolism in normal and fibrotic tissues. Semin Arthritis Rheum 13: 1-86, 1983, 35, van der Rest M, Garrone R: Collagen family of proteins. FASEB .1 5: 2814-2823, 1991. 36. Boskey AL, Wright TM, Blank RD: Collagen and bone strength, J Bone Miner Res 14: 330-335, 1999. 37, Uitto .1, Murray LW, Blumberg B, et al: Biochemistry of collagen in diseases [UCLA conference). Aru> Intern Med 105: 740-756, 1986. 38. Koch M, Foley JE, Hahn R, et al: e:t 1 (XX) collagen, a new member of the collagen subfamily, fibril associated collagens with interrupted triple helices. .1 Bioi Chern 276: 23120-23126, 2000. 39. Chou MY, Li HC: Genomic organization and characterization of the human type XXI collagen (COL21Al) gene. Genomics 79: 395-401, 2002. 40. Weiss JB, Sedowofia K, Jones C: Collagen degradation: a defended multienzyme system. In Viidik A, Vuust .1 (eds): Biology of Collagen. London, Academic Press, 1978, p. 113. 41. Muir H, Bullough 1', Maroudas A: The distribution of collagen in human articular cartilage with some of its physiological implications. .1 Bone Joint Surg Br 52: 554-563, 1970. 42. Piez K: Molecular and aggregate structures in the collagens. In Piez KA, Reddi AH (eds): Extracellular Matrix Biochemistry, New York, Elsevier, 1984. p. 1. 43. Prockop OJ, Kivirikko K1: Heritable diseases of collagen. N Engl J Med 311: 376-386, 1984. 44. Kainulainen K, Pulkkinen L, Savolainen A. et al: Location on chromosome 15 of the gene defect causing Marfan syndrome. N EnglJ Med 323: 935-939, 1990. 45. Dietz HC, Cutting GR, Pyeritz RE, et al: Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352: 337-339, 1991. 46. Lee B, Godfrey M, Vitale E, et al: Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 352: 330-334, 1991. 47. Prockop OJ, Kivirikko KI: Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 64: 403-434. 1995. 48. Raff ML, Byers PH: Joint hypennobility syndromes. Curr Opin Rheumatol 8: 459-466, 1996. 49. Prahalad S, Colbert RA: Genetic diseases with rheumatic manifestations in children. Curr Opin Rheumatol 10: 488--493, 1998. 50, Sandberg LB, Soskel NT, Leslie JG: Elastin structure, biosynthesis. and relation to disease states. N EnglJ Med 304: 566-579, 1981. 51. Ruoslahti E, Engvall E, Hayman EG: Fibronectin: current concepts of its structure and functions. Coil Relat Res 1: 95-128, 1981. 52, Beck K, Hunter I, Engel J: Structure and function of laminin: anatomy of a multidomain glycoprotein. FASEBJ 4: 148--160, 1990. 53. Bond JS, Butler PE: Intracellular proteases. Annu Rev Biochem 56: 333-364, 1987, 54. Cawston TE: Proteinases and inhibitors. Br Med Bull 51: 385-401, 1995. 55. Woessner .JFJ: Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEBJ 5: 2145-2154. 1991. 56. Edwards J: Second international meeting on synovium: cell biology, physiology and pathology. Aru> Rheum Dis 54: 389--391. 1995. 57. FitzGerald 0, Bresnihan B: Synovial membrane cellularity and vascularity. Ann Rheum Dis 54: 511-515. 1995. 58. EdwardsJC: Synovial intimal fibroblasts, Ann Rheum Dis 54: 395-397,1995, 59. Revell PA, al-Saffar N, Fish S, et al: Extracellular matrix of the synovial intimal cell layer. Ann Rheum Dis 54: 404-407, 1995. 60. Athanasou NA: Synovial macrophages. Ann Rheum Dis 54: 392-394, 1995. 61. Muller-Ladner U, Gay RE, Gay S: Molecular biology of cartilage and bone destruction. Curr Opin Rheumatol 10: 212-219. 1998. 62. McCutchen CW: Lubrication of joints. In Sokoloff L (ed): The Joints and Synovial Fluid. New York, Academic Press, 1978, p. 437. 63. Simkin PA: Synovial perfusion and synovial fluid solutes. Ann Rheum Dis 54: 424-428, 1995. 64. LevickJR, MCDonaldJN: Fluid movement across synovium in healthy joints: role of synovial fluid macromolecules. Ann Rheum Dis 54: 417-423, 1995. 65, Cho MH, Neuhaus OW: Absence of blood cloning substances from synovial fluid. Thromb Diath Haemorrh 5: 496, 1960. 66. Ropes MW, Bauer W: Synovial Fluid Changes in Joint Disease. Cambridge, MA, Harvard University Press, 1953, 67. Ropes MW, Muller AF, Bauer W: The entrance of glucose and other sugars into joints. Arthritis Rheum 3: 496--514. 1960. 68. 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71. Kushner I, Somerville JA: Permeability of human synovial membrane to plasma proteins: relationship to molecular size and inflammation. Arthritis Rheum 14: 560-570, 1971. 72. Hunder GG, Gleich GJ: Immunoglobulin E (JgE) levels in serum and synovial fluid in rheumatoid arthritis. Arthritis Rheum 1974; 17: 955-963. 73 Rose NR, de Marcario EC, Fahey lL, et al (eds): Manual of Clinical Laboratory Immunology, 4th ed. washington, DC, American Society for Microbiology, 1992. 74. Gatter RA, Schumacher HR: A Practical Handbook of Joint Fluid Analysis, 2nd ed. Philadelphia, Lea & Febiger, 1992. 75. Liew M, Dick We: The anatomy and physiology of blood flow in a diarthrodial joint. Clin Rheum Dis 7: 131-148, 1981. 76. CanosoJJ: Bursae, tendons and ligaments. Clin Rheum Dis 7: 189-221, 1981. 77. Niepel GA, Sit'aj S: Enthesopathy. Clin Rheum Dis 5: 857-872, 1979. 78. Canoso JJ: The premiere enthesis. J Rheumatol 25: 1254-1256, 1998. 79. Benjamin M, Kumai T, Milz S, et al: The skeletal attachment of tendons: tendon "entheses." Compar Biochem Physiol A 133: 931-945, 2002. 80. Goldman YE, Dantzig JA: Harris ED Jr, et al (eds): Keiley's Textbook of Rheumatology, 7th ed. Philadelphia, Elsevier, 2005, pp. 82-94. 81. Gowitzke BA, Milner M: Scientific Basis of Human Movement. Baitimore, Williams & Wilkins, 1988, p. 144. 82. Turner DC, Wallimann T, Eppenberger HM: A protein that binds specifically to the M-line of skeletal muscle Ls identified as the muscle form of creatine kinase. Proc Natl Acad Sci USA 70: 702-705, 1973.

83. Squire J: The Structural Basis of Muscular Contraction. New York, Plenum Press, 1981. 84. Kelly AM, Rubinstein NA: Development of neuromuscular specialization. Med Sci Sports Exerc 18: 292-298, 1986. 85. Faulkner JA, White TP: Adaptations of skeletal muscle to physical activity. In Bouchard C, Shephard RJ, Stephens T, et al (eds): Exercise, Fitness, and Health. Champaign, IL, Human Kinetics, 1990, p. 265. 86. Heffner RR .Ir (ed): Muscle Pathology. New York, Churchill Livingstone, 1984. 87. Stockdale FE: Mechanisms of formation of muscle fiber types. Cell Strucr Funct 22: 37-43, 1997. 88. Staron RS: Human skeletal muscle fiber types: delineation, development. and distribution. Can.l App! Physiol 22: 307-327, 1997. 89. Zhang M, Koishi K, Mclennan IS: Skeletal muscle fibre types: detection methods and embryonic detenninants. Histol Histopathol 13: 201-207, 1998. 90. Booth FW, Tseng BS, Fluck M, et al: Molecular and cellular adaptation of muscle in response to physical training. Acta Physiol Scand 162: 343-350. 1998. 91. Hargreaves M: 1997 Sir William Refshauge Lecture. Skeletal muscle glucose metabolism during exercise: implications for health ,lOd performance. .I Sci Med Sport 1: 195-202, 1998. 92. Taylor AW, Bachman L: The effects of endurance training on muscle fibre types and enzyme activities. Can.l Appl Physiol 24: 41-53, 1999.

3

( HAP T E R

THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE Marco Gattomo and Alberto Martini

;If

The irrunune system, H the function of which is to protect against infections, comprises two branches: a more primitive one called innate (natural, native) immunity and a highly sophisticated one called adaptive (specific) immunity. Innate and adaptive immunity are not two separate compartments but an integrated system of host defenses, sharing bidirectional interactions fundamental to both the inductive phase and the effector phase of the immune response. The cells of the immune system originate from the pluripotent hematopoietic stem cells that give rise to stem cells of more limited potential (lymphoid and myeloid precursors) (Fig. 3-1). The immune system functions by means of a complex network of cellular interactions that involve cell surface proteins and soluble mediators such as cytokines.

INNATE IMMUNITY The principal components of innate immunity are (1) physical and chemical barriers such as epithelia and antimicrobial substances produced at epithelial surfaces, (2) circulating effectors proteins such as the complement components and cytokines, and (3) cells with innate phagocytic activity: neutrophils, macrophages, and natural klller (NK) cells. Phagocyte surface receptors recognize highly conserved structures characteristic of microbial pathogens that are not present in mammalian cells. The binding of microbial structures to these receptors triggers the cell to engulf the bacterium and induces cytokines, chemokines, and costimulators that recruit and activate antigen-specific lymphocytes and initiate adaptive irrunune responses. Thus, innate irrununity not only represents an early effective defense mechanism against infection but also provides the "warning" of the presence of an infection against which a subsequent adaptive immune response has to be mounted. 4 The pivotal role of this compartment in the effector phase of the irrunune response is discussed later. Innate immunity represents an effective first line of defense against infections. However, its capacity to recognize infectious agents is limited. Moreover, innate immunity lacks of one of the most important characteris-

tics of the adaptive immunity: the capacity to memorize and to respond more vigorously to repeated exposure to the same infectious agent.

Cells Involved in Innate Immunity Phagocytes The cells of the phagocyte system originate from a common lineage in the bone marrow, circulate in the blood in inactive form, and are recruited and activated in the peripheral tissues in case of infection, tissue injury, or other pro-inflammatory stimuli. Monocytes are the classic example of immature circulating phagocytes; they are characterized by a granular cytoplasm with many phagocytic vacuoles and lysosomes. Once they enter the tissues, monocytes mature into macrophages. Macrophages are present in all tissues, where they act as "sentinels" together with dendritic cells (Des). One of their major roles is to recognize and respond to microbes and to amplify the response against a potentially harmful stimulus. Depending on the tissues in which they are found, macrophages are known by a number of different names: Kupffer cells in the liver, microglial cells in the central nervous system, and alveolar macrophages in the airways. These cells are the prototype of the effector cells of innate immunity. Once activated, macrophages initiate a number of crucial events, which include phagocytosis and destruction of ingested microbes and production of pro-inflammatory cytokines and other mediators of inflammation, that lead to further recruitment of cells of innate immunity (monocytes, neutrophils) and provide signals to T and B cells of adaptive immunity. Neutrophils, the other major group of phagocytes, are the most abundant type of circulating leukocytes. The cytoplasm is characterized by the presence of two types of granules. The so-called specific granules contain a number of enzymes, such as lysozyme, elastase, and collagenase. The azurophilic granules are lysosomes containing enzymes and microbicidal substances. Neutrophils are the first cells that enter the site of infection, and they represent the prevalent cell type in the early phases of

19

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

• Figure J-l Lineage of cells involved in the immune and inflammatory responses. Pluripotent hemapoietic stem cell (HSC) give rise to precursors for different hematopoietic lineages. The first step of HSC commitment generates common myeloid and common lymphoid progenitors. Most of the dendritic cells (DC) appear to be related to the mononuclear phagocyte lineage. Asubset of them is thought to be of lymphoid origin (plasmacytoid DC or interferon-produdng cells, IPC) (see also ref. 11). Development of natural killer (NK) cells is still under investigation; direct origin from HSC is assumed (see also ref. 18).

the inflammatory response. Within 1 or 2 days, neutrophils are almost completely replaced by newly recruited monocyte-macrophages, which represent the dominant effector cells in the later stages of inflammation.

Phagocyte Activation and Effector Functions Neutrophils and macrophages can be activated in several ways. The presence on their surface of multiple receptors

allows them to act as initiators as well as final effectors of the immune response (Fig. 3-2). These include receptors for components of infectious agents as well as receptors for molecules of the immune system (e.g., complement, cytoldnes, chemokines, immunoglobulins). As mentioned earlier, phagocyte surface receptors recognize structures, including nucleic acids and complex lipids and carbohydrates, that are characteristic of microbial pathogens but are not present on mammalian cells' (Table 3-1), Most of these substances are essential for the survival of invading

• Figure 3-2 Modalities of macrophage activation. A, Recognition of conserved molecular constituents of microbes (in the figure, lipopolysaccharide (LPSI) by spedfic receptors (I.e.,Toll-like receptors, mannose receptor, scavenger receptor). 8,T cell-mediated activation via interferon-y (IFN-y) and CD40CD40-ligand (CD40L) interaction. e, Recognition of antibodies, immune complexes, and complement by the membrane receptors for the Fe fragment of immunoglobulins and complement receptors. The main effector soluble mediators produced after macrophage activation are also shown.

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lIIi

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

E:xalllple~ 01 Palhogen-As~ocialed

LPS Unmethylated DNA with CpG motifs Terminal mannose residues LPS,dsRNA dsRNA ssRNA N-formylmethionine residues

Molecular Pallerns (PAMPs) and Respective Pattern Recognition

21

Re(eplor~ (PRR~)

Origin

PIR

Main Effector Function

Gram-negative bacteria Bacterial DNA

Toll-like receptors, CD14 Toll-like receptors

Microbial glycoprotein and glycolipids

Macrophage mannose receptor Plasma mannose-binding lectin

Bacteria, viruses Viral Viral Bacteria

Macrophage scavenger receptor Toll-like receptors Toll-like receptors Chemokine receptors

Macrophage activation Macrophage, B cell, and plasmacytoid cell activation Phagocytosis Complement activation, opsonization Phagocytosis IFN type I production IFN type I production Neutrophil and macrophage activation and migration

dsRNA, double-stranded RNA; IFN, interferon; LPS, lipopolysaccharide: ssRNA, single-stranded RNA.

microbes and are defined as pathogen-associated molecular patterns (PAMPs), The receptors of the innate immune system that recognize PAMPs are called patternrecognition receptors (PRRs). PAMPs may significantly differ among the various classes of microorganisms, but they ;Ire invariant among microorganisms of a given class. This characteristic allows a limited number of germ-line encoded PRRs to detect the presence of different microbial infections. Because PAMPs are essential for microbial survival, mutations or deletions of PAMPs are lethal. This greatly reduces the possibility that microbes could escape recognition by the innate system by undergoing PAMP mutations.

• fIIIn 3-3 Structure ofTolI-like receptors (TlR) and signaling pathway. Activation ofTlR4: lipopolysaccharide (lPS) binds to the CD14 molec.ule present on phagocyte surface and to a circulating protein, called M02. Then, the lPS-CDI4 complex associates with TlR4 for subsequent intracellular signaling. The lipopolysaccharidebinding protein (lPB) is a circulating protein that binds to lPS in the blood or in ~racellular flUid, forming a complex that facilitates lPS binding to CD14.TlR2 binds to peptidoglycan and forms an heterodimer with TlR6 through MAlP-2. After activation, the intraceliularTolVll-l receptor (TIR) domain triggers the signaling pathway that results in generation of NF-lCB (nudear factor-lCB) transcription factor and activation of activation protein-l (AP-l). IRAK,ll-l receptor-associated kinase; TRAF, tumor necrosis factor receptor-associated factor.

Many classes of PRRs are present on the surface of macrophages and Des, where they act as "tissue sentinels" through the continuous monitoring of peripheral tissues for the possible invasion of microbial pathogens (see Table 3-1). The Toll-like receptors (TLRs) are a large class of PRRs characterized by an extracellular leucinerich repeat (LRR) domain and an intracellular Toll/interleukin-1 CIL-1) receptor (TIR) domain (Fig. 3-3). There are at least 10 different classes of TIRs involved in responses to widely divergent types of PAMPs (Table 3_2).5,6 In some cases, recognition of PAMPs and the consequent transmission of intracellular signals for phagocyte activation require the presence of accessory proteins

22

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

loll-I ikl' Rl'( l'plIUS (fI Rs)

TLR

Ugand

Microbial Source

TLRI

Lipopeptides Atypical LPS Zymosan Peptidoglycans Lipotelchoic acids Lipoarabinomannan HSP70 (host) dsRNA LPS Lipoprotein HSP60 Fusion protein Flagellin Lipoprotein MALP-2 ssRNA ssRNA DNA with CpG motifs Unknown

Bacteria, mycobacteria Leptospira interrogans Fungi Gram-positive bacteria Gram-positive bacteria Mycobacteria

TLR2

TLR3 TLR4

TLR5 TLR6

TLR7 TLR8

TLR9 TLRlO

Vinlses Gram-negative bacteria Many pathogens Chlamydia pneumoniae Respiratory syncytial vinls Bacteria Mycoplasma Viruses Viruses Bacteria, protozoans

dsRNA, double-stranded RNA; HSP, heat-shock protein; LPS, lipopolysaccharide; MALP-2, mycoplasma-derived macrophage-activating 2-KDa lipopeptide; RSV, respiratory syncytial virus; ssRNA, single-stranded RNA.

(see Fig, 3-3). It is still debated whether TLRs may also recognize endogenous ligands, such as heat-shock proteins produced during stressing events, or extracellular matrix components, including fibronectin, hyaluronic acid, and heparin sulphate, produced in response to tissue injury (see Table 3-2).6,7

The binding of microbes to phagocytes through PRRs initiates the process of phagocytosis of the invading microorganism and its subsequent killing in phagolysosomes. In fact, activation of phagocytes through PRRs induces multiple effector molecules such as inducible nitric oxide synthase (NOS) and other antimicrobial peptides that can directly destroy microbial pathogens (Fig. 3-4). At the same time, peptides are generated from microbial proteins and presented to T cells to initiate the adaptive immune response (see later discussion), Moreover, the activation of signal transduction pathways by PRRs leads to the induction of genes that regulate both innate responses (inflammatory cytokines, growth factors, chemokines, proteolytic enzymes) and adaptive responses (major histocompatibility complex, costimulatory molecules) of the host to invading microbes. Other modes of macrophage activation include stimulation by type 1 T helper cell (ThO-oriented lymphocytes through the production of interferon-y (IFN-y) (see later discussion). Macrophages and neutrophils are also activated by immune complexes and complement fragments through binding with immunoglobulin and complement receptors expressed on their surface (see Fig. 3-2), This is the primary pathway of activation of neutrophils, which represent the first circulating leukocytes recmited at the site of inflammation.

Alternative Phagocyte Activation Macrophages playa cmcial role in the clearance of apoptotic cells, a function that is essential in normal home-

• Figure 3-4

Phagocytosis and intracellular destruction of microbes. A, The pathogen-associated molecular pattem present on a microbe is recognized by the pattem-recognition receptor expressed on the phagocyte membrane. 8, The microbe is intemalized into a phagosome. C, The phagosome fuses with cytoplasm Iysosomes to form a phagolysosome, in which the microbe is killed by reactive oxygen intermediates (ROI) and nitric oxide (NO).

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ostasis. During the process of phagocytosis of apoptotic cells, tissue macrophages undergo alternative activation, S stimulated by the binding of apoptotic cells to surface receptors, such as ~J-glycoprotein 1 receptor and the vitronectin receptor (avp/ The alternative activation of macrophages leads to the production of a number of anti-inflammatory molecules, including transforming growth factor-~ (TGF-~), IL-1O, and IL-l receptor antagonist (IL-IRa), that are crucial components in the suppression of acute inflammation and protect the host from tissue damage. 9 IL-lO inhibits production of pro-inflammatory cytokines, suppresses the release of reactive oxygen intermediates, and downregulates the expression of major histocompatibility complex (MHC) class II and costimulatory molecules. IL-IRa binds competitively to the IL-l receptor present on macrophages, thus inhibiting the pro-inflammatory action of IL-1. TGF-~ inhibits the production of another pro-inflammatory cytokine, tumor necrosis factor (TNF), and promotes the expression of matrix proteins by macrophages, contributing to extracellular matrix deposition, wound healing, and fibrosis. The alternative activation of macrophages is also stimulated by Th2 cytokines, IL-4, and IL-13 (see later discussion).

Dendritic Cells DCs are specialized antigen-presenting cells that originate from the bone marrow and playa critical role in the processing and presentation of antigen to T cells during the adaptive immune response. lO ,ll DCs should be considered as a bridge between innate and adaptive immunity. At their immature stage of development, DCs act as sentinels in the epithelia of peripheral tissues (skin, gastrointestinal, and respiratory systems), continuously sampling the antigenic environment. These cells are morphologically identified by their extensive membrane projections. Their prototypes are the Langerhans cells of the epidermis. Recognition of microbial or viral products through the same PRRs that are present on the surface of phagocytes initiates the migration of DCs to lymph nodes, where they mature (express costimulatory molecules) to present antigen to T cells. 12 ,13 The role of DCs in antigen presentation and in the regulation of the immune response is described in more detail in the discussion of the adaptive immune response. Recently, another type of DC (plasmacytoid DC) of probable lymphoid origin was identified. 14 Differences in function between myeloid DCs and plasmacytoid DCs are still unclear. Plasmacytoid DCs have the unique capacity to secrete large amounts of type I IFN (aI~) in response to certain viruses and other microbial stimuli (they are also called plasmacytoid interferon-producing cells). It was shown that monocytes isolated from the blood of patients with systemic lupus erythematosus (5LE), but not those from healthy individuals, act as DCs and that their activation is driven by circulating IFN-a, which may come from plasmacytoid DCS.15 This and other experimental and clinical observations point to a possible pivotal role for this cell subpopulation in the pathogenesis of some autoimmune disorders. 16 Although DCs are the most potent APCs able to activate naIve T cells, it is now clear that DCs may also be

23

tolerogenic through various mechanisms that include induction of T cell anergy, T cell apoptosis, T regulatory cells and production of immunoregulatory cytokines by T cells (see later discussion). This tolerogenic phenotype is displayed by myeloid-derived immature DCs and by immature and mature plasmacytoid DCs. The induction of tolerance through DC manipulation is an exciting possibility for future treatments in autoimmune diseases and transplantation. 17

Natural Killer Cells NK cells are large lymphocytes characterized by the presence of numerous cytoplasmic granules containing proteolytic proteins (perforin, granzymes). They lack antigen-specific receptors (e.g., immunoglobulins, T cell receptors) but are able to kill abnormal cells such as some tumor cells and virus-infected cells. IS The term "natural killer" refers to their capacity to rapidly kill target cells without the need of activation by other cell types or soluble molecules (as is the case for CD8+ cytotoxic T lymphocytes [CTLs]). Activation of NK cells is regulated through activating and inhibitory cell surface receptors. 19 The inhibitory receptors bind to self class I MHC molecules, which are expressed on most cell types (Fig. 3-5A). The ligands for activating receptors are only partially known. The engagement of both inhibitory and activating receptors results in a dominant effect of the inhibitory receptors. The infection of host cells, especially by viruses, leads to the loss of class I MHC from their surfaces and exposes these cells to the exclusive activity of activating receptors (see Fig. 3-5A,B),20 Once activated, NK cells release the contents of their granules. Perforin creates pores in target cell membranes, and granzymes enter into the cells through the perforin pores, inducing the death of target cells by apoptosis, with the same mechanism of cytolysis used by CDW cns (see later discussion). Other important activities of NK cells include their ability to recognize (via Fc receptors) and destroy antibody-coated cells (a process called antibody-dependent cell-mediated cytotoxicity, or ADCC) and their ability to produce high amounts of IFN-y, a potent stimulator of macrophage activity. In turn, activated macrophages produce IL-12, a potent inducer of NK-cell IFN-y production and cytolytic activity (see Fig. 3-5C,D).

Fibroblasts Fibroblasts play an active role in the effector arm of the inflammatory response. Connective tissue contains a mixture of distinct fibroblast lineages, including mature fibroblasts with a lesser capacity of transformation and immature fibroblasts (mesenchymal fibroblasts) that are capable of differentiating into several different cell lineages. Fibroblast precursors with a multipotent character also circulate in blood; because of their similarity with stromal cells of bone marrow, they are called mesenchymal stem cells. During inflammation, the pro-inflammatory cytokines produced by tissue macrophages activate mature tissue fibroblasts to produce cytokines, chemokines, prostaglandins (PGE 2), and proteolytic enzymes (Le.,

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

• Figure 3-5 Functional properties of natural killer (NK) cells. A, The inhibitory receptors bind to self class I major histocompatibility complex (MHO molecules, which are normally expressed by most cell types. 8, Infection of the host cells by virus leads to the loss of surface class I MHC and exposes the infected cells to the exclusive activity of activating receptors and subsequent killing. C, NK cells recognize antibodycoated cells through the Fc receptors expressed on their surface and subsequently kill the infected cell. D, NK cells respond to interleukin-12 (IL-12) produced by macrophages during phagocytosis and secrete interferon-y (IFN-y), which, in tum, activates macrophage to kill phagocytosed microbes.

metalloproteinases). The failure to switch off activated tissue fibroblasts has been proposed as a mechanism leading to chronic inflammation, through the persistent overexpression of chemokine and pro-inflammatory cytokines and consequent continuous recruitment of leukocytes. 21

Molecules of Innate Immunity The Complement System The complement system consists of several normally inactive plasma proteins that, after activation, interact to generate a number of products that mediate important effector functions, including promotion of phagocytosis and lysis of the cells on which complement is activated and stimulation of inflammation. Activation of complement involves sequential proteolytic steps that generate an enzymatic cascade similar to that of the coagulation system. 22 There are three major pathways of complement activation (Fig. 3-6). The alternative pathway involves the direct binding of one of the complement proteins, C3b, to cells. The classic pathway involves a more sophisticated mode of activation, in which Cl binds to the CH 2 domains of immunoglobulin G CIgG) or to CH 3 domains of IgM that have bound antigen (see later discussion). The same proteins involved in the classic pathway can be activated in the absence of antibodies by a plasma protein (mannose-binding lectin) that binds to mannose residues on microbial glycoproteins and glycolipids; this

is known as the lectin pathway. The three pathways of complement activation converge in a central complement component, C3, which is cleaved into two fragments. The larger fragment (C3b) becomes covalently attached to cells, where it acts as opsonin to stimulate phagocytosis and activates C5 with subsequent generation of C5b. C5b initiates the formation of a complex of the complement proteins C6, C7, C8, and C9 that is assembled on cell membranes (membrane attack complex, MAC), forming a pore that causes lysis of the target cell. During complement activation, smaller complement fragments (C3a, C4a, C5a) are released into the circulation. Also known as anaphylatoxins, they exert several pro-inflammatory effects, including activation of mast cells and neutrophils and increased vascular permeability!2 Another function of complement is to bind to antigen-antibody complexes, thus promoting their solubilization and clearance by phagocytes. Recently, complement has been shown to have a role in the clearance of apoptotic blebs by the phagocytic system. 23 ,24 The biologic activities of complement are mediated by the binding of complement fragments to membrane receptors. Receptors for the fragments of C3 are best characterized (Table 3-3). Type 1 complement receptor (CRl, CD35) is expressed by almost all blood cells and promotes phagocytosis of C3b-coated cells. CRI expressed on erythrocytes binds to circulating immune complexes with attached C3b. In this way, circulating erythrocytes are able to transport immune complexes to the liver and spleen, where they are removed from erythrocyte surface and cleared. Type 2 complement receptor (CR2, CD2l) is

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25

• R.-. 3-6

The complement cascade. The alternative pathway is activated when Ob binds to the microbial cell wall, after spontaneous cleavage of free circulating 0. Thereafter, Ob binds to factor B, forming a ObBb convertase. The dassic pathway is Initiated by the binding of the tril1ilolecular complex Cl (Clq, Clr, C1s) to antigen-antibody compleKes. The same proteins involved in the classic pathway can be activated in the absence of antibodies by a plasma protein called mannose-binding lectin (MBL), which binds to mannose residues on microbial glycoproteins and glycolipids (lectin pathway). Subsequent binding with the C4b and C2a subunits leads to the formation of C4b2a convertase. The three pathways of complement activation converge at 0, which is cleaved into two fragments. The larger fragment (Ob) activates CS with subsequent generation of CSb; CSb initiates the formation of a complex of the complement proteins C6, C7, CS, and C9 that is assembled on the cell membrane (membrane attack complex,

MAO.

present on B lymphocytes and follicular DCs of lymph node germinal centers. Its main function is to act as coreceptor for B cell activation by antigen (see later discussion) and to stimulate the trapping of antigen-antibody • ~. fABLE 3 3

(omplement Re(eptors

Receptor

Cell 'JYpes

Ugands

Function

CRl (C035)

Band T cells Erythrocytes Monocytes, macrophages Eosinophils FDCs, Neutrophils B cells FDCs Upper airways epithelium

C3b, C4b, iC3b

C3b and C4b decay Clearance of immune complexes Phagocytosis

C3d, C3dg, iC3b

Activation of B cells (coreceptor) Antigen presentation in germinal centers Receptor for EBV Phagocytosis Adhesion to endothelium (via ICAM)

CR2 (CD21)

CR3 (CD llb/ CD1S)

CR4 (COllc/ CDlS)

Macrophages Neutrophils. NK cells Dendritic cells, FDCs Macrophages Neutrophils, NK cells Dendritic cells

iC3b,ICAM

iC3b

Phagocytosis

CD, cluster of differentiation; CR. complement receptor; EBV, Epstein-Barr virus; FOC. follicular dendritic cells; lCAM. intracellular adhesion molecule: NK. natural killer.

complexes in germinal centers. Type 3 and type 4 complement receptors are members of the integrin family and are expressed by the cells of innate immunity (neutrophils, NK cells, mononuclear phagocytes), The binding of CR3 or CR4 promotes the activation of these cells and the phagocytosis of cells opsonized with C3h. Complement deficiencies are associated with a number of pathologic conditions (see Chapter 33). Genetic deficiencies of classic pathway components (Clq, Clr, C2, and C4) may cause a disease that resembles SLE,24 This may be related to the role of early complement components in the clearance of apoptotic cells and circulating immune complexes. The deficiency of C3 is associated with serious pyogenic infections. Defects of the terminal complement components (CS-C9) are associated with an increased risk of disseminated Neisseria infections, including Neisseria meningitidis. Activation of the complement cascade is regulated by a number of circulating and cell membrane proteins that prevent activation on normal host cells and limit the duration of complement activation on microbial cells and antigen-antibody complexes. The CI inhibitor (CI INH) regulates the proteolytic activity of CI, the initiator of the classic pathway of complement activation. Deficiency of this protein causes an autosomal dominant inherited disease called hereditary angioneurotic edema. A number of membrane proteins (membrane cofactor protein, MCPj type 1 complement receptor, CRl; decay-accelerating factor, DAF) and the plasma protein, factor H, prevent the activation of C3b if it is deposited on the surfaces of normal mammalian cells, The deficiency of an enzyme required for linkage of DAF with the cell membrane causes a disease called paroxysmal nocturnal hemoglobinuria, which is characterized by recurrent attack of intravascular hemolysis due to unregulated complement activation on the surface of erythrocytes. Similarly, the rare deficiency of factor H is characterized by an

26

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excess alternative pathway activation leading to C3 consumption and glomerulonephritis, Recent experimental observations have shown a role for complement components in the induction of regulatory T cells secreting anti-inflammatory cytokines such as TGF-~ and IL10,25,26 These data suggest a broader role of the complement system in the regulation of the immune response.

Other Circulating Proteins A number of circulating proteins behave as secreted PRRs (see earlier discussion) in their ability to specifically recognize microbial PAMPs and promote innate immunity, Mannose-binding lectin (MBL) belongs to a family of proteins (collectin) with a collagen-like domain separated by a neck region from a calcium-dependent (C-· type) lectin. 27 Like the mannose receptor expressed on the surface of macrophages, MBL binds carbohydrates with terminal mannose and fucose that are typically found on glycoproteins on the surface of bacterial but not mammalian cells. MBL is structurally similar to the C1q component of the complement system, binds the C1q receptor present on phagocytes, and may activate complement. Thus, MBL is able to opsonize microbes and induce phagocyte activation via C1q receptor. C-reactive protein (CRP) and serum amyloid protein (SAP) are plasma proteins belonging to the family of pentraxins. 28 They are abundantly produced during the acute phase of inflammation by the liver. They bind to phosphorylcholine present on the microbial membranes. Moreover, they are also able to activate the classic complement pathway and to act as opsonins for neutrophils. The lipopolysaccharide-binding protein (LPB) is a circulating protein that binds to LPS in the blood or extracellular fluid, forming a complex that facilitates LPS binding to CD14 (see earlier discussion). Other circulating proteins that participate in innate immunity include defensins, which are diverse members of a large family of antimicrobial peptides that contribute to the antimicrobial action of granulocytes, mucosal host defense in the small intestine. and epithelial host defense in the skin and elsewhere. 29

Cytoklnes and Chemoklnes Cytokines and chemokines are proteins secreted by cells of the innate and adaptive immune systems in response to a possible harmful exogenous stimulus (microbes, antigen) that mediate and regulate the immune and inflammatory response. Although some cytokines are produced in sufficient quantity to circulate and exert exocrine actions, they usually act locally in an autocrine or paracrine fashion. Their functions are mediated by cellular receptors belonging to a limited number of families (Table 3-4), All cytokine receptors consist of one or more transmembrane proteins whose extracellular portions are responsible for cytokine binding and whose cytoplasmic portions mediate the triggering of the intracellular signaling pathway (see Fig. 3-4). Cytokines may be classified in four main categories: (1) cytokines of innate immunity, which are produced mainly by mononuclear phagocytes in response to an infectious agent (Table 3-5); (2) cytokines of adaptive immunity, which are produced by T lymphocytes after specific recognition of foreign antigens (Table 3-6); (3) growth factors, which are produced by bone marrow stromal cells and leukocytes, stimulate the differentiation and proliferation of immature leukocytes, and sustain phenomena of angiogenesis; and (4) chemokines, a large family of cytokines produced by various cell types, which stimulate and regulate leukocyte migration (see also Table 3-12). Cytokines are the main functional molecular bridge between innate and adaptive immunity, and they are potent effectors in both systems, The functional characteristics of cytokines of innate immunity are outlined in more detail later in this chapter; the cytokines of adaptive immunity are described in the following section.

ADAPTIVE IMMUNITY The main characteristics of adaptive immunity are the capacity to recognize antigens with a high level of molecular specificity and the ability to remember and respond more promptly and more vigorously to subsequent exposure to the same antigens (immunologic memory). Any

Family

Structure

Spedfldty

Type I cytokines receptor (hematopoietin family)

Conserved cysteine residues + WSXWS sequence Common ~ chain Common y chain Common gpI30 subunit Conserved cysteine residues, no WSXWS sequence Conserved cysteine-rich extracellular domains Extracellular immunoglobulin domains Seven a-helical transmembrane domains

Erythropoietin, growth hormone, IL-13

Type II cytokines receptor TNF-receptor family Immunoglobulin superfamily receptors Chemokine receptors

IL-3, IL-S, GM-CSF IL-2, IL-IS, IL-7, IL-4, IL-9 IL-6, IL-ll IFN-a, -~, -y, IL-lO TNF, LT, C040, Fas, C027, NGF IL-I, M-CSF, stem cell factors Chemokines

CD. cluster of differentiation; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN. interferon; IL, interleukin; LT, Iymphotoxin; M-CSF. macrophage colony-stimulating factor; NGF, nerve growth factor; TNF, tumor necrosis factor.

3

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

(ytokines of Innate Immunity

CytGIcIne

Size and Form

Recepton

Main Cell Source

Main Biologic Effects

IL-Hx IL-I~

17 kD, monomer 33 kD (precursors)

CD121a, b (IL-l Rl, IL-l RlD

Macrophages, endothelial cells, epithelial cells

TNF-o.

17 kD homotrimer

p55, p75 (TNFRl, TNFRlI)

Macrophages, T cells, NK cells

Homotrimer

p55, p75 (TNFRl, TNFRII) ?

T cells, B cells

Fever Activation of endothelial cells and macrophage Acute phase reactants Fever Activation of endothelial cells, macrophage, and neutrophils Acute phase reactants Apoptosis Cachexia Killing, endothelial activation

CDl18 (IFNAR2)

Leukocytes Fibroblasts

IL-6R, gp130

T cells, macrophages, endothelial cells

IL-lO Ro. CRF2-4 IL-12 R~l IL-12 R~2 IL-15 R (CDI22)

Macrophages, T cells (Th2, Treg) DC, B cells Macrophages Macrophages and other non T cells Macrophage

TNP-~

(LT-o.)

27

MIF

Monomer

Type I IFNs IL-6

IFN-o.: 15-21 kD IFN-~: 20-25 kD monomers 19-26 kD, monomer

lL-lO

34-40 kD homodimer

IL-12 IL-15

Heterodimer of 35 and 40 kD· 13 kD, monomer

IL-18

17 kD, monomer

IL-23

Heterodimer of 19 and 40 kD·

T cells

IL-l Rrp (0. chain) AcPL (~ chain) IL-12 R~1 IL-23R

DC, B cells Macrophages

Macrophage activation Steroid resistance Antiviral response Activation of NK cells Fever Activation of endothelial cells Acute phase reactants B cell proliferation Suppression of macrophage function Differentiation of Th 1 cells Synthesis of IFN-y by T cells and NK cells NK cells and T cell proliferation Synthesis of IFN-y by T cells and NK cells Sustain survival and function of Thl cells

., IL-ll and IL-23 share the same p40 subunit. AcPL, accessory protein-like; CD, cluster of differentiation; CRF, Class" cytokine receptor family; lPN, interferon; IL, interleukin; LT, lymphotoxin; MIF, macrophage inhibitory factor; NK, natural killer; TNF, tumor necrosis factor; R, receptor; DC: dendritic cells; Thl, type I helper T cell; Th2, type 2 helper T cell; Treg, regulatory Teell .

• ~. IABLE 3--6

Cytokines of Adaptive Immunity

Cytaldne

Size and Fonn

Recepton

Main Cell Source

Main Biologic Effects

IL-2

14-17 kD, monomer

T cells

IL-4

18 kD, monomer

CD25 (0. chain) CD122 (~ chain) CD132 (y chain) CD124

IL-5

45 kD, homodimer

CD125

T cells (Th2)

IL-13

15 kD, monomer

IL-13 R

T cells (Th2)

IFN-y

50 kD, homodimer

CD119 (IFNGR2)

T cells, NK cells

LT-P TGF-~

Trimerizes with LT-o. 25 kD, homodimer

Proliferation and activation of T cells, NK cells Proliferation of B cells and antibody synthesis Fas-mediated apoptosis Isotype switching to IgE Th2 differentiation Inhibition of IFN-y-mediated macrophage activation Thl suppression Activation and proliferation of eosinophils B cell proliferation and 19A production B cell proliferation Isotype switching to IgE Inhibition of macrophage activation Macrophage activation Ig class switching to opsonizing and complement-fixing IgG antibodies Thl differentiation Th2 suppression Lymph node development Inhibition of proliferation and effector function of T cells Inhibition of B cell proliferation

T cells (Th2)

T cells, B cells T cells (Treg), macrophages

CD, cluster of differentiation; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LT, lymphotoxin; NK, natural killer; TGF, transforming growth factor; Thl, type 1 helper T cells; Th2, type 2 helper T cells; Treg, regulatory T cells.

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substance that is capable of being recognized by the adaptive immune system is called an antigen. Lymphocytes, the cells responsible for adaptive immunity, are the only cells capable of recognizing different soluble or membrane-bound antigenic determinants by specific antigen receptors. The adaptive immune response can be divided into three phases. The recognition phase consists of the binding of antigens to specific lymphocyte receptors. The activation phase is the sequence of events induced in lymphocytes after specific antigen recognition. Lymphocytes first proliferate and then differentiate into either effector cells (which are aimed at eliminating the antigen), or memory cells (which survive and are ready to respond promptly to antigen re-exposure). In the effector phase, activated lymphocytes perform their function of eliminating the antigen. Many effector functions require the participation of molecules or cells that belong to the innate immune system. For instance, some antibodies activate complement, whereas T lymphocytes release cytokines that stimulate the function of phagocytes and the inflammatory response. The immune system is able to recognize and eliminate a foreign antigen but does not normally react harmfully to self molecules (self-tolerance) . Lymphocytes display common morphologic features but differ in their origin, in how they recognize antigens, and in their functions. Lymphocytes that have not encountered antigen (nai've lymphocytes) are small (8 to 10 /lm in diameter), with a large nucleus and a small amount of cytoplasm containing mitochondria and ribosomes but no specialized organelles. After antigenic stimulation, naIve lymphocytes enter into the cell cycle and become larger 00 to 12 /lm) and have more cytoplasm and organelles (lymphoblasts). There are two main types of lymphocytes: B lymphocytes (which mature in the bone marrow) and T lymphocytes (which mature in the thymus). B lymphocytes produce antibodies and are responsible for humoral immunity. Their antigen receptors are membrane-bound antibodies that can recognize soluble antigens. Cell activation leads to a sequence of events that culminates in the generation of plasma cells, which secrete antibodies. T lymphocytes are responsible for cell-mediated immunity, The T cell receptor (TCR) recognizes cell surfaceassociated antigens, but not soluble antigens. Specifically, the TCR recognizes peptide antigens that are generated inside antigen-presenting cells (APCs) and are brought to the cell surface in association with specialized molecules of the MHC. This allows the immune system to detect intracellular pathogens. There are two functionally distinct populations of circulating T lymphocytes: helper T lymphocytes and cytotoxic T lymphocytes (CTLs). Helper T lymphocytes play the pivotal role in adaptive immunity and activate other cells, such as B lymphocytes, macrophages, and cytotoxic T cells, to perform their effector functions. CTLs lyse cells that are infected by virus or other intracellular microorganisms. A distinctive subpopulation of circulating T lymphocytes with a suppressor activity (defined as naturally occurring regulatory T cells [TregJ) has also been characterized (see later discussion).

Some antigen-stimulated Band T lymphocytes differentiate into memory cells, whose function is to mediate a rapid and enhanced response to a subsequent exposure to the specific antigen. These cells survive in a quiescent state for many years, not requiring antigen recognition for their prolonged survival in vivo. NaIve lymphocytes migrate through the peripheral (or secondary) lymphoid organs, where they recognize and are activated by antigens that are introduced through the skin and via the gastrointestinal and respiratory tracts, These effector and memory lymphocytes circulate in the blood and localize in peripheral sites of antigen entry, where they exert their effector functions. Different subsets of lymphocytes express different membrane proteins that identify their particular stage of differentiation and function. The membrane proteins are defined by means of specific monoclonal antibodies and are designated by the abbreviation CD (cluster of differentiation). Those membrane proteins mentioned in this chapter are listed in Table 3-7.

B Lrmphocytes and Their Antigen Receptors B lymphocytes develop in the bone marrow and are found mainly in secondary lymphoid organs and, in low number, in the circulation. B lymphocytes express cell surface immunoglobulins that act as antigen receptors.

Immunoglobulin Molecules Antibodies, or immunoglobulins, are the antigen-specific products of B cells. Immunoglobulins (1) serve as membrane-bound B-cell antigen receptors (see later discussion), (2) are produced and released by antigen-activated B cells, 0) bind their specific antigen, and (4) recruit other molecules or cells to destroy the target to which they are bound. The immunoglobulin variable region (antigen-binding fragment, or Fab) binds to the antigen; the constant region (crystallizable fragment, or Fc) binds to a limited number of effector molecules and cells. The immunoglobulin structure is substantially the same for all five main immunoglobulin classes or isotypes (IgM, IgD, IgG, IgA, and IgE).30 Antibodies are Y-shaped molecules composed of two identical heavy (H) chains (each 50 or 70 kD) and two identical light (L) chains (each about 25 kD). In all antibodies, there are only two types of functionally eqUivalent light chains; they are called lambda 0..) and kappa (K) chains. The light and heavy chains each have an aminoterminal sequence (variable region, or V region) that varies greatly among different antibodies; in each antibody, the variable regions of the light and heavy chains (VL and VH, respectively) form pairs to generate two identical antigen-binding sites that lie at the ends of the arms of the Y. The carboxylterminal sequences, on the other hand, are constant among immunoglobulin chains of the same heavy-chain isotype (Fig. 3-7), The heavy chains define the isotypes of immunoglobulins and are designated by the Greek letters /l, 0, 1.., E, and n. IgM and IgE heavy chains contain an extra constant-region domain. IgM molecules occur as pentamers; IgA is found in mucous secretions but not in plasma and

,-

I' •

1ABLE 3 ~ 7

Some Examples of Differentiation Antigens'

CD AntIgen Common Names

Main Cellular Expression

Known or Supposed Functions

CDl (a,b,c,d)

Thymocytes, dendritic cells

CO2

T cells, NK cells T cells, thymocytes

MHC class I-like molecule, presentation of nonpeptide antigens to some T cells Adhesion molecule (binds LFA-3) Associated with the T-cell receptor and involved in signal transduction Coreceptor for MHC class II molecules Signaling molecule Coreceptor for MHC class I molecules Subunit of LFA-l (adhesion molecule) Subunit of LFA-l (adhesion molecule) Role in B cell activation Role in B cell activation Binds to CD70, mediates costimulatory signals for T cell and B cell activation Receptor for costimulatory molecules B7-1, B7-2 Adhesion molecule (ligand for L-selectin)

CD3

CD40

Helper T cells T cells, B cell subset Cytotoxic T cells Leukocytes Leukocytes B cells B cells T cells, memory B cells, NK cells T cell subsets Precursors of hematopoietic cells, endothelial cells in high endothelial venules B cells, macrophages, DCs

CD44 CD45

Leukocytes Leukocytes

CD80

APCs

CD86

APCs

CD95 CDlS2

Multiple cell types Activated T cells

CD154

Activated CD4+ T cells

CD4 CDS CDlB CDlla CD18 CD19 CD21 CD27 CD28 CD3 4

Tyrosine phosphatase, role in activation of B cells, macrophage, and DCs induced by T cells; binds CD40L (CDl54) Mediates adhesion of leukocytes Tyrosine phosphatase, role in signal transduction Costimulator for T cell activation; ligand for CD28 and CTLA-4 Costimulator for T cell activation; ligand for CD28 and CTLA-4 Role in activation-induced apoptosis; binds FasL Inhibitory signaling to T cells; binds to CD80 and CD86 on APCs Ligand for CD40

Other Common Names

LFA-3

LFA-l a chain LFA-l ~ chain CR-2

Leukocyte common antigen B7-1 B7-2 Fas CTLA-4

CD40L

'Defined by means of monoclonal antibodies and designated by the abbreviation CD (cluster of differentiation) followed by a numbet. APCs. antigen-presenting cells; CfLA, cytotoxic lymphocyte-associated antigen; CR, complement receptor; DCs, dendritic cells; L, ligand; LFA, leukocyte functionassociated antigen; MHC, major histocompatibility complex; NK, natural killer.

• figure 3-7 Basic: Immunoglobulin structure, linear structure of atypical Immunoglobulin G molecule. The variable regions of the light and heavy chains are Indicated by the brackets, Each chain can be divided into domains on the basis of sequence similarities; the light chains comprise two domains and the heavy chain four. The Fab (fragment antigen binding) and the F~ (fragment crystallizable) regions are defined by analysis with papain and pepsin.The hinge region that links the Fc and Fab portions is flexible and allows independent movement of the two Fab arms. Membrane immunoglobulins have a very short cytoplasmic: tail that is unable to transduce the signal to the cell after reaction with their spedfic antigen. Immunoglobulins in the cell membrane are assodated with two other chains, Iga and Ig~. in a receptor complex. The cytoplasmic: tails of these two chains contains particular sequence motifs, called immunoreceptor tyrosine activation motifs (ITAMs), that transduce the intracellular signaling.

30

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

is present principally as dimers. Pentamers and dimers are formed using the joining 0) chain, a 15-kD polypeptide synthesized by the plasma cell that binds the Cterminus of heavy chains. The structural features that distinguish the heavy-chain constant regions of the various isotypes confer distinct properties that enable them to activate different effector mechanisms and to be transported across epithelia or the placenta (Table 3-8). Within the variable regions, there are hypervariable (HV) regions, also called the complementarity-determining regions, or CDRs (CDR1, CDR2, CDR3). They are localized to the surface of the molecule in such a way that when the VH and the VL regions pair in the antibody molecule, the hypervariable regions are brought together, creating a single hypervariable site that forms the binding site for antigens. Thus, final antigen specificity is particularly determined by the juxtaposition of the CDRs. The molecular region that is recognized specifically by an antibody is called the antigenic determinant, or epitope.

Membrane Immunoglobulins On B lymphocytes, immunoglobulins are bound to the membrane, where they serve as specific antigen receptors. Membrane immunoglobulins have a very short cytoplasmic tail that is unable to transduce the signal to the cell once the immunoglobulin has reacted with its specific antigen. Immunoglobulins in the cell membrane, however, are associated with two other chains, Iga and Ig~, to form a receptor complex,31 The cytoplasmic tail of these two chains contains particular sequence motifs, called immunoreceptor tyrosine activation motifs (ITAMs), which are common to other signaling molecules of the immune system, including those of the TCR complex (see Fig. 3-7 and later discussion).

Generation of Antibody Diversity The heterogeneity of antibodies allows each molecule to recognize a particular antigen. The entire collection of

( ' . TABLE 3 8

antibody specificities in a given individual (the antibody repertoire) is large enough to ensure that virtually any structure can be recognized. The problem of how this almost infinite range of specificities could be encoded by a finite number of genes was solved with the demonstration that different parts of the variable region are encoded by different sets of gene segments. 32 Indeed, each immunoglobulin chain, both light and heavy, is encoded by distinct genomic regions, one for the variable portion and one for the constant portion. For the light chain, each variable region is encoded in two different DNA segments: the variable (V) chain segment and the joining (J) chain gene segment. In the case of heavychain variable regions, in addition to the V and J segments, there is also a diversity (D) gene segment. There are multiple functional copies of the V, D, and J segments. During the development of a lymphocyte, one copy of each gene segment is joined randomly to the others by irreversible DNA recombination (somatic recombination), This process generates light- and heavychain variable regions. Several enzymes act in concert during somatic gene recombination, including the product of recombination-activating genes 1 and 2 (RAG-l and RAG-2), terminal deoxynucleotidyl transferase (TdT), and DNA-dependent protein kinase. In mature lymphocytes that respond to antigens in secondary lymphoid organs, somatic hypermutation-" introduces a very high rate of point mutations into rearranged variable region genes and generates further variability; some of the mutant immunoglobulin molecules bind antigens better than the original surface immunoglobulin, and B cells expressing them are selected to mature into antibody-secreting cells, a phenomenon called affinity maturation. Constant-region genes in the same species are polymorphic, and the allelic variants are called allozypes. The determinants of the antigen receptor that are specific for a given lymphocyte clone are called idiotopes, and the collection of all the idiotopes of a given receptor is called the idiozype. The idiotype therefore represents the col-

Immulloglobulins

Normal adult serum level (mg/mL) Molecular weight (x 103) Intravascular (%) Total circulating pool (mg/kg) Half-life (days) Rate of synthesis (mg/kg/day)

IgGI

IgG2

IgG3

IgG4

IgAl

IgA2

IgM

IgD

IgE

9 146 45 325 23 30

3 146 45 115 23

1 170 45 35 9 4

0.5 146 45 20 25

3 160 40 80 6 25

0.5 160 40 15 6

1.5 970 75 37 5 7

0.03 184 75 1 3 0.4

0,0005 188 50 0.02 3 0.02

++ ++

±

+ +++

+

+

-'

-

+++

±

±

+++ +++ +

+ +

+++ +++ +++

+ +

+

+

+

+

+

+

Biologic function Crosses placenta Fixes complement Binds cells Mononuclear cells Neutrophils Lymphocytes Mast cells Platelets

±

.

±

+ +++

'. Alternative pathway fixation; - , none; ±, weak; +, moderate; ++, intense: +++. strong. [g, immunoglobulin.

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lection of specific determinants that distinguish each lymphocyte clone from all the others. In the antibody molecule, a given variable region can be associated with any constant region. Indeed, the constant region expressed in a B lymphocyte changes during the maturation of the cell and its subsequent proliferation in the course of the immune response, a phenomenon known as isotype switch.

BCell Development and Selection The process of gene rearrangement that gives rise to membrane immunoglobulins continually generates new populations of B cells of highly diverse specificity and provides the material on which clonal selection acts during the adaptive immune response. Nonlymphoid stromal cells of the bone marrow provide the essential microenvironment for B cell development by means of specific cell-to-cell contacts and release of growth factors. The process is characterized by sequential rearrangements and expression of the immunoglobulin genes, which regulate progression from one stage to the next.-\4 The random generation of the B cell repertoire gives rise to autoreactive immature B cells, which are eliminated during development in the bone marrow. Immature B cells express only surface IgM; in contrast to mature B cells, they undergo apoptosis and are removed from the repertoire (clonal deletion) if they bind abundant multivalent antigens such as ubiquitous cell siUrface molecules. However, a small proportion of these autoreactive immature B cells may escape this fate by replacing their autoreactive receptors with receptors that are not autoreactive. This rescue process is made possible by further gene rearrangement (receptor ectitingJ.35 Immature B cells that bind to soluble antigens are inactivated but not deleted; this state of nonreactivity is called anergy. Because anergic B cells cannot be activated by T cells, they fail to compete with other B cells in the periphery and are rapidly lost. Moreover, because B cells specific for protein antigens need T cell help in order to be activated, T cell self-tolerance by itself appears to be sufficient to prevent the production of high-affinity autoantibodies specific for self-proteins. Mature B cells leave the bone marrow and enter the peripheral lymphocyte pool as naive B cells. The influx of new mature B cells must compensate for the death of an equal number of peripheral B cells to maintain the steady state of the peripheral pool. Some naiVe B cells have a half-life of only a few days, probably because they are excluded from the lymphoid follicles. Naive B cells that successfully enter lymphoid follicles have a half-life of several weeks. After encountering the specific antigen, some B cells differentiate into effector cells that actively secrete antibodies, and some become nondividing, very-long-lived memory cells. Some B cells do not follow the developmental pathways so far described and have a distinctive receptor repertoire and t\lllctional properties. These cells are called Bl or CDS+ B cells (conventional B cells are called B2 B cells}\6 because they were first identified by the surface expression of the protein CDS (which is also present on T cells). Little is

31

known about their function. They arise early in ontogeny and, in adults, form a self-renewing population that is abundant in pleural and peritoneal cavities. They have a limited diversity in their repertoire; they produce low-affinity, polyspecific, and autoreactive antibodies (mainly IgM); and they contribute little to the adaptive immune response against protein antigens, but they do contribute to the immune response against some bacterial polysaccharides. All of these characteristics suggest that Bl B cells mediate a more primitive, less adaptive immune response than do conventional B cells. Recent studies have focused on the physiologic role of CDS in the context of regulation of antigen receptor activation, Band T cell selection, and generation and maintenance of immune toleranceY

T L,mphocytes and Their Antigen Receptors Immunoglobulins bind antigens in the blood and in the extracellular space. However, some bacteria and parasites, and all viruses, replicate inside cells, where they cannot be recognized by antibodies. These pathogens are destroyed by T cells, which are responsible for cellmediated immunity and recognize only antigens displayed on the cell surface, by molecules encoded by the genes of the MHC. Because T cells are essential in helping B cells, both cellular and humoral immune responses to protein antigens depend on antigen recognition by T lymphocytes. Infectious agents may replicate inside the cell either in the cytosol or in the vesicular system (endosomes and lysosomes). Cells infected with viruses or bacteria that live in the cytosol are killed by CTLs, which are distinguished by the presence of the cell surface molecule CD8. Pathogens or their products that are internalized by the cell in the vesicular system are detected by T cells that express the cell surface molecule CD4. CD4+ T cells, also called helper (Th) cells, do not directly kill the infected cells but activate other types of effector cells. Helper T cells comprise different cell types, the best characterized of which are Thl cells, which activate macrophages to kill intracellulose bacteria, and Th2 cells, which activate B cells to make antibodies. MHC class I molecules deliver peptides from the cytosol to the cell membrane, where the peptide-MHC complex is recognized by CD8+ T cells. MHC class II molecules deliver peptides from the vesicular system to the cell surface, where the peptide-MHC complex is recognized by CD4+ T cells. Therefore, depending on the type of MHC molecule that presents the peptide, the immune system can recognize the intracellular compartment in which the infectious agent is localized and activate different and appropriate effector mechanisms.

T Cell Receptor The antigen receptor of T cells (TCR) is a heterodimer composed of two different transmembrane glycoprotein chains (ex. and ~) bound in a structure that is very similar to the Fab fragment of the immunoglobulin molecules (Fig. 3-8).58 The organization of the gene segments encoding the TCR is very similar to that of immunoglobulins. 39 Each TCR locus consists of variable (V), joining CJ), and constant (C) region genes; the ~ locus also

32

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contains the diversity (D) gene segments. As for immunoglobulins, the different gene segments coding for the variable regions of the TCR are present in multiple copies and undergo a process of gene rearrangement that, if successful, leads to the production of a functional TCR. During rearrangement, TCR genes are recognized by the same enzymes that recognize immunoglobulin genes. A further similarity between immunoglobulin and TCR rearrangements is the random addition of nucleotides at gene segment junctions. Because the TCR recognizes antigen but does not directly mediate the effector function, its constant chain is much simpler than that of immunoglobulins. The TCR recognizes the complex formed by the peptide and the presenting human leukocyte antigen (HLA) molecule. Moreover, T cells recognize and respond to antigens presented by an APC only if that APC expresses MHC molecules that the T cell recognizes as self-in other words, they are self-MHC restricted (see later discussion).40 Although the vast majority of T cells have the a:~ TCR, some lymphocytes have another type of TCR41 consisting of a heterodimer formed by "( and 15 polypeptide chains ("(:15 TCR). Both types are associated with a CD3 complex on the cell membrane. The function of "(:15 T cells is unknown, but they appear to represent a link between innate and adaptive immunity.42 They account for less than 5% of blood T cells; are present in epithelia of the gut, lungs, and skin; and appear to be able to recognize pathogens as well as stress-associated antigens expressed on cell surfaces. Growing evidence supports the possible relevant role of "(:15 T cells in the regulation of immune response at the tissue level.43

Membrane Coreceptors The TCR specifically recognizes the peptide-MHC complex but is independently incapable of activating the T cell. This function is carried out by a complex of pro-

teins-the CD3 complex-which is associated with the TCR on the cell surface. 44 Like the ex and ~ chains associated with membrane immunoglobulin, the cytoplasmic domains of the CD3 proteins contain sequences called ITAM that allow them, after receptor stimulation, to associate with tyrosine kinases and signal to the interior of the cell that antigen binding has occurred (see Fig. 3-8).45 Helper T cells and CTLs are characterized by the presence of the cell sUlface coreceptor proteins CD4 and CD8, respectively. CD4 binds to invariant parts of MHC class II molecules, and CD8 binds to invariant parts of MHC class I molecules. During antigen recognition, the CD molecules associate on the cell membrane with components of the TCR, participate in signal transduction, and bring about a IOO-fold increase in the sensitivity of the T cell to the antigen presented by MHC molecules (see Fig. 3-8).46

Antigen Recognition MHC class I molecules are heterodimers composed of a membrane-spanning ex chain noncovalently linked with ~2-microglobulin. The Il chain has three domains. The III and 112 domains fold together to form a cleft that represents the peptide-binding site. MHC class II molecules are heterodimers composed of two noncovalently joined transmembrane glycoproteins, Il and ~. Each chain has two domains. The III and ~I domains together form the peptide-binding cleft. Unlike antibodies that can recognize both conformational and continuous epitopes on a protein surface, T cells respond only to continuous short amino acid sequences that bind to the cleft of the outer surface of the MHC molecule.47 Because the composition of the MHC peptide-binding cleft is highly polymorphic, different allelic variants of MHC molecules bind preferentially to different peptides. Amino acids that are critical for the binding of a peptide

• Figure 3-8 Structure of the T cell receptor (TCR) complex. The a~ TCR complex of a CD4+ T cell is fonned by one a chain and one ~ chain covalently linked by a disulfide bond.The antigenbinding portion is fonned by the Va and V~ domains.TheTCR is noncovalently linked to the CD3 and ~ proteins. The cytoplasmic domains of CD3 and ~ chain contain one copy of a conserved sequence motif that is important for signaling function, called the immunoreceptor tyrosine activation motif (ITAM). The coreceptor CD4 molecule interacts with nonpolymorphic regions of class II major histocompatibility complex (MHC) molecules at the moment of antigen presentation. The major function of CD4 (and CD8) is to cooperate in signal transduction (together with the TCR) and in Tcell activation.

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to a given MHC molecule (the peptide-binding motif) are called anchor residues. A change in anchor residues may prevent the peptide from binding; on the other hand, peptides with the same anchor residues bind the appropriate MHC molecule, regardless of the sequence of the peptides at other positions. The anchor residues binding a given MHC molecule need not be identical, but they are always related (e.g., aromatic or hydrophobic amino acid,,). Peptides that bind to MHC class I molecules are about 8 to 10 amino acids long; because of the open ends of the peptidebinding cleft of MHC class II molecules, peptides that bind MHC class II molecules are usually longer (13 amino acids or more). MHC molecules irreversibly bind peptides as an integral part of their stmcture and are unstable in the absence of peptides. This phenomenon prevents peptide exchange at cell surfaces, which would impair the efficiency of intracellular antigen recognition. MHC class I and class II molecules have different functions and are differently expressed on cells. MHC class I molecules present peptides to CTLs. Vimses can infect any nucleated cell, and MHC class I molecules are expressed with variable intensity on all cells except erythrocytes. The main function of CD4+ T cells is to activate other cells of the immune system. Therefore, MHC class II molecules are normally present on these effector cells. Class II molecules are also abundant on cells that are able to present antigen to T cells in lymphoid tissues (DCs, B lymphocytes, and macrophages). The expression of MHC molecules of both classes is enhanced by some eytokines (particularly interferons), which can induce MHC class II molecules on several cells that normally do not express them.

Complex intracytoplasmic machinery, which differs for class I and class II molecules, is responsible for the formation and loading of peptides on MHC molecules, as well as the delivery of the peptide-MHC complex to the cell surface. All proteins, including viral proteins, are formed in the cytosol. Proteins, such as the MHC molecules, that must be delivered to the cell surface are translocated into the lumen of the endoplasmic reticulum. For both MHC class I and class II molecules, loading of the specific peptide into the peptide-binding groove occurs in the vesicular system (Fig. 3_9).48,49 The MHC is not only polygenic but also highly polymorphic, because there are multiple alleles of each gene. All MHC class I and class II molecules are able to present antigens to T cells, and each molecule binds a different range of peptides. Diversity is further increased by the fact that, because of the marked polymorphism, most humans are heterozygous at these loci, and the expression of MHC genes is codominant; indeed, both alleles are expressed on the same cell, and both can present peptides to T cells.

Because there are three MHC class I genes and four potential sets of MHC class II genes, a heterozygous person expresses six different MHC class I molecules and eight different MHC class II molecules. For MHC class II molecules, the number of different products may be further increased by the combination of a and ~ chains from different chromosomes. Differences among the various HLA alleles are mainly related to variations in the residues that line the peptide-binding groove and therefore affect the peptide-binding specificity. Because T cells respond to protein-derived peptides, the expression

33

of several different HLA molecules on cell surfaces, each with different peptide-binding motifs, ensures the recognition of at least some of the peptides derived by proteolysis of the antigen. Although there is no response to the antigen in the absence of peptides available for HLA binding, HLA polymorphism extends the range of antigens to which the immune system can respond and makes antigen nonresponsiveness unlikely.<;o Allelic differences among MHC molecules also imply that the immune response against a given antigen may differ among individuals; this is a major factor in the individuality of the immune response. The polymorphism of other genes encoded in the MHC and involved in antigen presentation may also affect the immune response. For instance, the products of the two TAP alleles differ in their capacity to transport peptides; therefore, allelic variations in the TAP proteins can affect the repertoire of peptides available for MHC class I binding. The MHC contains many other genes whose function in the immune response is still not well established or is unknown. Some are induced in response to cell stress and encode the heat-shock proteins, which function as chaperones and are relevant to both adaptive and innate immunity. 51

T Cell Development and Selection T cells originate in the bone marrow and migrate at a very early stage to the thymus, where they undergo TCR gene rearrangement. In the thymus, thymocytes proliferate and mature into T cells through a series of events characterized by rearrangement of the TCR genes and expression on the cell membrane of the TCR, the coreceptors CD4 and CD8, and other surface molecules that reflect the functional maturation of the celp253 Thymocytes enter the thymic cortex and, dUring maturation, migrate from the cortex toward the medulla, coming in contact with epithelial cells, macrophages, and DCs. The medulla contains mostly mature T cells, and only mature CD4+ or CD8+ T cells exit the thymus and enter the blood. A fundamental step in thymocyte maturation (after expression of the TCR, CD4, and CD8 molecules) is the selection of cells that will make up the repertoire of mature T cells in the periphery. Mature T cells recognize only peptides bound to self-MHC molecules. On the other hand, the random generation of TCR can give rise not only to lymphocytes that do not recognize self-MHC molecules (and are therefore useless) but also to lymphocytes that recognize complexes of self-peptides/self-MHC molecules with high affinity (and are therefore potentially harmful). The dual need of selecting only cells that recognize self-MHC molecules and eliminating autoreactive cells is accomplished through processes of positive and negative selection (Fig. 3-10) that occur after the thymocytes have rearranged their a:~ TCR genes.<;4 Evidence from fetal thymic organ cultures suggests that these processes, which shape the future immunologic repertoire, are driven by the differential avidity for self-peptide/self-MHC complexes." Thymoeytes that express a TCR with low but measurable avidity for a self-peptide/self-MHC complex are allowed to

34

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• Figure 3-9 Schematic representation of class I and class II major histocompatibility complex (MHC) pathways of antigen presentation. In the class I MHC pathway, protein antigens in the cytosol are processed (A) by proteasomes, and peptides are transported (8) into the endoplasmic reticulum (ER) by transporter proteins (transporter associated with antigen processing [TAP». In the ER, peptides bind to class I MHC molecules; the stable peptlde-class I MHC complex moves through the Goigi complex (0 and is transported to the cell surface by exocytic vesicles. In the class II MHC pathway, microbes are internalized into phagolysosomes (0) and are enzymatically degraded to generate peptides. Class II MHC molecules are synthesized in the ER (E) and transported to endosomes by exocytic vesicles. The exocytic vesicles transporting class II MHC molecules fuse with the endocytic vesicle containing the processed antigen (F). Thereafter, the MHC class II-peptide complex is transported to the cell surface.

differentiate into mature T cells, whereas immature lymphocytes that express TCRs with no avidity or with strong avidity for selfpeptide/self-MHC complexes die by apoptosis. More than 95% of developing thymocytes are thought to die in the thymus by apoptosis because they do not recognize self-MHC molecules or undergo negative selection. Cells that survive this dual selection process leave the thymus as mature na'ive T cells.

Lymphocyte Activation and Effector Functions T 4'mphocytes

Two Signals Recognition by the TCR of the specific peptide presented in the context of MHC molecules is necessary but not sufficient to activate T cells. To induce cell activation, TCR

recognition must be Simultaneously accompanied by the delivery of a second, costimulatory signal. This may occur when T cells interact with APCs. The activation of T cells on initial encounter with the specific peptide on the surface of an APC (priming) occurs in peripheral lymphoid organs. The initial interaction between naive T cells and APCs is mediated by adhesion molecules. If the naive T cell recognizes its specific peptide-MHC complex on the surface of an APC, signaling through the TCR induces conformational changes in the adhesion molecules that enhance the adhesiveness between the two cells. If no recognition takes place, the T cell dissociates from that APC and samples other APCs. The binding of the TCR and of the coreceptors (CD4 or CD8) transmits a first signal to the cell indicating that the specific antigen has

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35

• fItIu'e 3-10 Processes of thymocyte maturation and selection in the thymus. Precursors ofT cells (CD4-CD8-TCR-) coming from the bone marrow arrive in the thymic cortex, where they mature into pre-T thymocytes (bearing a pre-T cell receptor formed by a ~ chain and a pre-T IX chain). In the ensuing maturation process, thymocytes express a complete Tcell receptor (TCR) together with both CD4 and C08 (double-positive thymocytes). During their migration from the cortex to the medulla, CD4+C08+ thymocytes go through the process of thymic selection. (1) The engagement of thymocyte TCR in a low-affinity interaction with a self-major histocompatibility complex (MHO molecule expressed on athymic epithelial cell rescues it from programmed cell death and allows the progression of thymocyte maturation as a na'ive CD4+ (or CD8+) mature T cell (positive selection). (2) If the thymocyte TCR does not engage in any interaction with peptide-MHC molecule complelles, it will die byapoptosis (lack of positive selection). (3) High-affinity or high-avidity binding between the thymocyte TCR and the peptide-MHC complex expressed by athymic antigen-presenting cell induces the death of the thymocyte by apoptosis (negative selection).

been recognized. The second signal is delivered through specialized molecules called costimulatory molecules,56,57 the best known of which are two structurally related molecules, B7-l (CD80) and B7-2 (CD86). The receptors for B7 molecules on T cells are two similar molecules, called CD28 (which is constitutively expressed on most T cells) and cytotoxic lymphocyte-associated antigen 4 (CTLA-4). Once the first signal has been provided, ligation of CD28 by B7 molecules induces lymphocyte activation. T cell activation also induces the expression on the cell surface of CTLA-4, which has a higher affinity for B7 molecules than CD28 does and delivers a negative signal to the cell, thereby limiting the proliferative response of activated T cells. The CD28/CTLA-4 and B7-1/B7-2 interactions therefore provide a regulation system that ensures that immune responses are turned on when needed and turned off when not needed (Fig. 3-11). A number of additional molecules with costimulatory function have been identified on the membrane of T lymphocytes. One of them, inducible costimulator (lCOS), presents many homologies with CD28 and its ligand is highly homologous to B7-l and B7-2. ICOS is thought to be important for stimulating the production of certain eytokines, such as IL-lO. In the same way, molecules other than CTLA-4, such as programmed death-l (PD-l), provide a negative signal for T cell activation in peripheral tissues. 5H

Approximately 100 specific peptide-MHC complexes are required on a target cell to trigger a T cell. Then, TCR aggregation initiates the events that lead to T cell activation. One of these events involves a cytoplasmic phosphatase, calcineurin, which activates nuclear activation factor of T cells (NAFT), which in turn binds to the promoter region of the IL-2 gene and is necessary to activate transcription. Because NAFT is a T cell-specific factor, blockade of the signaling pathway leading to NAFT is a way to specifically inhibit the T cell response. Both cyclosporin and FK506 inhibit calcineurin and therefore prevent the activation of NAFT. T cell activation leads to a 100-fold increase in IL-2 production, to the expression of anti-apoptotic proteins of the Bcl family, and to synthesis of the a chain of the IL-2 receptor. Resting T cells express a low-affinity IL-2 receptor composed of a ~ and a y chain. The association of the a chain with the ~ and y chains generates a receptor with a much higher affinity. Interaction of IL-2 with its receptor activates cell proliferation, which leads to the production of many T cells, all bearing an identical TCR (clonal expansion). Activation also induces the expression of CD40 ligand (CD40L) on T lymphocytes. 59 CD40L specifically binds to the CD40 molecule constitutively expressed on APe. This interaction induces and sustains the further activation of APC. This latter mechanism plays a pivotal role in the activation and differentiation of B

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• Rgure 3-11 Mechanisms of T cell activation and the regulatory role of cytotoxic lymphocyte-associated antigen 4 (CTLA-4). A, Adhesion molecules are involved in the interactions between T cells and antigen-presenting cells (APCs). ICAM, intracellular adhesion molecule 1; LFA. leukocyte function-associated antigen. 8, Cross-linking of C028 delivers the costimulatory signal for Tcell activation and Induces the expression of C040 ligand (C) and CTLA-4 (D). See text for further explanations.

cells during the response to protein antigens (see later discussion). Once activated, CD4+ T lymphocytes can differentiate into either Thl or Th2 cells (see later discussion). Na'ive CD8+ T cells, because of their highly destructive effects, are kept under strict control and require high levels of costimulatory activity to be activated by APCs. 60 The delivery to the na'ive T cell of the first signal alone not only fails to activate the cell but also induces a state of unresponsiveness (anergy) in which the T cell is refractory to activation. The most important change induced in anergic T cells is their inability to produce IL-2. The need of the second costimulatory signal for T cell activation and the fact that this signal is provided only by APCs is important in preventing autoimmune diseases, hecause not all potentially self-reactive T cells are deleted in the thymus.

Antigen-Presenting Cells There are three main types of APCs: macrophages, DCs, and B cells. Macrophages normally express few MHC class II and no B7 molecules on their surface. Both molecules are expressed when macrophages engulf microhial constituents and are activated. As already noted, APCs have a number of receptors for common microbial constituents, which allow the immune system to distinguish antigens that are derived from infectious agents from those derived from innocuous proteins. 61 Antigens derived from infectious agents, but not those associated with innocuous proteins, induce costimulatory molecules. Indeed, innocuous proteins administered in conjunction with bacterial products (the so-called adjuvants) may elicit an immune response because bacterial prod-

ucts induce costimulatory activity in APCs that have ingested the protein. Experimental autoimmune diseases are also induced in susceptible animals by the administration of antigens mixed with bacterial adjuvants, a phenomenon that underscores the importance of costimulatory activity in the process of selflnonself discrimination. Not all infectious agents effectively induce MHC class II and costimulatory molecules on the surface of macrophages. This is particularly tme for viruses that replicate inside the cell. DCs, which constitutively express large quantities of MHC class II and costimulatory molecules, are thought to have a major role in presenting viral peptides to na'ive T cells and in priming both CD4+ and CD8+ T cells. 62 B cells also internalize soluble antigens bound to their surface immunoglobulins; peptide fragments generated from these antigens are displayed on the cell surface in association with constitutively expressed MHC class II molecules. 63 This is the pathway by which B cells can be the target of antigen-specific CD4+ helper T cells.

T Cell Receptor Degeneracy The same TCR may be activated by different peptides that share relatively little primary sequence homology (TCR degeneracy).64 Unlike the case with antibodies, there is no affinity maturation process that improves the fit of a TCR for a given peptide-MHC molecule complex during an ongoing immune response. The specificity of the TCR repertoire most likely represents a balance between two possible extremes: highly specific TCRs and highly degenerated TCRs. The former recognize partiClIlar amino acids at many positions of the MHC-bound

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peptide; the latter recognize only certain sequence features and therefore may cross-react, although with different degrees of affinity, with many different micro1;>ial peptides, The highly specific TCR has a low probability of meeting its corresponding antigen and may never be eng'lged in the immune response; the highly degenerated TCR has a higher probability of being engaged but may also theoretically cross-react with self-peptide and induce an autoimmune response. 65 TCR engagement by different peptide ligands may lead to different functional outcomes that depend on whether the peptide acts as an agonist, partial agonist, or antagonist. Indeed, the functional consequences of T cell antigen recognition may vary depending on the nature of the peptide that contacts the TCR. It has been shown that peptides in which one or two TCR contact residues have been changed (known as altered peptide ligands, or APL<;) induce only a subset of the functional changes induced by the wild-type peptide or may even induce a state of T cell anergy that prevents response on secondary exposure to the wild-type peptide. The APLs appear to induce different intracellular pathways with respect to those induced by the usual T cell activation. These differences may depend on differences in affinity or conformational changes of the TCR. By these mechanisms, antigen receptors may translate quantitative differences in ligand binding into qualitatively different biolOgic responses. 65 T cell anergy may therefore be induced not only by antigen recognition in the absence of costimulation but also when, despite the availability of adequate costimulation, the antigen receptor signal is suboptimal-for example, when a T cell encounters an APL that does not optimally bind to the TCR. APLs have been successfully used to prevent experimental autoimmune diseases.6(,

Superantigens Some products of bacteria, mycoplasmas, and viruses induce a potent polyclonal and potentially harmful immune response. These superantigens bind to the outer surface of both the MHC class II molecules and the V~ region of the TCR, outside the peptide-binding site, and lead to T cell activation. 67 Each superantigen may activate all the T cells that express a particular set or family of Vp TCRgenes. This stimulation does not prime an adaptive specific immune response against the pathogen but may cause massive production of inflammatory cytokines such as IL-l and TNF and may lead to septic shock, the most severe cytokine-induced complication of infection by gram-negative and some gram-positive bacteria. Bacterial superantigens include the staphylococcal enterotoxins, the most common cause of food poisoning in humans, and the toxic shock syndrome toxin 1.

Effector Functions of Helper T Cells The Thl and Th2 subsets of helper T cells are distingUished on the basis of the cytokines they produce: IL-2, IFN-y, and TNF for Thl cells and IL-4, IL-5, IL-I0, and IL13 for Th2 cells. 68 ,69 It is increasingly evident, however, that many T cells cannot easily be classified as Thl or Th2

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and that some (called ThO) have a heterogeneous pattern of cytokine secretion, Nevertheless, the differentiation of naIve CD4+ T cells into either Thl or Th2 cells appears to be a fundamental step for the subsequent evolution of the immune response, Production of Thl cells induces cellmediated immunity; production of Th2 cells leads to humoral immunity, a phenomenon that profoundly influences disease outcome, as exemplified by infections with intracellular pathogens such as leprosy. Mycobacterium leprae grows in macrophage vesicles, and effective host defense requires macrophage activation by Thl cells. In patients with tuberculoid leprosy, which is characterized by a predominantly Thl response, the infection is controlled and the patient usually survives. In lepromatous leprosy, which is characterized by a predominantly Th2 response, the main response is represented by antibody production; these antibodies cannot kill the intracellular bacteria, and the patients eventually die.

Helper T Cell Differentiation Mechanisms controlling helper T cell differentiation involve several factors, including the type of cytokines released at the time of antigen presentation, the amount and sequence of the antigenic peptide, and possibly the nature of the APC. 70 IL-12 and IL-23, the most important cytokines that stimulate the development of Thl cells, are produced by macrophages and NK cells. IFN-y, which is produced by macrophages, NK cells, and Thl cells themselves, enhances IL-12 secretion by macrophages, probably has a direct Thl-inducing effect, and inhibits the development of Th2 cells, IL-4, produced by Th2 cells, stimulates Th2 development. Both IL-4 and IL-1O inhibit the generation of Th1 cells. It has been hypothesized that activated CD4 cells produce small amounts of IL-4, which leads to Th2 differentiation, unless they are counteracted by the presence of Thl-inducing cytokines. The differing capacity of pathogens to interact with macrophages and NK cells may therefore influence the overall balance of cytokines produced early during the immune response and thus determine the preferential development of Th1 or Th2 cells. The intracellular signals that regulate Th1 or Th2 conunitment of CD4+ T cells have been the subject of intense investigations. During antigen presentation in secondary lymphoid organs, the regulatory cytokines IL-12 and IL-4 playa critical role in the orientation of the functional phenotype, through the activation of signal transducer and activator of transcription 4 CSTAT-4) or STAT-6 signaling pathways, respectively71 (Fig, 3-12). Differentiation signals regulate the expression of critical tissuespecific transcriptor factors, which further specify the Th1 or Th2 orientation through regulation of chromatin structure and accessibility of cytokine genes, The Th1-restricted transcription factor, T-bet, directly transactivates the ifng promoter and induces remodeling of the ifng locus,n Conversely, the Th2restricted transcription factor, GATA-3, is responsible for the induction of chromatin remodeling at the Th2 cytokine locus acting on several control sequences, including Il4. 73 The ability of T-bet or GATA-3 to induce remodeling at the corresponding loci suggests that modification in chromatin structure underlies the acquisition of heritable competence to transcribe the Th1 or

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• Rlllre 3-12 Development of Thl and Th2 effector T cells. Cytokines produced In the innate immune response to microbes or early in adaptive immune response influence the differentiation of na'ive CD4+T cell into Th 1 and Th2 cells (see text for explanations). Cytokines produced by Thl cells inhibit the development of Th2 cells and vice versa (dashed arrows). For sake of simplicity. other cytokines produced byThI (interleukin-2 (Il-21. tumor necrosis factor-a, Iymphotoxin) and Th2 (ll-5, Il-IO, Il-13) are not shown.

Th2 cytokines. 74 DCs may function as distinct subsets able to provide T cells with selective signals leading to either Thl or Th2 responses. 12 •70 Each T cell subset produces cytokines that serve as autocrine growth factors and promote differentiation of naIve T cells to that subset. Moreover, the two subsets produce cytokines that cross-regulate each other's development and activity (see Fig. 3-12). Indeed, as previously mentioned, IFNy produced by Thl cells amplifies Thl development and inhibits proliferation of Th2 cells, whereas IL-4 and IL-IO produced by Th2 cells blocks activation of Thl cells and suppresses numerous macrophage responses. Thl and Th2 cells may be interconvertible early in their development and, in some cases, also in the late phases of the immune response. 7S Also, CD8+ T cells can respond to antigen by secreting cytokines typical of either Thl or Th2 cells. Thl and Th2 cells express different chemokine receptors 76 and therefore can be differentially attracted to the site of inflammation (see later discussion). For these reasons, chemokine receptor antagonism appears to be a promising approach for future treatment of autoimmune and allergic disorders.

Thl andTh2 Effector Functions Thl cells are important activators of macrophages; Th2 cells are the most effective activators of B cells, particularly in primary responses (Fig. 3-13). The principal Thl effector cytokine is 1FN-y, which display two main functions: it activates macrophages to destroy microbes, and it stimulates the production of 19G antibody subclasses that bind to complement and high-affinity Fey receptors and are the principal antibodies involved in microbe

opsonization and phagocytosis. An additional mechanism of macrophage activation is represented by the expression on Thl cells of CD40L, which activates the CD40 molecule on the surface of macrophages. Activated macrophages undergo several changes that augment their antimicrobial capacity and potentiate the immune response (e.g., upregulation of B7 molecules, further IL12 secretion).6H.69 Thl cells also are fundamental in recruiting macrophages to the site of infection. This occurs through the secretion by Thl cells of several additional cytokines, including (1) 1L-3 and granulocyte/ macrophage colony-stimulating factor (GM-CSF), which stimulate the production of new phagocytic cells in the bone marrow; (2) TNF-a, which induces the expression of adhesion molecules on endothelial cells; and (3) macrophage chemotactic factor (MCF) and other chemokines that direct the migration of macrophages from the endothelium to the site of infection (see later discussion). Many autoimmune disorders (e.g., rheumatoid arthritis, Crohn's disease) are characterized by infiltration and activation of Thl lymphocytes in the inflamed tissues. Th2 cells induce the production of IgM and non-complementfiXing IgG subclasses. The Th2 cytokine IL-4 induces a B-cell switch to IgE production, and IL-5 is the principal cytokine that activates eosinophils. Th2 cells typically mediate the immune response to helminths, stimulating the production of specific IgE antibodies that opsonize the parasites. Eosinophils activated by IL-S bind to IgE-coated helminths, through Fc receptors specific for e heavy chain, and release their granule contents. The same mechanism of activation via IgE is also the

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• figure 3-13 Effectorfunction of hel~r T cells (Th I and Th2). Cytokines produced by Th I cells act on phagoeytes to increase phagocytosis and kllling. Interferon-y (IFN-y) also stimulates Bcells to produce immunog.lobulin G(lgG) antibodies that opsonize cells for phagocytosis. Interieukin-2 (IL-2) acts as a growth factor for Thl proliferation. LT, Iymphotoxin; TNF, tumor necrosis factor. Cytoldnes produced byTh2 cells (IL-4 and IL-l3) stimulate production of IgE antibodies, which bind to mast-cells during an allergic response. IL-4 represent also an autocrine growth factor for Th2 cells. IL-S activates eosinqphils, playing a pivotal role in the response against helminthic infections. IL-IO produced by Th2 cells (dashed alTOw) inhibits macrophage activation.

cause of mast cell degranulation in the immediate hypersensitivity immune response in allergic diseases. 68 .69

Another net result of Th2 activation is to inhibit Thlmediated inflammation through the release of antiinflammatory cytokines. IL-4 and IL-13 antagonize the macrophage-activation effect of IFN-y, IL-lO suppresses various macrophage responses, and TGF-~ (produced by some Th2 cells and by the Treg cell) inhibits leukocyte proliferation and activation. The Th2 response therefore limits the potentially dangerous consequence of uncontrolled Thl-mediated immunity. The possibility of downmodulating the Thl response through enhancement of the natut'al regulatory function of Th2 cytokines is an attractive therapeutic target in many Thl-mediated diseases. 68.69

Effector Functions of Cytotoxic T Cells CD8+ CTLs are required to eradicate intracellular microbes. After recognition of a specific class I MHC-associated antigen and subsequent activation, CTLs deliver their cytoplasmic cytotoxic granule proteins (perjorin and granzymes) to the target cell (Fig. 3-14),77 Perforin, which is also present in NK cells, has the capacity to polymerize in the lipid bilayer of the target cell membrane, thus forming an aqueous channel. Granzymes are serine proteases that enter the target cell through the perforin-induced channels and activate intracellular enzymes, called caspases, that play a pivotal role in the induction of programmed cell death (apoptosis). Activated CTL'! may also induce apoptosis through cell surface expression of the Fas ligand (FasL), which binds to and activates Fas on the cellular surface of target cells (see later discussion).

B Lymphocytes In addition to the binding of surface immunoglobulin (the antigen receptor) to its specific antigen, a second signal is required to activate B cells. The second signal is usually delivered by an already-primed CD4 cell (for thymusdependent [TD] antigens). In other cases, the second signal is provided by the pathogen itself (thymUS-independent [TI] antigens).

Thymus-Independent Activation The so-called TI antigens78 are nonprotein antigens that stimulate antibody production in athymic persons. The most important TI antigens are polymeric polysaccharides or glycolipids present in the bacterial cell wall. They induce maximal cross-linking of membrane immunoglobulins, leading to activation of B cells without the requirement of T cell help. Moreover, many polysaccharides activate the alternative pathway of complement system, generating C3d, which binds to the antigen and provides the second signal to the B cell receptor complex (Fig. 3-lSA). Antigen activates the signaling cascade by cross-linking the surface immunoglobulin molecules and therefore bringing receptor-associated tyrosine kinases (Fyn, Blk, and Lym) together with the ITAMs they phosphorylate. When phosphorylated on tyrosine, the !TAMs are recognized by cytoplasmic molecules that activate a cascade of events resulting in cell activation. Surface immunoglobulin function is also modulated by a membrane coreceptor complex, the CR2-CD19CD81 complex (see Fig. 3-1 SA). Coligation of the surface immunoglobulins with this coreceptor complex greatly increases the efficiency of cell activation. CR2 is a

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• Figure 3-14 Effector functions of cytotoxic CD8+T cells (CTLs). A, After recognition of a spedfic class I MHC-associated antigen and subsequent activation, CTLs deliver their cytoplasmic cytotoxic granule proteins (perforin and granzymes) to the target infected cell. Perforin polymerizes the lipid bilayer of the target cell membrane, thus forming an aqueous channel. 8, Granzymes enter the target cell through the perforin-induced channels and activate the caspase cascade, indudng programmed cell death (apoptosis). C, Antigen-spedfic CTL is now ready to recognize and kill another adjacent infected cell.

receptor for the complement protein C3d. Therefore, as for T cell activation, the innate immune response provides signals that are essential for B cell activation. In most instances, however, the activation of B cells requires the presence of other additional signals, the most important of which is delivered by helper T cells that recognize antigen on the surface of B cells. Antibodies produced in the absence of T cell help are generally of low affinity and consist mainly of IgM because of a lack of T-mediated isotype switching processes. The antibody response to TI antigens occur mainly in the marginal zones of lymphoid follicles of the spleen. In this site, macrophages are particularly efficient at trapping polysaccharides.

Thymus-Dependent Activation Antibody responses to protein antigens require antigenspecific T cell help.79 Antigen-specific helper T cells must therefore have been primed earlier during the course of the immune response. B cells internalize the antigen bound to their surface immunoglobulin, degrade it, and present peptides on the cell surface in association with MHC class II molecules for recognition by specific helper

T cells (see Fig. 3-15B). The two cells do not need to recognize the same epitopes. What is crucial is that the epitope recognized by the T cell is part of the antigen that has been recognized and internalized by the B cell; this allows the B cell to present on the cell surface the peptide to which the T cell is specific. This linked recognition explains the immune response to the so-called haptens, small chemical groups that are unable to elicit an immune response because they are not recognized by T cells. However, haptens coupled to a protein can elicit an immune response, because T cells recognize the protein-derived peptides and provide the necessary help. This phenomenon is responsible for antibody production against substances such as penicillin that interact with host proteins and become able to induce an immune response.

B CellfT Cell Interactions The functional interaction between T and B cells take place in peripheral lymphoid organs (lymph nodes, spleen, mucosal immune system).79 Naive lymphocytes enter lymph nodes through the high endothelium venules (HEVs) (Fig. 3-16). In lymphoid organs, na'ive B

• Figure 3-15 Thymusindependent (A) and thymus-dependent (8) activation of B cells. See text for explanations. CD40L, ligand for (040; CR, complement receptor; ITAM, immunoreceptor tyrosine activation motif; TRAF,TNF receptor-associated factor.

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• FI...... 3-16 Tcell and Bcell interactions in a lymph node (schematic representation).The cortex consists 01 an outer cortex (B cell zone) consisting 01 B lymphocytes organized into lymphoid follicles and some follicular dendritic cells (FOC). A deep or paracortical area (T cell zone) is composed mainly ofT lymphocytes and dendritic cells (DC).The medulla consist of strings of macrophages and plasma cells. A, Experimental models show that 1 to 2 days after antigen administration antigen is captured and processed by DCs present in the T cell zones. Na'ive T cells continuously recirculate through lymph nodes via high endothelial venules (HEY).Those Tcells whose receptors bind peptides derived from the antigen presented by DCs are trapped in the Tcell zone. Bcells recognize antigen in the primary follicle and are activated. Antigen-stimulated B cells move toward the Tcell zone. 8, At the border between T and B cell zones, antigen-specific lymphocytes proliferate, establishing a primary focus. Some proliferating Bcells differentiate into short-living, antibody-secreting plasma cells, which migrate to the spleen or to the medulla of the lymph node. Other antigen-specific Bcells migrate into primary lymphoid follicles, where they continue to proliferate (centroblasts). C, The germinal center is composed mainly of proliferating Bcells, FOCs, and a few helper Tcells. Centroblasts are closely packed in the dark zone (OZ). Later, they move into the so-called light zone (lZ), where they come in contact with a dense network of FOCs, mature into centrocytes, and express high levels of surface immunoglobulins. Germinal center B cells undergoV-region somatic hypermutation, which improves their affinity for antigen. B cells that lose their ability to bind the antigen die by apoptosis.Those with the highest affinities move to the outer edge of the LZ, where helperT cells expressing CD40 ligand are concentrated. Some germinal center cells differentiate into plasmablasts and then into plasma cells, which migrate to the bone marrow, where a subset provides a source of long-lasting, high-affinity antibody. Other germinal center cells differentiate into memory Bcells.

and T cells are anatomically segregated but are induced to migrate toward one another after activation with antigen. T lymphocytes recognize antigens presented by APC in the T cell zone; once activated, they reduce the expression of CCR7, the chemokine receptor produced in the T cell zone, and start to move. B lymphocytes recognize antigens in the follicles; once activated, they increase the expression of CCR7 and start migration to the T cell zone. The encounter between antigen-stimulated Band T cells occurs, therefore, at the interface of the follicles and the T cell zone. Recognition of the specific peptide-MHC complex on the surface of B cells activates T helper cells to express the cell surface molecule CD40L and secrete cytokines. The interaction between CD40L expressed on activated helper T cells and CD40 constitutively expressed on B cells leads to further activation of B cells. This mechanism, common also to other interactions between T cells and APCs, is particularly important for the activation and differentiation of B cells in a TD response (see Fig. 3-15B). The interaction with CD40L leads to the oligomerization of CD40 molecules. This induces the association of cytoplasmic proteins (TNF receptor-associated factors, or

TRAFs) with the cytoplasmic domains of CD40, initiating the enzymatic cascade that leads to the activation of transcription factors such as nuclear factor-KB (NF-KB) and activation protein-l (AP-l). These intracellular events play also an important role in the induction of isotype switching,80 a DNA recombination process during which the same variable region of the clonally expanded B cell is associated with different constant regions. B cells initially express IgM and IgD; later in the immune response, the same variable region may be associated with other constant portions, giving rise to IgG, 19A, or IgE. Unlike variable-gene segment recombination, switch recombination occurs only after antigen stimulation and not during B cell development. B cells undergo isotype switching to express transmembrane immunoglobulins of a different isotype before initiating the production of the secreted corresponding antibody. The second T helper-dependent mechanism of B cell activation and differentiation is related to the production of cytokines by activated T cells. Cytokines play two principal functions in antibody response: They increase the proliferation of B cells, and they promote the switch of immunoglobulin classes. Three different T-derived

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cytokines (IL-2, IL-4, and IL-5) are known to enhance B cell proliferation; moreover, IL-6 produced by activated T cells and macrophages acts as an important growth factor on already differentiated and antibody-secreting B cells. IL-4 preferentially induces switching to IgE. TGF-~ induces switching to 19A, whereas IL-5 augments 19A production by cells that have already undergone switching. Although Thl cells are poor inducers of antibody production, the release of IFN-y induces switching to the IgG3 subclass that binds to high-affinity Fey receptors and complement.

and spleen migrate to the bone marrow; those originating from the mucosa-associated lymphoid tissue migrate to the lamina propria of epithelial surfaces. Plasma cells are terminally differentiated B cells that produce immunoglobulins, no longer interact with helper T cells, and are unable to change isotypes or undergo somatic hypermutation. Germinal centers last about 3 to 4 weeks after the supply of extrafollicular antigen is exhausted. Small numbers of B cells continue to proliferate in the follicles for months.

Effector Functions of Antibody-Mediated Immunity Affinity Maturation and Generation of Plasma Cells: The Germinal Center Reaction B cells that have been activated by T cells follow one of two patterns. Some migrate to the medullary cords and differentiate into short-lived plasma cells secreting IgM or IgG, thus providing an early immune response. Others migrate together with the specific helper T cells into the primary follicles, where they divide and form germinal centers (see Fig. 3-16).81 Primary follicles contain resting B cells clustered around a network of processes that extend from a specialized cell, the follicular dendritic cell, which plays a central role in the selection process during an antibody response. Although they have similar morphology, follicular dendritic cells (FDCs) are unrelated to the DCs that present antigens to the T cells. They are not derived from the hematopoietic stem cell, lack MHC class II expression, and express membrane receptors for complement and the Fc portion of immunoglobulins. FDCs play an important role in driving the maturation of the humoral immune system through their capacity to bind antigen-antibody complexes by their Fc receptors and to retain antigens on their surface for long periods. The early antibodies secreted by B cells of the medullary cord not only provide early protection but also trap antigen, in the form of immune complexes, on the surface of FDCs. Selection of B cells with surface immunoglobulins of the highest affinity for the antigen occurs at the surface of FDCs (see Fig. 3-16). B cells that lose their ability to bind the antigen die by apoptosis. On the contrary, those with the highest affinity move to the outer edge of the zone where helper T cells expressing CD40L are concentrated. Interaction with helper T cells induces B cells to become plasma cells or memory cells and prevents the selection of B cells that have acquired selfreactivity during somatic hypermutation. Other surface and soluble molecules, produced by cells other than T cells (DCs, macrophages, and monocytes), have been shown to playa fundamental role in the survival and maturation of B cells. One of these molecules is Bcel~activating factor of TNF family (BAFF). Notably, BAFF-deficient mice lack a mature B cell compartment, and BAFF overexpression has been suggested as a possible crucial mechanism for B cell hyperplasia in many autoimmune diseases. 82 Some B cells leave germinal centers as pre-plasma cells (plasmablasts) and migrate to distant sites, where they are supposed to differentiate into plasma cells with a long life span. 83.84 Those originating from lymph nodes

The first humoral response is characterized by the production of low-affinity IgM, which neutralizes microbes and circulating microbial toxins, blocking their binding to the host cellular receptors. IgG is the principal immunoglobulin in the blood and extracellular fluid, whereas 19A is the principal immunoglobulin in mucosal secretions. The different immunoglobulin isotypes have distinct properties that enable them to induce different effector mechanisms (see Table 3-8).85 Antibodies can activate a variety of effector cells that bear a receptor for their Fc portion. 86 Fc receptors are a family of related molecules with different affinities for different isotypes; the isotype determines which effector cell is preferentially activated (Table 3-9). Only Fc portions of immunoglobulins that have interacted with their antigens can activate Fc receptors. This occurs because of aggregation of immunoglobulin on the pathogen surface or because of conformational changes in the Fc portion occurring after antigen binding, or both. Antibodies coat (opsonize) the surface of microbes. The recognition of antibodies by Fc receptors on phagocytes triggers phagocytosis and killing of the opsonized microbes (see Fig. 3-2). Fc receptors may also activate mast cells, basophils, and eosinophils. Through their action, Fc receptors on NK cells and eosinophils may initiate antibody-dependent cellular cytotoxicity (ADCC) of antibody-coated infected cells and destroy them (see Fig. 3-50. Binding of antibodies to Cl is an important mode of complement activation (see Fig. 3-6).

Immunologic Memory Immunologic memory allows rapid and effective response to antigens that have been encountered previously and represents the presence of an already clonally expanded population of specific lymphocytes. These responses are called secondary, teniary, and so on, depending on the number of antigen exposures. Several hypotheses have been proposed to explain immunologic memory. It may depend on the persistence of long-lived lymphocytes in a resting state. Alternatively, lymphocytes activated by the original exposure to antigen may be restimulated repetitively by a small amount of persistent antigen (possibly at the level of FDCs), by stimulation with cross-reactive antigens, or by the release, during subsequent immune responses to other antigens, of soluble mediators that restimulate memory cells. 87-89

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fl Receptors

Receptor

Structun

Cell Type

III Binding (affinity)

Function

FcyRI (CD64)

Two subunits: a chain (72 kD, CD64), Ychain (9 kD)

IgGI, IgG3 (10-" kD)

Activation of phagocytes and phagocytosis

FcyRIIA (CD32)

a chain (40 kD) with a y-Iike domain

IgGI (10-7 kD)

Phagocytosis

FcyRIIB (CD32) FcyRIIIA (CDi6) FCEIU

a chain (40 kD) with an ffiM domain Two subunits: a chain (50 kD), Ychain Three subunits: a chain (CD64), ~ chain 03 kD), y chain (9 kD) Two subunits: a chain (55 kD, CD89), Ychain (9 kD)

Macrophages Neutrophils Eosinophils Dendritic cells Macrophages Neutrophils Eosinophils Platelets B cells Mast cells Natural killer cells

IgGI, IgG3 00-7 kD)

Inhibition of activation

IgGI, IgG3 00-6 kD) IgE (10- 10 kD)

Antibody-dependent cell mediated cytotoxicity Cell activation (degranulation)

IgAI, IgA2 (10-7 kD)

Cell activation

FcaR (CD89)

Mast cells Basophils Eosinophils Macrophages Neutrophils Eosinophils

CD. cluster of differentiation: Ig, immunoglobulin: 111M, immunoreceptor tyrosine-based inhibition motif.

BCells Secondary antibody responses due to the stimulation of memory B cells differ in several aspects from primary immune responses. Memory cells not only have been clonally expanded but also have undergone somatic mutation, affinity maturation, and isotype switching. The antibody response is therefore more intense, and it is mainly high-affinity IgG. Secondary and subsequent responses lead to increasing affinity of antibody by a mechanism that is similar to that observed in a primary response and based on further somatic hypermutation and selection by antigen on FDCs in germinal centers. The first explanation offered for the maintenance of immunologic memory suggested the existence of long-lived plasma cells surviving in bone marrow. 90 However, their half-life is calculated to be at most 3 months, and it is unlikely that they are able to maintain a constant production of specific antibodies over a human lifespan. Memory B cells can survive in secondary lymphoid organs in the absence of antigen and mediate secondary immune response on restimulation. 91 Moreover, there is evidence that memory B cells also maintain serologic memory by undergoing continuous polyclonal activation. 92

TCells Long-lived effector T cells are difficult to distinguish from memory cells. The identification of memory T cells rests largely on the existence of a population of cells that have the surface characteristics of activated effector T cells but are distinct from them in that they require additional stimulation before acting on target cells. Changes in three cell surface proteins-L-selectin, CD44, and CD45-are particularly significant after exposure to antigen. L-selectin is lost on most memory cells, whereas CD44 levels increase on all memory cells and CD45 changes from a high- to a low-molecular-weight isoform (CD4SRA and CD45RO, respectively). These changes are characteristic of all activated effector T cells, yet some of the cells in which these changes occur have many char-

acteristics of resting T cells, suggesting that they are memory CD4+ T cells. The chemokine receptor CCR7 is a marker of memory T cell differentiation. According to Sallusto and coworkers,93 under physiologic conditions, memory T cells in secondary lymphOid organs are CCR7+ and express L-selectin at high levels; these cells have been defined as "central memory" T cells. 93 Conversely, memory T cells lacking CCR7 express low levels of L-selectin and high levels of integrins, a phenotype consistent with migration and tissue homing. CCR7- memory T cells are enriched for effector cells capable of producing large amounts of cytokines, as opposed to CCR7+ central memory T cells, which are poor cytokine producers. 93.94

Regulation of Lymphocyte Activation (Immune Homeostasis) During a normal immune response, after the eliciting foreign antigen has been eliminated, the immune system must terminate its activation and return to a state of rest. Moreover, because lymphocytes bearing receptors capable of recognizing self-antigens are generated constantly, the immune system must be able to prevent or abort potentially self-reactive responses. Several mechanisms, only partly understood, fulfill these control functions (Fig. 3-17),95 and their disruption may lead to autoimmune reactions. A number of the possible control mechanisms have been already described for T cells. For example, CTLA-4 appears 3 or 4 days after T cell activation and has a much higher affmity for B7-1 and B7-2, the same ligands on APCs of the T cell-activating CD28 molecule (see also Fig. 3-11). Thus, CTLA-4 is an important mechanism for the physiologic termination of T cell activation; disruption of the CTLA-4 gene in mice results in massive accumulation of activated lymphocytes in lymph nodes and spleen and inftltration of tissues by activated lymphocytes. 96,97 Cytokine counter-regulation is another important mechanism of T lymphocyte homeostasis. Th2 cytokines

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• Rgure 3-17 Regulation of lymphocyte activation (immune homeostasis). See text for explanations. APC, antigen-presenting cell; IL, FasL, ligand for Fas; interleukin; MHC, major histocompatibility complex;TCR, T cell receptor; TGF, transforming growth factor.

OL-4, IL-13) inhibit macrophage activation and therefore control Th1-mediated immunity. Conversely, IFN-y, released by Th1 cells, inhibits IL-4-stimulated B-cell switching to IgE (see Fig. 3-12). Therefore, cytokines released by different T cell populations suppress different types of immune responses. Regulatory T cells (Treg) suppress or downmodulate T lymphocyte activation via the release of suppressive cytokines such as TGF-~ or IL10,98 or through direct cell-to-cell contact. Although IL-2 is an important T-cell growth factor that stimulates clonal expansion of antigen-stimulated lymphocytes, mice lacking IL-2 or the a or p chain of the IL-2 receptor develop lymphadenopathy and various manifestations of autoimmunityy9-101 This suggests that, although the function of IL-2 as a growth factor can be supplanted by other cytokines, IL-2 is part of a necessary feedback mechanism that controls lymphocyte responses, mainly through the induction of cell death for apoptosis with a pathway called activation-induced cell death. 95 ,102 Important mechanisms of regulation are also involved in humoral immune responses. Antibodies inhibit B cell activation by forming antigen-antibody complexes that bind simultaneously to Fey receptor II (FcyRIIB) and to antigen receptors of B cells. The cytoplasmic tail of FcyRIIB (see Table 3-9) contains the immunoreceptor tyrosine-based inhibition motif (ITIM) that mediates negative signals to B cells.

Apoptosls On exposure to antigen, clonal expansion of specific T and B lymphocytes increases their frequency by more than lOOO-fold within 1 week. After 1 to 3 months, the number of specific lymphocytes returns to baseline levels, leaving long-lived, functionally quiescent memory cells. This rapid decline in antigen-specific lymphocyte numbers results from apoptosis.

Apoptosis occurs by two main pathways (Fig. 3-18). Lymphocytes that are deprived of survival stimuli, such as costimulators and cytokines, lose expression of specialized anti-apoptotic proteins, mainly belonging to the Bcl familY,103 and die "by neglect." This mechanism leading to apoptosis, called passive cell death, is probably the most important mechanism that downregulates the immune response once the eliciting antigen has been eliminated and the innate immune response subsides. The stimuli that maintain quiescent and viable naive cells and memory cells are probably sufficient to maintain the expression of anti-apoptotic proteins and therefore to prevent cell death. Passive cell death differs from activation-induced cell death, in which apoptosis is actively induced, although both share the same terminal biochemical pathway. Activation-induced cell death104.105 is important in preventing uncontrolled T cell activation and as an effector mechanism of CD8+ cns and NK cells. It results from the interaction of two molecules that are coexpressed on activated cells: the surface receptor Fas (CD95) and its ligand (FasL or CD95L). Fas belongs to a family of proteins that includes TNF receptors (TNF-R) I and II and the B cell-activating molecule CD40. This family of proteins dictates signals that can induce cell survival and proliferation or apoptotic death. Activated, mature T cells express both Fas and FasL. Their interaction induces a series of intracellular events that lead to apoptosis. These events are initiated by the cytoplasmic region of Fas, which contains a sequence called the death domain and involves a proteolytic system, the central component of which is represented by a family of proteases called caspases. 106 The activation of TNFRI probably triggers a pathway of events similar to those triggered by Fas activation. The expression in the cell of

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• fIIure 3-18

Pathways of apoptosis. A, Activation-induced cell death mediated by the interaction between Fas and Fas ligand. The intracellular death domains of Fas receptors bind acytosolic death dornahH.ontaining adapter called Fasassodated death domain (FADO). FADD binds and activate pro-caspase 8 (or caspase 10), which activates the effector caspase cascade, with the final activation of the caspase being activatable DNase (CAD), which is present in cytoplasm in inactive form, termed (O-CAD. Thereafter, CAD enter the nucleus and deaves DNA. 8, Intracellular mechanisms of programmed cell death. If the cells are deprived of necessary survival stimuli, the result is a rapid increase in permeability of mitochondrial membranes and release of cytochrome Co This event is allowed by the inactivation of anti-apoptotic proteins of the Sd family. Cytochrome c acts as a cofactor with activating factor-l (APAF-l), which, together with a caspase recruitment domain (CARD), activates pro-caspase 9, with the consequent further activation of the effector caspase cascade.

anti-apoptotic proteins (such as those belonging to the Bel family) protects against passive cell death but does not prevent activation-induced apoptosis. Fas appears to be a major mediator of apoptosis in CD4+ T cells; apoptosis induced by TNF-R is more relevant for CD8+ T cells. In mice, mutations in the Fas receptor Opr, lymphoproliferation phenotype) or its ligand (gld, generalized lymphoproliferative disease) are associated with massive lymphadenopathy and lupus-like autoimmunity. 107 In humans, Fas mutations cause the so-called autoimmune lymphoproliferative syndrome (ALPS),108 which is characterized by lymphadenopathy and autoimmunity. Fas-mediated apoptosis is important for eliminating cells that are specific for persistent antigens such as self-antigens. Indeed, mutations in Fas and FasL genes cause autoimmune diseases but not prolonged responses to foreign antigens. On the contrary, a prolonged immune response occurs with the constitutive expression of Bcl-2 as a transgene in B or T cells,109 a phenomenon that underlines the importance of passive cell death in the termination of responses to foreign antigens. In lymphocyte development in the thymus, apoptosis that occurs from a lack of positive selection appears to be secondary to lack of a rescue signal by the TCR, leading to passive cell death. On the contrary, apoptosis during negative selection is actively induced (activation- induced cell death) but does not appear to be secondary to Fas-FasL interactions, as occur in peripheral deletion mechanisms.

Immunologic Tolerance Immunologic tolerance is antigen-induced functional inactivation or death of specific lymphocytes that results both in the inability to respond to that antigen and in the

inhibition of lymphocyte activation during subsequent administration of the same antigen in an immunogenic form. 110 Antigens that induce an immune response are called immunogens, whereas antigens that induce tolerance are called tolerogens. Self-antigens are normally tolerogens; many foreign antigens, depending on their physicochemical form, dose, and route of administration, may act as immunogens, tolerogens, or both. For instance, protein antigens administered subcutaneously or intradermally are usually immunogenic, whereas large amounts of protein antigens administered intravenously or orally often induce unresponsiveness. The need to avoid self-aggression during the immune response to foreign antigens has been a determinant factor during the evolution of the immune system. The persistence of autoimmune diseases in the population could be explained by the fact that they more frequently affect people after they have passed the reproductive age and therefore no longer represent a serious threat to the survival of the species. Although the question concerning the balance between immunity and tolerance, including self-tolerance, has yet to be resolved, many observations are yielding a general framework. l1l- m The random generation of antigen receptors during lymphocyte maturation can give rise to lymphocytes that are specific for self-antigens. As described earlier (see Fig. 3-10), lymphocytes with high avidity for abundant self-antigens that are constitutively expressed by all cells (and therefore present in high concentration in the thymus and the bone marrow) are deleted during their development in central lymphoid organs (central tolerance). Although elonal deletion of self-reactive

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lymphocytes in central lymphoid organs is an efficient process, not all self-antigens are expressed in central lymphoid organs. Lymphocytes that are specific for these antigens survive and must be eliminated or held in check by other mechanisms. These mechanisms, only partly understood, are responsible for peripheral tolerance and include not only clonal deletion but also clonal anergy, active suppression, and ignorance.

T Cell Tolerance Central Tolerance During their maturation in the primary lymphoid organs, lymphocytes encounter a number of antigens to which they respond by developing tolerance rather than activation. In fact, most of the antigens normally present in the thymus or bone marrow are self-antigens. Lymphocytes that recognize, with high affinity, self-antigen presented in association with MHC molecules by thymic APCs die by apoptosis (negative selection). This fundamental process avoids the possibility that lymphocytes with high affinity for receptors for ubiquitous self-antigens may reach maturation (see Fig. 3-10). This process affects both class I and class II MHC-restricted T cells and is therefore important for tolerance in CD8+ and CD4+ lymphocyte subpopulations. It has been shown that thymic stromal cells in both cortical and medullary epithelium also collectively express a number of tissue-specific antigens. 114 The expression of these self-antigens is regulated by a transcription factor called autoimmune regulator (AIRE). 115 Mutations in the AlRE gene cause a rare recessive inherited disorder characterized by an autoimmune polyendocrinopathy, called autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED).116 Many of the genes regulated by AIRE encode tissue-specific proteins such as insulin, thyroglobulin, and zona pellucida glycoprotein. Thus, central tolerance seems to play an important role also in the mechanisms of tolerance toward tissue-specific antigens. ll ?

Peripheral Tolerance Because only a limited number of self-antigens are present in primary lymphoid organs, the mature lymphocyte repertoire contains many cells capable of recognizing other self-antigens that are exclusively expressed in the peripheral tissues. Therefore, other mechanisms of tolerance are required to avoid the response of these mature self-reacting lymphocytes. Most of the mechanisms involved in peripheral tolerance are related to the strategy of control of lymphocyte activation (see Fig. 3-17). As previously noted, activation of CD4+ T cells after recognition of antigens presented by APCs requires the simultaneous presence of a second signal given by the costimulatory molecules that are expressed only by activated and not by resting APCs. In the absence of such a costimulatory signal, T cells are able to survive but are rendered incapable of responding to the same antigen in a future encounter (clonal anergy). Thus, the continuous

presentation to mature T cells of self-antigens by resting APCs makes many self-reacting T cells anergic (Fig. 3-19). Anergy may be also induced by the inhibitory receptor CTLA-4, at the time of antigen recognition. In this situation anergy is not induced by the absence of costimulation, but by the delivery of active inhibitory signals to T cells. The possible mechanism of the preferential binding of costimulatory molecules expressed by APCs to CTLA-4 rather than to CD28 on T cells is not completely understood. However, the importance of CTLA-4 in the induction of tolerance is proven by the development of uncontrolled lymphocyte activatlon and fatal multiorgan lymphocytic infiltration suggestive of autoimmunity in knockout mice lacking CTLA-496 (see Fig. 3-19), Another important mechanism of peripheral tolerance is represented by the deletion of self-reactive T cells by activation-induced cell death. Repeated stimulation of T cells by persistent antigens induces the death of the activated cells by apoptosis. It is believed that Fas-mediated activation-induced cell death is responsible for the elimination of T cells specific for abundant peripheral antigens that are most likely responsible for the repeated activation of T cells (see Fig. 3-19). Most patients with the Fas receptor mutation associated with massive lymphadenopathy and lupus-like autoimmunity are heterozygous for the defect lOS; however, other family members, with the same heterozygous mutation and showing defective in vitro apoptosis, do not develop disease. Therefore, in addition to the Fas mutation, other genetic factors are required for disease development. In humans, a FasL mutation associated with autoimmunity has been reported, llS as well as an autoimmune Iymphoproliferative syndrome (type II) caused by caspase 10 mutations. 1l9

Studies on apoptosis have provided a possible answer for two mysteries that surround systemic autoimmune diseases: (1) why are autoantibodies directed against antigens that are normally found inside the cell, even in the nucleus? and (2) how do these antibodies contribute to disease pathogenesis? During apoptosis, nuclear autoantigens, as well as other intracellular autoantigens (such as RNA and ribosomal endoplasmic reticulum components) become localized within surface blebs. In addition, phosphatidylserine (PS), a membrane phospholipid that is normally distributed on the intracellular portion of the membrane, is redistributed to the outer membrane early in apoptosis and can bind autoantigens such as the phospholipid-binding protein ~2-glycoprotein 1. Under normal circumstances, uptake of apoptotic cells by macrophages induces the production of anti-inflammatory cytokines such as TGF-~ and the downregulation of inflammatory cytokine production. DC maturation and presentation of antigens are suppressed by the uptake of apoptotic cells, which leads to the promotion of tolerance. 120 If something goes wrong in the recognition and management of apoptotic cells, intracellular autoantigens presented at the cell surface during apoptosis could prime an autoimmune response. A further important mechanism of peripheral tolerance is related to inhibitory regulatory T cells (Treg).121.122 Distinct T cell subpopulations may presumably play these regulatory functions using different mechanisms

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• fItIn 3-19 Possible mechanisms of peripheral tolerance. See text for explanations. TcR, Tcell receptor; APC, antigen-presenting cell; FasL, ligand for Fas; IL, interleukin; MHC, major histocompatibility complex; TCR, T<:ell receptor; TGF, transforming growth factor.

(see Fig. 3--19), Antigen-specific T cells (Trl) selectively producing high levels of the anti-inflammatory eytokine IL-lO are able to inhibit the development of experimental autoimmune colitis. 123 ,124 The same cytokine-mediated regulatory mechanism was also observed for cells having high production of TGF-~ and defined as Th3. 125 A third population of Treg cells is represented by resting circulating CD4+ T cells expressing high levels of the IL-2 receptor ex chain (CD2S).126 In this case, the inhibitory action requires cell-to-cell contact between CD4+CD2S+ T cells and APC or naIve T cells. Treg cells presumably arise in the thymus or in peripheral organs after self-antigen recognition. CD4+CD2S+ Treg in the thymus selectively express a particular gene (FoxP3), that produces a regulatory transcription factor, scurfin. 127 A defect of this gene in humans is associated with a severe autoimmune disease known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPIDO syndrome,l28 which develops in early infancy. The study of the mechanisms of peripheral tolerance offers opportunities for the elaboration of new therapeutic approaches for many autoimmune disorders. In fact, the reinstatement of tolerance toward a self-antigen relevant in disease pathogenesis may represent the most promising strategy for the cure of these disorders. The mechanisms for B cell tolerance induction were discussed earlier, in the section on B cell development and selection.

The Cryptic Self and the Immune Privilege Many self-proteins are presented too poorly to T cells to be recognized. These self-antigens are called cryptic epitopes and are collectively referred to as cryptic self. T cells that are specific for these epitopes are not tolerant, because they can respond if the antigen is presented

appropriately. They are considered ignorant, because they are not aware of the existence of the self-antigen they are able to recognize. Given the number of self-protein epitopes, an immune system from which all potential selfreactivity has been removed would probably not respond to foreign antigens. 129 It is therefore likely that a large number of potentially autoreactive T cells reside in the immune system in a resting state, without causing disease because they ignore their respective self-antigens. Ignorance may also be related to the difficulty with T cells' gaining access to some tissues, such as brain, gonads, and eye ("immunologically privileged sites"), because of the existence of blood-tissue barriers. It is now apparent that the "immune privilege" of these tissues is a complex and active phenomenon that includes local production of immunosuppressive neuropeptides and cytokines, limited MHC antigen expression, and, in the eye and testis, constitutive expression of FasL, which promotes the death of invading Fas-positive cells during viral infections. 130

Oral Tolerance Oral tolerization 131 is a phenomenon in which the oral (or, more generally, the mucosal) administration of an antigen induces a marked suppression of systemic humoral and cell-mediated immune responses to immunization with the same antigen, without affecting the response to other antigens. It is presumed that this mechanism has evolved to prevent systemic immune responses to ingested proteins and to bacteria that normally reside in the intestinal lumen. The mucosal immune system is important in the defense against infection. 132 Much of the current knowledge of mucosal immunity is based on studies of the gastrointestinal tract, but it is likely that the general features of mucosal immunity are similar in all mucosa-associated

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lymphoid tissues. Immune responses to antigens delivered by the oral route differs from those to antigens encountered in other sites in two main respects: 0) the predominant production of IgA in mucosal tissues and (2) the tendency of oral immunization with protein antigens to induce systemic T-cell tolerance rather than activation, a phenomenon that is particularly appealing for the possible induction of tolerance to autoantigens in autoimmune diseases. In the intestinal mucosa, lymphocytes are scattered both among epithelial cells Cintraepithelial lymphocytes) and in the lamina propria. Ten percent of intraepithelial lymphocytes bear the y:8 TCR. Both y:8 and a.:~ intraepithelial T cells show a limited diversity of antigen receptors and are thought to have evolved to recognize commonly encountered intraluminal antigens. The small intestine contains organized mucosal lymphoid follicles (Peyer's patches). Similar follicles are found elsewhere along the gastrointestinal and respiratory tract (e.g. pharyngeal tonsils). Peyer's patches have B cell-rich areas that often contain germinal centers and CD4+ T cells, mainly in the interfollicular regions. The epithelium overlying Peyer's patches contains specialized cells, called membranous cells (M cells), which lack microvilli and engulf and transport macromolecules from the intestinal lumen into subepithelial tissues. M cells are thought to be important in delivering antigens to Peyer's patches. Lymphocyte homing to Peyer's patches and the lamina propria of . the gut has particular characteristics. Most of orally administered antigen is carried by lymphatics to the draining mesenteric lymph nodes, where an immune response is initiated. Some protein antigens are transported by M cells into Peyer's patches, where they can stimulate both T and B cells. Lymphocytes derived from both the mesenteric lymph nodes and Peyer's patches may then reach the bloodstream or the lamina propria. The reason why some protein antigens induce oral tolerance whereas others elicit effective immunity is not known. One possible explanation may be the capability of infectious organisms to activate APCs to express costimulatory molecules. Another explanation involves deletion mechanisms, the induction of a state of anergy, and active immunosuppression through the release of immunosuppressive cytokines such as TGF-~ or lL-1O, by Th3 and Tr1 regulatory T cells, respectively (see Fig. 3-19). The antigen dose influences the mechanism involved: low doses favor active suppression, and high doses favor deletion or anergy. Several studies have shown that oral administration of the specific autoantigen is effective in treating experimental autoimmune diseases, including experimental allergic encephalomyelitis and collagen-induced arthritis. 133 Induction of oral tolerance by nasal or oral administration of antigen could be an interesting therapeutic option for human autoimmune diseases in which the relevant eliciting antigen is unknown. 134 The cytokines secreted by T cells induced in the gut-associated lymphoid tissue by oral antigen administration suppress inflammation in an antigen-nonspecific way (bystander immunosuppression) in the microenvironment where the fed antigen is localized. The induction of oral tolerance to an antigen present, for instance, in the joint could theoretically result in suppression of joint inflammation when the elicited regulatory cells migrate to the joint, meet the specific antigen, and release suppressive cytokines.

THE MULTIFACTORIAL ORIGIN OF AUTOIMMUNE DISEASES Autoimmune recognition was once viewed as a distinct abnormality, as indicated by the term used by Ehrlich: "horror autotoxicus." In recent decades, it has become increasingly evident that autorecognition is a phenomenon that occurs normally in the immune response and represents the basis of formation of the normal adaptive immune response. As summarized earlier, the normal immune T cell repertoire is selected by low-affinity recognition of self-peptides presented in the context of self-MHC molecules. Moreover, in normal immune responses, a transient and limited autoimmune response may occur but is rapidly downregulated and does not lead to tissue injury. Yet, in about 5% of the population, for reasons that are still incompletely understood, a strong autoimmune response arises and leads to inflammation and tissue damage. Despite the great number of potential autoantigens, there are relatively few distinct autoimmune diseases and, in persons with a given autoimmune disease, the same autoantigens tend to be recognized. This suggests that only a small fraction of self-proteins can actually serve as autoantigens. It is also conceivable that lymphocytes that mediate autoimmune responses do not undergo clonal deletion in central lymphoid organs but rather are present in a tolerant or ignorant state in all normal persons and may be activated only in particular circumstances. The development of an autoimmune disease is presumably initiated by an aberrant, genetically regulated immune response to environmental antigens. The importance of environmental factors in eliciting disease is supported by the relatively low disease concordance in monozygotic twins and by reports that migrant populations tend to acquire the disease prevalence of the geographic area to which they move. l3S The importance of the genetic component varies among diseases; the frequency of a given disease in relatives of an index case (Le., the recurrent risk) is about 4 for rheumatoid arthritis and approaches 50 to 100 for SLE and spondyloarthropathies. Similarly, the concordance in twins is between 25% and 50% for SLE and almost lO-fold lower for rheumatoid arthritis. 136 The interaction of environmental and genetic factors at many levels determines the development and expression of an autoimmune disorder (Fig. 3_20).1 37 These considerations may explain the relatively small proportion of individuals who develop autoimmune diseases (3% to 5% of the general population), the spectrum of possible autoimmune disorders, and the heterogeneity in the clinical presentation and olltcome of many autoimmune conditions.

Genetic Predisposition The human and animal genomes contain mutations that affect the control of the immune response. That these allelic variants act in combination explains both the difficulty in mapping them and the observation that autoimmune diseases are not inherited in a simple mendelian way.

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• FIfure 3-Z0

Pathogenic events related to development of autoimmune diseases. Genetic predisposition and environmental factors may variably act on different levels of the normal immune response leading to autoimmunity.

Almost 40 genes that predispose to autoimmunity in human and animal autoimmune diseases have been localized. There appear to be both genes that cause general defects in immune regulation, which are shared between different diseases, and genes that are unique to a given disease, which may confer susceptibility of the target organ to the autoimmune process. Some conclusions have been drawn from the analysis of murine autoimmune disease models 135 : (1) no single allele but rather a combination of genes causes the disease, and more than one combination may exist; (2) the risk of the disease depends on the number of susceptibility alleles at unlinked loci; (3) some alleles have a greater effect than others; and (4) several predisposing alleles have a weak effect and are therefore difficult to map. Only a few autoimmune syndromes have been shown to be caused by single gene mutations. These mutations usually affect genes that regulate pivotal mechanisms involved in peripheral and central tolerance. As previously mentioned, mutations of the autoimmune regulator AIRE gene leads to an autosomal recessive disease APECED,l16 whereas mutations of the FoxP3 gene (which causes complete loss of the regulatory functions of CD4+CD25+ regulatory T cells) provokes IPEX syndrome. 127 Mutations in many genes involved in regulating apoptotic pathways and IL-l production cause some monogenic autoinflammatory diseases, such as ALPS (Fas, FasL, caspase 10J, familial Mediterranean fever (MEFVJ,138 TNF-receptor-associated periodic syndrome or TRAPS (1NFRIJ,139 chronic infantile neurologic cutaneous and articular syndrome or CINCA (CIASJ),l4o and Blau syndrome (CARDl5/ NOD2J,I41 or have been associated with disease susceptibility in Crohn's disease (CARD15/NOD2J. 142 Several polymorphisms of genes related to immunologic reactivity are associated with autoimmunity. For example, polymorphisms in the gene encoding CTLA-4, the molecule involved in mechanisms of clonal anergy and immune homeostasis, are related to susceptibility to autoimmune conditions such as multiple sclerosis,I43 inflammatory bowel diseases,I44 autoimmune thyrodi-

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tis,145 and rheumatoid arthritis. 146 An intronic polymorphism of the gene regulating the expression of another molecule involved in lymphocytic homeostasis (programmed death-1 [PDI]) has been associated with susceptibility to SLE. 147 Associations between particular MHC class I or II genes and many autoimmune diseases have been repeatedly observed. 148,149 This may be because different MHC alleles differ in their ability to present peptides to autoreactive T cells. Alternatively, some MHC alleles might enhance positive selection or decrease negative selection of autoreactive T cells in the thymus. 137 Another possible cause of autoimmunity may be related to an increased availability of autoantigens to the immune system. Mutations of genes controlling the mechanisms of clearance of apoptotic cells and nuclear material, such as Clq, predispose to a lupus-like disease. lso Finally, some genes increase susceptibility to autoimmune disease through changes in the response in the peripheral tissues. For example, some polymorphisms of the cellular receptors for the Fe portion of IgG (FcyR) are associated with susceptibility to lupus nephritis, probably by facilitating immune complex deposition in renal tissue. lSI

Environmental Fadors Infection and Autoimmunity Infection is a potentially important exogenous factor in the induction of autoimmunity. However, the mechanisms by which infections can trigger activation of autoaggressive T cells and cause tissue destruction are unknown, New insights have been provided by the observations that a single TCR may bind different peptides (so-called TCR degeneracy) and that autoreactive "ignorant" T cells are present in the circulation of normal persons. Bacterial or viral DNA or lipopolysaccharides may act as adjuvants. Coadministration of a microbial adjuvant together with the relevant antigen or peptide is necessary to induce experimental autoimmune disease. Exposure to microbial agents is important for the development of some spontaneous autoimmunity models in transgenic mice. 152 Therefore, the presence of autoreactive lymphocytes per se does not appear to be sufficient to trigger the disease; additional factors, such as infections or cyrokine release or both, seem to be needed to activate selfreactive anergic or ignorant T cells. For instance, tolerance can be broken if anergic T cells are exposed to high concentrations of IL-2 (which may theoretically occur if adjacent T cells are stimulated by another antigen) or if the inflammatory process causes efficient presentation of cryptic self-antigen on activated APCs. Epitope spreading during an autoimmune response was initially demonstrated in experimental allergic encephalomyelitis l53 induced by immunization with myelin basic protein (MBP) or its immunogenic peptides. During the course of the disease, an encephalitogenic T cell response develops not only to the original immunizing peptide but also to some cryptic epitopes within MBP. Subsequent work in other experimental models, such as nonobese diabetic (NOD) mice,I54 confirmed

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these results and showed that epitope spreading can be both intramolecular and intermolecular, because determinants of other antigens at the site of inflammation, including heat-shock proteins, can also become targets of the autoimmune response. Thus, during the course of the disease, a sequence of pathogenic autoimmune responses to several cryptic epitopes develops, probably as a consequence of upregulation of processing and presentation of self-molecules in the context of inflammation. Various mechanisms, not necessarily mutually exclusive, have been hypothesized to explain how infection can trigger autoimmune diseases. Three of them (molecular mimicry, bystander activation, and superantigen activation) have been the subjects of particular attention. According to the theory of molecular mimicry, microbial antigens that share structural similarities with selfantigens can elicit a pathogenic immune response that cross-reacts with self-antigens. Many experimental autoimmune animal models are generated by hyperimmunization of genetically susceptible strains with foreign proteins that are homologous to tissue-specific selfproteins. Although in this case the triggering antigen is a homologous nonmicrobial antigen, the mechanism is equivalent to that which occurs after infection with a pathogen whose antigens, although nonhomologous, share structurally related epitopes with self-antigens. In experimental autoimmune uveitis and experimental ovarian autoimmune disease, microbial peptides induce tissue-specific autoimmunity.15s Immunization with heat-killed Mycobacterium tuberculosis in mineral oils (complete Freund's adjuvant) induces arthritis in Lewis rats. The disease can be transferred to naive, irradiated recipients with a T cell clone specific for the mycobacterial heat-shock protein 65 peptide 180-188. 156 Activation of human autoreactive T cell clones by viral and bacterial peptides has been reported. In insulin-dependent diabetes mellitus, molecular mimicry at the T cell level between glutamate decarboxylase (a pancreatic-islet autoantigen) and a coxsackievirus antigen has been demonstrated. 157 In multiple sclerosis, seven viral and a single bacterial peptide were found to stimulate at least one of seven autoimmune T cell clones specific for MBP. I 58 In patients with Lyme disease who develop chronic arthritis that is resistant to antibiotic treatment, Gross and colleagues159 demonstrated cross-reactivity between a peptide of OspA, the major surface antigen of Borrelia burgdorferi, and the self-protein LFA-l. Albani and colleagues l60 showed an abnormal immune response to a bacterial DNA) antigenic determinant carrying the "shared epitope" amino acid sequence QKRAA, which is characteristic of the HLA-DR alleles that confer susceptibility to rheumatoid arthritis. Mucosal tolerization with DNA)Pl, a peptide that induces proinflammatory T cell response CIFN-y and TNF-a) in patients with rheumatoid arthritis, was able to change T cell reactivity to production of IL-4 and IL-I0. 161 These studies demonstrated that microbial peptides with limited sequence homology are effective activators of autoreactive T cells. Moreover, they suggested the possibility that epitopes present on different microbial peptides may all be responsible for the activation of autoreactive T cells in a given autoimmune disease. In diseases in which a single pathogen has not been implicated, cross-reactive epitopes that are common to various pathogens may be important.

The bystander activation hypothesis postulates that infection-induced local inflammation-by provoking cell

death and the release of abundant quantities of self-antigens, potentiating antigen presentation and perturbing the cytokine balance-leads to bystander activation of a preexisting but controlled autoimmune response.162.163 Superantigens induce a potent polyclonal immune response and could trigger autoimmune diseases either by driving anergic autoreactive T cells out of their nonresponsive state or by facilitating activation of ignorant T cells that are specific for cryptic epitopes. 164 Superantigen-induced immune activation could also be a cause of disease exacerbation in already established autoimmune diseases.

MECHANISMS OF TISSUE INJURY IN AUTOIMMUNE-MEDIATED DISEASES The clinical and pathologic manifestations of a given autoimmune disease are determined by several factors, including the nature and location of the trigger stimulus and the type of effector mechanisms that the immune system activates to eliminate the aberrant stimulus.

General Mechanisms of Dssue Damage The effector mechanisms in autoimmunity are the same as those observed during normal immune response against microbes or other foreign antigens (Table 3-10). The majority of immune-mediated inflammatory diseases are the results of a complex combination of humoral and cellular-mediated immune responses in which multiple effector mechanisms operate.

Type I Hypersensitivity Immediate (type I) hypersensitivity is the mode of tissue damage mediated by IgE. Mast cells involved in this type of response also playa role in non-IgE-mediated autoimmune diseases. 165 However, in the vast majority of autoimmune diseases the other three types of hypersensitivity predominate.

Type " Hypersensitivity The evidence that antibodies are able to induce autoimmune disease comes from the classic experiments of induction of disease in normal animals by adoptive transfer of immunoglobulin purified from blood or tissues of affected animals. Maternal transfer of pathogenic autoantibodies to the fetus during pregnancy causes neonatal IUpUS,166 autoimmune thyroiditis,167 and autoimmune thrombocytopenia.168 Antibodies cause tissue damage by various mechanisms (Fig. 3-21). In type II hypersensitivity, antibodies opsonize the target cells and activate the complement cascade. When the opsonized cells arrive in the reticuloendothelial system of secondary lymphoid organs (especially the spleen), resident phagocytes are activated by the binding of their Fc or C3d receptors, leading to the destruction of antibody-coated cells. Antibodies can also activate the complement cascade that ultimately leads to cell lysis in the circulation. These mechanisms are responsible for

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

51

Immunopathoqeni< Mechanisms of Immune-Mediated Diseases

TYJN! of Hypersensitivity

Immune-pathologic Mechanisms

Mechanism of nssue Damage

Type 1Immediate hypersensitivity Type ll-Antibody-mediated hypersensitivity

IgE antibody

Activation of mast cells and release of vasoactive mediators Recruitment and activation of leukocytes by complement and Fc receptors Opsonization of target cells and complement activation Alteration of tissue normal function

Type III-Immune complex-mediated hypersensitivity

Tissue deposition of circulating immune complexes

Recruitment and activation of leukocytes by complement and Fc receptors

Type N-T cell-mediated hypersensitivity

Delayed hypersensitivity (CD4+ T cells) T cell-mediated cytolysis (CD8+ T cells)

Activation of tissue macrophage Direct lysis of target cells

IgM or IgG against cellular or extracellular antigens

cell destruction in autoimmune hemolytic anemia and immune thrombocytopenic purpura. Antibodies bind to tissue-specific autoantigens and recruit and activate neutrophils and macrophages through complement and Fc receptors. Tissue damage is mediated by the release of proteolytic agents from phagocytes. This occurs in acute rheumatic fever, in which antibodies directed to streptococcal cell wall antigen cross-react with myocardial antigens; Goodpasture s syndrome, in which the tissue target for autoantibodies is a noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli; and pemphigus vulgaris, in which antibodies are directed against epidermal cadherin. In other circumstances, autoantibodies do not cause inflammation but interfere with cell receptor function and cause disease without eliciting tissue damage. This is the case in Graves' disease, which is caused by antibody-mediated stimulation of thyroid-stimulating hormone (TSH) receptors, and in myasthenia gravis, in which antibodies inhibits acetylcholine binding and downmodulate receptors. 169

• f1ture 3-21 Examples of antibody-mediated mechanisms of tissue or cellular damage. A, Two different modes of destruction of red blood cells (RBQ during the course of autoimmune hemolytic anemia are shown. RBC coated by specific antibodies are recognized and destroyed by maaophages of the reticular endothelial system (predominantly the spleen). Antibodies activate complement, leading to cell lysis in the drculation. B, Antibodies recruit leukocytes and activate them directly through their Fc receptors or indirectly through the complement cascade, or both.

Human or AnImal Model of Autoimmune Diseases Allergic manifestations (bronchial asthma, anaphylactic shock, urticaria) Autoimmune hemolytic anemia Autoimmune thrombocytopenic purpura Goodpasture syndrome Pemphigus vulgaris Acute rheumatic fever Antiphospholipid syndrome Neonatal lupus Myasthenia gravis Graves' disease Systemic lupus erythematosus Mixed cryoglobulinemia Rheumatoid arthritis (rheumatoid factor) Insulin-dependent diabetes Rheumatoid arthritis Multiple sclerosis Crohn's disease Autoimmune myocarditis

Type III Hypersensitivity The mechanism of tissue damage in type III hypersensitivity is similar to that described for antibodies directly bound to tissue antigens, but it is mediated by organ deposition of circulating immune complexes. The prototype of systemic immune complex-mediated disease is serum sickness, which was observed originally during passive immunization of human volunteers against diphtheria infection using serum from horses immunized with the diphtheria toxin. The preferential deposition of immune complexes in small arteries, with particular tropism to those structures in which the blood is ultrafiltered (e.g., kidney glomeruli, synovia), causes immune complex-mediated diseases including vasculitis, arthritis, SLE, and mixed cryoglobulinemia.169.170 In both type II and type III hypersensitivity, antigenspecific helper T cells are involved in the activation and maturation of B cells for the subsequent production of high-affinity autoantibodies.

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Type IV Hypersensitivity In type IV (delayed-type) hypersensitivity (DTH), T cells are responsible for tissue damage. In most instances, damage is induced by the secretion (by the Thl subset of CD4+ T cells and by CD8+ T cells) of cytokines that activate tissue macrophages (lFN-y) and induce inflammation (TNF-a) (see later discussion). Occasionally, self-reactive CD8+ CTLs directly kill target cells (see Fig. 3-16). The finding of T lymphocytes and macrophages in close anatomic proximity in tissues and the predominant Thl orientation of T cells isolated from tissue lesions are considered clear evidence of the involvement of a DTHlike reaction in the determination of tissue damage in many autoimmune disorders. Diseases in which DTH plays a major role are multiple sclerosis,171 insulin-dependent diabetes mellitus, 172 Crohn's disease, 173 rheumatoid arthritis,174 and juvenile idiopathic arthritis (JIA).175.176 In the two last conditions, the dramatic hyperplasia of synovial tissue is also caused by infiltration of the lining layer with monocyte-derived macrophages recruited from the circulation. These cells, together with the resident fibroblastlike cells, play the major role in the determining cartilage and bone destruction. J77 In addition to the predominant role of DTH in inflammatory arthritis, a significant infiltration of B cells can also be found in inflamed synovial tissue, with a tendency to a discrete lymphoid organization and with formation of germinal center-like structures. 17S Moreover, a clear infiltration of immunoglobulin-producing plasma cells is consistently found in synovial tissue, even in clear proximity with macrophages and fibroblasts of the lining layer. Figure 3-22 is a schematic representation of the complex network of various cell type interactions in determining tissue damage in a classic model of inflammatory-mediated tissue damage observed in the chronic synovitis of idiopathic arthritides. There is little evidence for a direct role of CD8+ CTLs in the pathogenesis of human autoimmune diseases. This mechanism has been postulated in myocarditis associated with coxsackievirus infection, in which autoreactive CTLs have been shown to kill also myocardial cells not affected by the viral infectionY9

Recruitment of Leukocytes Into Inflamed TIssue One of the critical mechanisms leading to the initiation and maintenance of tissue inflammation is the migration of leukocytes from the circulation to the site of inflammation. This multistep process involves many soluble and surface molecules leading to the attachment of circulating cells to endothelial cells and migration through the endothelium (Fig. 3-23). 180 The capture and rolling of circulating cells by activated endothelium is followed by the activation of cells and their firm adhesion to endothelium and, finally, by the migration of cells across the endothelium (diapedesis).180.IHI A pro-inflammatOly stimulus (trauma, an infectious or other exogenous agent) leads to the production of pro-inflammatOly cytokines (TNF-ct, IL-1) by the resident cells of innate immunity. These cytokines induce the expression of a series of membrane glycoproteins (selectins) that act as adhesion molecules for circulating leukocytes 182 ,183 (Table 3-11). In particular,

endothelial (E)-selectin and platelet (P)-derived selectin are selectively expressed on the surface of cytokine-activated endothelial cells. Circulating leukocytes flowing in the bloodstream first loosely adhere to the endothelium through other constitutively expressed surface glycoproteins (Sialyl Lewis x for E-selectin, P-selectin glycoprotein ligand 1 [PSGL-IJ for P-selectin), which allows the sampling of the local environment for signs of inflammation. Similarly, leukocyte (L)-selectin is expressed on monocytes and neutrophils and naive T cells. At least three different ligands for L-selectin (glycosylationdependent cell adhesion molecule-l [GlyCAM-IJ, CD34, and mucosal addressin cell adhesion molecule-l [MadCAM-lD are expressed on endothelial cells in various organs and conditions. The engagement of PSGL-l or L-selectin with its respective endothelial ligands enhances the strength of adhesion and induces the rolling of leukocytes on endothelium. 1s4 Notably, the lack of one enzyme needed for the expression of the carbohydrate ligand CSialyl LewisX) for P- and E-selectins present on PSGL-l and on other selectin ligands results in a syndrome characterized by a significantly impaired leukocyte recruitment and increased susceptibility to infections, called type 2 leukocyte adhesion defiCiency CLAD-2).

The second step of leukocyte migration requires their firm adherence to endothelial cells. This is ensured by integrins that are constitutively expressed on circulating leukocytes. 182,183 Integrins are a large family of heterodimeric proteins composed of two noncovalently linked polypeptide chains, a and ~ (see Table 3-11). The N-termini of both chains form a globular head that interacts with specific ligands, whereas the cytoplasmic domain binds to the cell cytoskeleton. These surface proteins mediate a large number of interactions with other cells and with the extracellular matrix and are involved in many cellular functions, including cell activation, recognition, and migration. 185 After rolling, leukocytes undergo integrin affinity maturation stimulated by a series of specific cytokines (chemokines) produced by activated endothelial cells and by other cell types (epithelial cells, fibroblasts) of the inflamed tissue (see later discussion). In the meanwhile, pro-inflammatory cytokines (lL-l, TNF-a) mediate the overexpression of the ligands that are specific for highaffinity integrins. In this way, a firm adhesion between leukocytes and endothelium occurs. During inflammation, the very late antigen-4 (VLA-4, or a 4Pl) is selectively expressed on leukocytes and mediates their adhesion to activated endothelial cells expressing its ligand, vascular adhesion molecule-l (VCAM-1).186 Similarly, the leukocyte function-associated antigen-l (LFA-l, or CD11aCD18) binds to its specific ligand, the intracellular adhesion molecule (ICAM). A mutation of the gene coding for the ~ chain of LFA-l leads to a genetic disease characterized by recurrent bacterial and fungal infections and defective leukocyte accumulation at sites of infection, named type 1 leukocyte adhesion defiCiency (LAD-I). The specific inhibition of integrins involved in leukocyte recruitment is a possible therapeutic target in autoimmune diseases. ls7 The final step in leukocyte recruitment is the transmigration of cells across the endothelial lining into the site of inflammation. This process is facilitated by interaction between other integrins expressed on leukocytes and their specific ligands, which are present at the level of the adherence junction between the endothelial cells

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53

• fIture 3-ZZ Pathogenic events leading to tissue damage during chronic synovitis. Various cell types are involved in the disease process at the level of synovial membranes. A, Effector Tcells express cytokines that activate maaophages to produce pro-inflammatory cytokines, growth factors, and other soluble products leading to tissue damage. 8, Resident fibroblast-like cells proliferate and became activated. C, Bcells may cluster in follicle-like structures, with maturation of a large number of antibody-secreting plasma cells. 0, Pro-inflammatory cytokines produced by inflammatory cells activate endothelial cells for recruitment of leukocytes from peripheral blood. E, Growth factors and proteolytic enzymes such as matrix metalloproteinases (MMPs) sustain the continuous remodeling of extracellular matrix (EM) and formation of new blood vessels. These are the two key mechanisms for the continuous growth of synovial tissue (hyperplasia), which leads to the progressive invasion and destruction of joint cartilage and bones. F, Mechanisms involved in the control of tissue inflammation ultimately lead to synovial fibrosis. HMGB-1, high mobility group box chromosomal protein 1; IFN, interferon; IL, interleukin; LTB4,Ieukotriene B4; NO, nitric oxide; PGE2, prostaglandin E2;TNF, tumor necrosis factor.

• FIglIre 3-ZJ Recruitment of leukocytes into the inflammatory site. (1) Pro-inflammatory cytokines produced by macrophages stimulate expression of adhesion molecules (selectins and integrin ligands) on the endothelial cells. (2) Chemokines produced by stromal cells, inflammatory cells, and endothelial cells attract leukocytes bearing.spedfic chemokine receptors. (3) Leukocytes bearing selectin ligands (Le., Sialyl LewisX ) weakly adhere to endothelium (rolling). (4) Leukocytes undergo integrin affinity maturation stimulated by chemokines. In this way, afirm adhesion between leukocytes and endothelium occurs (adhesion). (5) Cells transmigrate across the endothl!liallining into the site of inflammation. ECM, extracellular matrix; ICAM, intracellular adhesion molecule; IL, interleukin; JAM, junctional adhesion molecule; LFA-l, leukocyte function-assodated antigen 1; TNF, tumor necrosis factor.

54

I!:..

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lABl£ 3 II

3

THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

Adh('~ioll M()I(,(IIIl'~

Family

Name

Cell DIstribution

Ugands

Main Functions

Selectins

P-selectin (CD62P) E-selectin (CD62E) L-selectin (CD62L)

Endothelium', platelets Endothelium' Leukocytes

Sialyl Lewisx PSGL-l GlyCAM-l, CD34, MadCAM-l

Initiate leukocyte-endothelium interactions

VLA-l, -2, -3 VLA-4, -5 VLA-6 CD51CD29

Leukocytes Leukocytes Leukocytes Leukocytes

Laminin, collagens JAM-B Fibronectin, lamlnin Vitronectin, fibronectin

Cell matrix-adhesion, homing to inflamed tissues

LFA-l Mac-l

Leukocytes Leukocytes

lCAM-l, -2, -3 JAM-A

Leukocyte adhesion to endothelium Interaction between T cell and APC

Vitronectin receptor

Leukocytes, endothelium, osteoclasts

Fibronectin, fibrinogen, osteopontin, vitronectin, thrombospondin

Cell matrix-adhesion, leukocyte activation, osteoclast activation, angiogenesis

CD49CDlO4

Leukocytes

Laminin

Cell matrix-adhesion

~;av

Leukocytes, endothelium

Vitronectin

Cell matrix-adhesion, angiogenesis

~6Uy

Leukocytes

Fibronectin

Cell matrix-adhesion

~ll6

~7a4

LPAM-l

Leukocytes

VCAM-l, fibronectin

Homing to lymphoid tissues

Immunoglobulin superfamlly

ICAM-l (CD54) lCAM-2 (CDlO2) VCAM-l (CD106) PECAM (CD3l)

Endothelium' Dendritic cells Endotheliumt Leukocytes, endothelium

LFA-l, Mac-l LFA-l VLA-4 PECAM, Uy~3

Cell adhesion, ligands for integrins

Cadherins

VE-cadherin

Endothelium lateral junctions

VE-cadherin

Cell-to-cell adhesion

•Activated endothelial cells. tResting endothelial cells. APC. antigen-presenting cell; CD, cluster of differentiation; GlyCAM-I, glycosylation-dependent cell adhesion molecule-I; tCAM, intracellular adhesion molecule; JAM, junctional adhesion molecule; LFA, leukocyte function-associated antigen; Mac-I, macrophage adhesion molecule 1; MadCAM-I, mucosal addressin cell adhesion molecule-I; PECAM-I: platelet/endothelial cell adhesion molecule; PSGL-I, P-selectin glycoprotein ligand-I; VCAM-I, vascular adhesion molecule-I; VE-cadherin: vascular endothelial cadherin; VLA, very late antigen.

(platelet/endothelial cell adhesion molecule [PECAM-l] and the junctional adhesion molecule GAM] family) or in the subendothelial extracellular matrix (fibronectin, osteopontin, collagen) (see Table 3-11).181 The main stimuli for the migration of inflammatory cells through interendothelial spaces, however, are inflammatory chemokines that specifically attract adherent leukocytes to the infection site toward a chemical concentration gradient. Chemokines (chemotactic cytokines) are a large family of structurally homologous small cytokines (8 to 15 kD) that control the trafficking of leukocytes. 188.189 Chemokines are classified into four families according to the motif displayed by the first two cysteine residues (C) at the N-terminus: CC, CXC, C, and C2SC (Table 3-12). The two main subfamilies of chemokines, CXC and CC, differ from each other by the presence of one amino acid (X) between the cysteine residues. Chemokines are produced by leukocytes and by several types of tissue cells (endothelial cells, fibroblasts, epithelial cells) in both physiologic and pathologic states. Chemokines can be broadly

classified in two functional groups: inflammatory and lymphoid (or homing).189 Inflammatory chemokines are produced by leukocytes and tissues in response to a pro-inflammatory stimulus. Homing chemokines such as CCL19, CCL21, or CXC13 are constitutively expressed in the microenvironment of lymphoid tissues, skin, and mucosa. They are involved in the control of leukocyte trafficking between circulation and lymphoid structures. l90 Chemokines of both subgroups bind to heparan sulfate-containing proteoglycans on endothelial cells and are displayed in this way to circulating leukocytes expressing the specific chemokine receptors on their surfaces (see Fig. 3-23). These receptors have a characteristic structure with seven-transmembrane a-helical domains coupled to trimeric guanosine triphosphate-binding proteins. Seventeen CXC and 12 CC chemokine receptors have been identified to date (see Table 3-12), The interactions between chemokines and their respective cellular receptors induce the activation of intracellular signaling pathways that provoke cytoskeletal rearrangements by stimulating alternating polymerization and depolymerization of actin filaments, eventually leading to cell mobilization. 191 Although the

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

receptors exhibit overlapping specificity for chemokines within each subfamily, the expression of different chemokine receptors on the surface of circulating leukocytes is closely related to their specific function, state of differentiation, and degree of activation (see Table 3-12). This complex network of chernokines and cellular receptors allows the selective recruitment of circulating leukocytes to peripheral or lymphoid tissues on the basis of their actual discrete microenvironment and functional needs.

Many inflammatory chemokines and leukocytes displaying their specific surface receptors have been identified in inflamed tissues. In particular, some receptors for inflammatory chemokines (CCRl, CCR2, CCR5, and CXCR3) are regularly detected in tissues where inflammation is characterized by chronic infiltration of macrophages and predominantly Thl-oriented lympho-

.:. rABLE

3 - 12

55

cytes (Le., rheumatoid arthritis and Crohn's disease).192 Conversely, expression of CCR3 and CCR4 characterizes the leukocyte infiltration of allergic diseases, 193 and chemokine receptors for CXCLB (previously known as IL-8), CXCRl, and CXCR2 are most frequently found in acute inflammation. l88 The selective blockade of inflammatory cheniokines and their cellular receptors is a promising possible strategy for the treatment of many autoimmune disorders. 194

Cytokines and Growth Factors TNF represents the prototype of a pro-inflammatory cytokine produced by activated phagocytes. l 9S-197 TNF-a

was originally identified as a soluble molecule, present in

Chemokines and (hemokinl' Rl'( ('plots

Major Sources

Receptor

Cells Attradecl

Main Fundlons

CXCLl (Gro-a) CXCL2 (Gro-~) CXCL3 (Gro-y) CXCLS (ENA78) CXCL6 (GCP-2) CXCL7 (NAP-2) CXCLS OL-8) CXCL9 (MIG) CXCLlO OP-IO) CXCLlI 0-TAC) CXC112 (SDF-I) CXCLl3 CECA-I)

M, M, M, M, M, M, M, M, M, M, Sc Sc

CXCR2 CXCRZ CXCR2 CXCR2 exCRl CXCR2 CXCRl/2 CXCR3 CXCR3 CXCR3 CXCR4 exCRS

N, M, Tc, NK N, M, Tc, NK N, M, Tc, NK N N, M, Tc, NK N N, M, Tc, NK Tc, NK, M Tc, NK, M Tc, NK, M NaIve Tc, Bc B cells

Leukocyte recruitment Leukocyte recruitment Leukocyte recruitment Leukocyte recruitment Leukocyte recruitment Neutrophil activation, angiogenesis Neutrophil recruitment and activation Leukocyte recruitment Leukocyte recruitment, Thl response Leukocyte recruitment Lymphocyte recruitment Lymphocyte homing to lymphoid organs

Class CC chemoldnes CCLl 0-309) CCL2 (MCP-I)

M, Tc, Ec M, F

CCR8 CCR2

M, Tc M, NK, Tc, F

CCL3 (MIP la) CCL4 (MIPl~) CCL5 (RANTES)

M, Tc, Mc, F M, Mo, N, Ec Tc, Ec, P

CCRI/S CCRS CCRl/5/3

M,NK,B, Dc M, NK, Tc, Dc M, NK, Tc, B, E, Dc

CC1.7 (MCP-3) CCLS (MCP-2) CCLII (Eotaxin) CCLl3 (MCP-4) CCLl7 (TARC) CCLl9 (ELC)

M, F, P, Ec M, F, Ec Ec, M, Ep, Tc Ec, M, Ep Ec, M, Ep Sc, Ec

CCRI/2 CCR2 CCR3 CCR2/4 CCR4/8 CCR7

E, B,NK E, B E, M, Tc (Th2) E, B, Tc E, B, Tc Tc, Dc

CCL20 (MIP-3a) CCl21 (SLC)

M, Tc, DC, E, Mc Sc, Ec

CCR6 CCR7

Tc, Dc Tc, Dc

CCL22 CCL25 CC127 CCl28

Ec, M, Ep Ep K, Ec Ep

CCR4 CCR9/11 CCRIO CCR3/IO

E, B Tc Tc Tc

Leukocyte recruitment Activate macrophage and basophils, Th2 response Leukocyte recruitment, Thl response Leukocyte recruitment, HIV coreceptor Activation of basophils and Tc, chronic inflammation Leukocyte recruitment Leukocyte recruitment Allergy, Th2 response Leukocyte recruitment Tc and basophil recruitment Lymphocyte and Dc recruitment in lymphoid organs Lymphocyte and Dc recruitment Lymphocyte and Dc recruitment in lymphoid organs Tc and basophil recruitment Tc migration Tc migration to skin Tc migration to skin

XCL1 Oymphotactin)

Tc

XCRI

Dc, NK, Tm

Lymphocyte trafficking and development

Class ~C chemoldnes CX I eLl ( ractalkine)

M, Ec, Mig

C~CRI

M, Tc

Leukocyte-endothelium adhesion, brain inflammation

N. . (previous name)

Class CXC chemoldnes

(MDC) (TECK) (CTACK) (MEC)

F, Ec F, Ec F, Ec F, Ec F, Ec F, Ec Mo, F, Ec Tc, F, Ec Tc, F, Ec Tc, F, Ec

Class C chemoldnes

B, Basophils; Be, B cells; Dc, dendritic cells; E. eosinophils; Ec, endothelial cells, Ep, epithelial cells, P, fibroblasts; HIV, human immunodeficiency virus; K, keratinocytes; M, macrophages; Me, mast cells; Mig, microglial cells; Mo, monocytes/macrophages, N, neutrophils; NK. natural killer cells; P, platelets; Sc, stromal cells; Tc, T cells; Thl, type I helper T cells; Th2, type 2 helper T cells; Tm, thymocytes.

56

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the sera of animals treated with LPS, that displayed the ability to cause tumor necrosis in ViVO. I98 Although several cell types can produce TNF-(X (T cells, NK, cells, mast cells), macrophages are the most important source of this cytokine, especially during infection with gram-negative bacteria. After cell activation, TNF-(X is synthesized as a membrane protein that is expressed as a homodimer. It is cleaved by membrane-associated metalloproteinases and released as a 17-kD polypeptide, three molecules of which polymerize to form a 51-kD TNF protein. The various biologic actions of TNF are mediated by two distinct receptors; the 55-kD TNF receptor I (TNFRI or p55 receptor) and the 75-kD TNFRII (or p75 receptor).I96 The binding of circulating TNF-(X to TNFRs leads to the recruitment of cytoplasmic proteins called TNF receptor-associated factors (TRAPs). TRAPs initiate the intracellular signaling that leads to the activation of transcription factors, such as NF-lCB and AP-1, which ultimately cause the production of inflammatory mediators and anti-apoptotic proteins (Fig. 3-24A). Notably, in the case of TNFRI, the binding with TNF-(X may lead to either inflammation or apoptosis. In the latter case, different signaling proteins (TNF receptor-associated death domain [TRADD]) are involved. Activation of this particular intracellular pathway leads to the activation of caspases, which eventually results in cell apoptosis (see Fig. 3-24A). This latter mechanism is similar to Fas-mediated apoptosis involved in activation-induced cell death (see Fig. 3-18) and represents an important strategy for self-limitation of cell activation. l99 The principal function of TNF-(X during inflammation is to stimulate the recruitment of phagocytes into the site of inflammation and promote the killing of microbes (Table 3-13). TNF-(X also induces the expression of adhesion molecules and chemokines by endothelial cells and

enhances the affinity of leukocyte integrins for their ligands. It can activate recently recruited monocytes and stimulate the pro-inflammatory activity of resident fibroblasts (see Fig. 3-22).197 When produced in large amounts, TNF-(X may enter the bloodstream and act at distant sites as an endocrine hormone. In this way, TNF-(X is able to stimulate the hypothalamus to induce fever, to act on hepatocytes for the production of acute phase reactants, and to promote metabolic changes leading to wasting of muscle and fat cells (cachexia). Very high levels of circulating TNF-(X (greater than 10-7 M) play a major role in the pathogenesis of septic shock (e.g., severe systemic hypotension, disseminated intravascular coagulation), which is induced by massive LPS-induced production of pro-inflammatory cytokines. Excessive production of TNF-(X plays a central role in macrophage activation syndrome, a complication mainly observed in patients with systemic JIA. 200 The potentially lethal effects of TNF-(X are balanced by a strategy for the downregulation of TNF activity that is related to the shedding of TNFRs from the surface of activated cells, which generates circulating soluble receptors that prevent the binding of free TNF-(X to cell-bound receptors (see Fig. 3-24A). This strategy has been successfully adopted for the therapeutic blockade of TNF activities. 196 IL-1 shares many biologic function with TNF. 201 Like TNF, its major source is activated macrophages, although neutrophils, epithelial cells, and endothelial cells can also produce IL-1. Two different isoforms of circulating IL-1 CIL-1(X and IL-1~) are known. Both are synthesized as 33-kD peptides. Biologically active IL-1(X is a 17-kD protein that is released from the cell after cleavage by an intracellular cysteine protease called caspase-l (preViously

IL·\

/

FADD

G)

TRADD ~ It

,

\\

Caspases cascade \,

Apoptosls

~ TRAF ,

AP·I

'o,~

~'j

No Signal

.-

J

Jt'l

"'"

fL.J Ra

~

,IRAK

No Sional '"

Signal

\ Gene tran.•crlplion \, Inj/ammatlon Survival signals

• Rgun 3-Z4 Mechanisms of cell activation induced by pro-inflammatory cytokines and strategies for their downregulation. Panel A: (1) The binding of circulating TNF-a to TNF receptors (TNFR) leads to the recruitment of cytoplasmic proteins, called TNF receptor-associated factors (TRAFs), that initiate the intracellular signaling. DD, death domain. (2) In the case ofTNFRl, the binding with TNF-a may lead to either inflammation or apoptosis. In the latter case, different signaling proteins (Fas-associated death domain IFADDJ) are involved. The activation of this particular intracellular pathway, due to the loss of survival signals, leads to the activation of caspases that eventually result in cell apoptosis. (3) TNFRs are shed from the surface of activated cells, and free TNF-a binding to cell receptors is prevented. Panel 8: Type I receptor for interleukin-1 (IL-1) is constitutively expressed on many cell types and mediates intracellular transmission of the signal after binding with soluble IL-1, through activation of the IL-1 receptor-associated kinase (IRAK), which eventually leads to cell activation. Type II receptor (decoy receptor), is expressed only after cell activation and lacks a cytoplasmic tail. Thus, the binding with IL-1 does not result in intracellular signal transmission. Activated macrophages also secrete a protein with a close structural homology to IL-1 that binds to the same surface receptors but is biologically inactive (IL-1 receptor antagonist ilL-RaJ).

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THE IMMUNE SYSTEM AND THE INFLAMMATORY RESPONSE

known as IL-ln converting enzyme). IL-l~ may exert its biologic function either as 33-kD precursor or as a smaller cleaved product. Although the two isoforms of IL-l display a low degree of homology, they bind to the same surface receptors (lL-IR) and mediate the same biologic activities. 202 There are two different membrane receptors for IL-1. Type I receptor is constitutively expressed on many cell types and mediates the intracellular transmission of the signal after binding with soluble IL-l, through the activation of the IL-l receptor-associatedkinase (lRAK), which eventually leads to activation of NF-KB and AP-l transcription factors (see Fig. 3-24B).202 Type II receptor, which is expressed only after cell activation, lacks a cytoplasmic tail; consequently, binding with IL-l does not result in intracellular signal transmission. The major function of this receptor is to downmodulate the biologic action of IL-l; it acts as a "decoy" receptor in competition with the type I receptor (see Fig. 3-24B).203 A second strategy also downmodulates IL-l activities. Activated macrophages secrete a protein with a close structural homology to IL-l that binds to the same surface receptors but is biologically inactive (lL-l receptor antagonist, IL-Ra) (see Fig. 3-24B).204 This natural pathway of regulation of IL-l biologic activity has been adopted with the use of recombinant IL-IRa in the treatment of rheumatoid arthritis. 205 ,206 The biologic functions of IL-l largely overlap, both locally and systemically, with those described for TNF (see Table 3-13). Interleukin-6 (lL-6) is another important eytokine mainly produced by macrophages, endothelial cells, and tissue fibroblasts during acute and chronic inflammation. 207 ,20R Its biologic actions are mediated by specific binding with an IL-6 receptor that is present on cell membranes or in soluble form; this complex then binds to a signal transducing subunit, called gp130, which is also involved in signal transduction for other cytokines.209.210

11'1 • -

fABLE 3-13 Main Systl'l11i< Biologic Effects of IL-1. I NF ", 'Illd IL 6 During Inflammation

IL-l

TNF-a

IL-6

CNS Fever Production of CRH

++ +

+ +

+++ ++

Liver Acute phase reactants

+

+

++

Endothelium Chemokine expression AdheSion molecules Neoangiogenesis

++ +++ ++

++ +++ +++

+

Bone marrow Myelopoiesis Thrombocytopoiesis Inhihition erythropoiesis

++

++

++

+

++ +++ ++

CNS, ct'ntml nervous system; CRH, corticotrophin-releasing hormone; IL. interleukln; INF, tumor necrosis factor. -, none; +. moderate; ++, intense; +++, strong.

57

IL-6 has many pro-inflammatory functions (see Table 3-13). It stimulates the synthesis of acute phase reactants by the liver and the production of neutrophils from bone marrow. It induces endothelial cells activation, fibroblast proliferation, and osteoclast activation. In adaptive immunity, IL-6 stimulates the growth of B cells that have differentiated in antibody producers. 208 During the last decade, a large body of evidence has stressed the pivotal role of this cytokine in systemic JIA. In fact, many of the clinical features peculiar to this disease (chronic anemia, severe growth retardation, osteoporosis, thrombocytosis, amyloidosis) have been related to the biologic actions of IL_6. 211 - 214 Recently, the use of anti-IL-6 receptor monoclonal antibodies has been shown to be a possible promising therapeutic option for systemic JIA. 215 In recent years, a growing interest has been focused on a proinflammatory cytokine named high mobility group box chromosomal protein 1 (HMGBl).216 This nuclear protein stabilizes nucleosomes, allowing binding of DNA and facilitating gene transcription. It is passively released by necrotic cells after tissue injury. Binding of HMGBI to unactivated macrophage/ monocytes stimulates translocation of NF-KB, with the subsequent production of pro-inflammatory cytokines that, in turn, stimulate further HMGBI production, The possible crucial role of HMGBI in sepsis, lung inflammation, and arthritis has been proposed. 217 Cells of innate immunity isolated from inflamed tissues characterized by a prevalent DHT response also produce other cytokines that have pivotal roles in the cross-talk between cells of the innate and adaptive immune responses, For instance, IL12, IL-18, and IL-23 are key inducers of cell-mediated immunity that may contribute to the differentiation of recently recruited CD4+ helper T cells into IFN-y-producing Thl cells. 21 B-220 Similarly, IL-15 produced by macrophage may stimulate T cells to drive further TNF-a production by macrophages through direct cell contact (see also Fig. 3-22).221

During chronic inflammation, a large number of growth factors are also secreted by inflammatory cells. Platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), TGF-~, epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) have been shown to play a part in the induction of angiogenesis. 222 Angiogenesis is a physiologic process that consists of the formation of new blood vessels from a preexisting microvascular bed. During chronic inflammation, this process proVides oxygen and nutrients necessary for the high metabolic requirement of resident cells and permits the migration and progressive infiltration of newly recruited inflammatory cells. In inflammatory arthritis, the growth of inflamed tissue (synovial pannus) has been compared with that of a solid tumor because its unregulated outgrowth leads to the invasion and destruction of normal tissues (e.g., joint cartilage, bone). Angiogenesis supports the extensive vascularization that occurs during the proliferation of rheumatoid pannus (see also Fig. 3-22).223 VEGF is one of the most potent endothelial cell-specific mitogens locally produced by activated monoeytes/macrophages and tissue fibroblasts on stimulation by a number of pro-inflammatory cytokines (lL-l, TNF-n, IL-6), other inflammatory mediators (e.g., PGE 2), and physical factors (e.g., hypoxia).224 The downmodulation of this growth factor has been shown to dramatically dampen the degree of inflammation in animal models of arthritis. 225

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traenoic acid (5-HPETE), followed by leukotriene A4 (LTA4). LTB 4 is the most stable molecule among the leukotrienes and is the hydrolytic product of LTA4• LTB 4 is rapidly synthesized by neutrophils and macrophages on challenge with stimuli such as microbial pathogens, toxins, aggregated immunoglobulins, and pro-inflammatory cytokines. LTB 4 is one of the most powerful chemoattracrants; it induces neutrophil aggregation and degranulation and macrophage production of the pro-inflammatory cytokines, O2- and PGE/ 27

Prostaglandins and Leukotrlenes Prostaglandins and leukotrienes are acid lipids that are derived from enzymatic cleavage of arachidonic acid and are produced by most mammalian cells in response to mechanical, chemical, and immunologic stimuli. Arachidonic acid is a member of the 00-6 series of essential fatty acids contained in membrane phospholipids. Activation of the enzyme phospholipase A2 releases arachidonic acid, which is further metabolized by two main enzymatic pathways leading to the final production of a class of mediators belonging to the family of bioactive eicosanoids (Fig. 3-25), Cyclooxygenases (COX) are responsible for the production of prostaglandins both in physiologic and pathologic conditions. Two different isoforms of COX are currently known. COX-l is constitutively expressed in most tissues at a constant level throughout the cell cycle. Prostaglandins are produced in many tissues and regulate many functions, including platelet-dependent homeostasis, renal blood flow, and gastric mucosal integrity. Conversely, COX-2 is usually undetectable in normal tissues but can be rapidly induced by particular cell types (fibroblasts, monocytes, and endothelial cells) on pro-inflammatory stimulation. Activation of COX-2 is thought to playa major role in the inflammatory reactions. 226 Together with the mast cell-derived PGD 2 , the most abundant COX-2 product is PGE 2 . It can sensitize nerve endings to painful chemical and mechanical stimuli, and it also acts as a potent vasodilator. Furthermore, PGE? has a crucial role in the induction of fever after stimulation of specialized endothelial cells in hypothalamic tissue by endogenous pyrogens such as TNF and 1L-6. Leukotrienes are derived from the combined actions of 5-lipoxygenases (5-LOX) and 5-LOX-activating protein (FLAP), with initial formation of 5-hydroperoxyeicosate-

The study of the metabolism of arachidonic acid in inflammatory responses led to the discovery of lipid molecules called lipoxins (LXs), which are derived from different enzymatic cascades that are efficient endogenous mediators of inflammation resolution. 218 Lipoxins are produced after activation of two distinct intracellular pathways, depending on the cell involved and the mode of activation. As previously mentioned, the interaction between leukocytes and platelets at the site of tissue int1ammation leads to the activation in the latter cells of S-LOX, which generates LTA4• However, the activation of adherent platelets leads also to the activation of I2-LOX, which ultimately results in the production of lipoxin A4 and B/ 29 A second pathway of lipoxin production occurs in monocytes and macrophages that are exposed to anti-inflammatory cytokines such as IL-4 and IL-13. In this case, lipoxin production is initiated by a IS-LOX that leads to the generation and release of ISS-hydroxyeicosatetraenoic acid (HETE), which is rapidly taken up and converted by polymorphonuclear cells to lipoxins. 229 Therefore, in peripheral blood neutrophils, a switch in eicosanoid biosynthesis occurs, from predominantly pro-inflammatory molecules (PGE 2 and LTB4) to anti-inflammatory lipoxin, Notably, PGEs itself promotes both S-LOX and I2-LOX gene expression, thus initiating a mechanism of self-limitation of inflammation. 128

Lipoxins display a number of anti-inflammatory activities in many animal models of inflammatory diseases, mainly related to inhibition of recruitment of inflammatory cells into the site of inflammation. They have been

• Figure 3-Z5 Metabolic pathways of lipid-derived proinflammatory and anti-inflammatory mediators (eicosanoids). See text for explanation. COX, cydooxygenase; HETE, hydroxyeicosatetraenoic add.

Membrane phospholipid

I

Phospholipase A,

Arachidonic acid 5-LiPOXygena;/

L T8 4 + - -

/ Inflammation

Leukotriens (LTA 4)

!

COX-l

Prostaglandins 15-LiPOXyg7

12-LiPoxygenase

Lipoxins (LXA4, LXB4)

Control of inflammation

~OX-2

15S-H (HETE)

~poxygenase

(POE 2, P00 2)

~

Inflammation

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59

shown to stimulate the nonphlogistic phagocytosis of apoptotic neutrophils by macrophages. 23o

THE AUTONOMIC NERVOUS AND ENDOCRINE MEDIATORS IN INFLAMMADON

Nitric Oxide and Reactive Oxygen Products

Many studies have demonstrated the role of the nervous and endocrine systems in the maintenance and control of acute and chronic inflammation. The autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis act cooperatively to sustain and regulate tissue inflammation. Similarly, gonadal hormones are known to actively influence the immune response, estrogens being generally implicated as immune response stimulators and androgens as natural suppressors,238.239 The noradrenergic innervation of lymphoid organs and the expression of ~2-adrenergic receptors on lymphocytes, NK cells, and monocyte/macrophages suggest that the autonomic nervous system may influence the immune response, Peripheral tissues are densely innervated by postganglionic sympathetic adrenal fibers and unmyelinated C fibers containing substance P and calcitonin gene-related peptide. 240 Peripheral afferent (sensory) neurons (PAN) are stimulated by several inflammatory mediators, including prostaglandins, bradykinin, leukotrienes, IL-1, IL-6, and neural growth factor, which act as sensitizers for the transmission of pain to the central nervous system via the nociceptive type IVC fibers that pass through the dorsal root to the spinal cord. All these sensitizers act by increasing the intraneuronal concentration of cyclic adenosine monophosphate (cAMP), which can in turn be modulated by morphine/endogenous opioids. 241 Normally, PAN do not communicate with the peripheral efferent postganglionic sympathetic neurons (PGSN) that innervate peripheral tissues. However, dUring inflammation, sensitization of PAN leads to the activation of PGSN, which may ultimately lead, through a vicious circle, to persistent inflammation and pain, mainly because of the release of neuropeptides (e.g., substance P) that promote vasodilatation, plasma extravasation, and leukocyte recruitment and activation. The sympathetic stimulation leads to a negative feedback with release of norepinephrine and other anti-inflammatory mediators (e.g., neuropeptide Y) that are able to suppress neurogenic inflammation. 241 Inflammation leads also to activation of the hypothalamic-pituitary-adrenal axis. 239 Therefore, inflammatory stress can affect immune function both via peripheral responses mediated by sympathetic innervation and via central activation of the HPA axis. The activation of the HPA axis through the overproduction of corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) leads to the adrenal production of anti-inflammatory glucocorticoids (GC). Glucocorticoid effects are mediated by their ability to modulate gene expression. GC act by binding to their specific receptors (GCR), which exist as a and ~ isoforms. 242 The binding of GC with GCRa leads to translocation of the GC/GCRa complex to the nucleus, where it interferes with the activation of genes inducible by AP-1 and NF-KB, such as those for IL-2, IL-6, IL-8, IL1-~, and TNF-a, and with T cell proliferation. Conversely, GCR~ is devoid of signal transmission after GC binding and can act as an inhibitor of GCRa. Enhanced GCR~ expression

Nitric oxide (NO) is produced by mammalian cells by the action of nitric oxide synthase (NOS).231 The production of NO plays an integral part in the maintenance of several physiologic functions involved in the control of cardiovascular, respiratory, and nervous systems. During inflammation, inducible NOS is activated by pro-inflammatory cytokines (IFN-y, IL-17, TNF, IL-1). This enzyme catalyzes the production of NO and L-citrulline from Larginine and molecular oxygen. The induction of NO under conditions of immune activation can be both beneficial, in the eradication of microorganisms, and harmful, by causing tissue damage. 232 Similarly, generation of reactive oxygen products is essential for the microbicidal activity of phagocytes and in directly mediated tissue damage in acute and chronic inflammatory conditions. Their generation is mediated by the activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme located in the plasma membrane of phagocytes. The activation of NADPH oxidase leads to the formation of superoxide (0 2-), a univalently reduced oxygen radical. Superoxide spontaneously dismutases into hydrogen peroxide (H 20), which may react with chloride ions to form the toxic hypochlorous acid (HOC!) in a reaction catalyzed by myeloperoxidase. This latter enzyme is abundantly present in the preformed granules of phagocytes, and it is rapidly released after cell activation. 233

Proteolytic Enzymes Myeloperoxidase and a number of other proteolytic enzymes are abundantly present in the granules of professional phagocytes, such as neutrophils. 234 ,235 Among them are serine proteinases (elastases, cathepsin G), acid hydrolases (~-glucuronidases, a-mannosidases), and other peptides with bactericidal activity (lysozyme, defensins, lactoferrin, azurocidin). Monocytes and macrophages do not possess preformed granules, but they possess lysozymes that contain preformed enzymes or may actively synthesize them after activation. Matrix metalloproteinases (MMPs) comprise a large family of proteolytic enzymes produced by fibroblasts, macrophages, neutrophils, and chondrocytes on stimulation with pro-inflammatory cytokines and growth factors. 236 Their main function is the remodeling of extracellular matrix during tissue resorption. The proteolytic activity of MMPs is thought to represent a crucial component of both physiologic (embryonic development, organ morphogenesis, angiogenesis) and pathologic (chronic inflammatory diseases, tumors) conditions. 237 According to many authorities, MMPs are one of the most important classes of final mediators of tissue damage in many chronic inflammatory conditions, and their specific inhibition is considered to be a possible promising therapeutic target.

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has been found on peripheral blood mononuclear cells from patients resistant to glucocorticoids. 242 ,243 The physiologic counter-regulation of GC is mediated by pro-inflammatory hormones and cytokines. Prolactin is a pro-inflammatory neuropeptide that is produced by pituitary gland but also by circulating mononuclear cells. In vitro and ex vivo studies show that prolactin antagonizes the immunosuppressive effects of GC in murine species and stimulates production of anti-DNA antibodies by normal lymphocytes. 244 Macrophage inhibitory factor (MIF) is a cytokine produced by activated macrophages in response to proinflammatory stimuli. In addition to a number of pro-inflammatory functions, such as amplification of TNF, IL-6, IL-1, and NO production by macrophages, MIF displays the unique ability to counteract the immunosuppressive effect of GC by a poorly understood mechanism. Notably, a single-nucleotide G-to-C polymorphism at position -173 of the MIF gene, which is related to an increased expreSSion of MIF by peripheral blood mononuclear cell stimulation, has been associated with systemic-onset JIA. Patients with this polymorphism required significantly longer GC treatment than did patients with the more frequent GG genotype. 245 ,246

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Mediterranean fever locu, CMEFV) on chromosome 16p 13.3. Genomics 42: 83-95, 1997. McDermott MF, Aksentijevich I, Galon J, et al: Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97: 133-144, 1999. Feldmann J, Prieur AM, Quartier P, et al: Chronic infantile neurological cutaneou, and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocyte,. Am J Hum Genet 71: 198-203, 2002. Miceli-Richard C, Lesage S, Rybojad M, et al: CAR015 mutation, in Blau syndrome. Nat Genet 29: 19-20, 2001. Hugot JP, Chamaillard M, Zouali H, et al: A~sociation of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 41: 599--{i03, 2001. Kantarci OH, Hebrink DO, Achenbach SJ, et al: CTI.A-4 is associated with su,ceptibility to multiple sclerosis. J Neuroimmunol 134: 133-141, 2003. Xia B, Crusius JB, Wu J, et al: CTLA-4 gene polymorphisms in Dutch and Chinese patients with inflammatory bowel disease. Scand J Gastroenterol 37: 1296-1300, 2002, Kouki T, Gardine CA, Yanagawa T, et al: Relation of three polymorphi"u, of the CTI.A-4 gene in patients with Grave, di,ea,e. .l Endocrinol Invest 25: 208-213, 2002. Rodrigue, MR, Nunez-Roldan A, Aguilar F, et al: A'Sociation of the CTI.A-4 3' untranslated region polymorphism with the susceptibility to rheumatoid arthritis. Hum Immunol 63: 76-81, 2002. Prokunina L, Ca'tillejo-Lopez C, Oberg F et al: A regulatory polymorphism in PDCD1 is associated with susceptibility to 'ystemic lupus erythematosus in humans, Nat Genet 32: 666-669, 2002. Ridgway WM, Fathman CG: The a'5ociation of MHC with autoimmune di,ea'es: understanding the pathogenesis of autoimmune mabete,. Clin Immunollmmunopathol 86: 3-10. 1998. Andersson EC, Svendsen P, Svejgaard A, et al: Rev Immunogene!. A molecule ba,i, for the HLA a'5ociation in rheumatoid arthritis, Rev Immunogenet 2: 81-87, 2000. Botto M, Walport MJ: C1q, autoimmunity and apopto,i" Immunobiology 205: 395-406, 2002. Salmon .lE, Millard S, Schachter LA, et al: Fe gamma RlIA alleles are heritable risk factors for lupus nephritis in African American" Clin Inve't 97: 1348-1354, 1996, Hau,mann S, Wucherpfennig W: Activation of autoreactive T cells by peptides from human pathogens, Curr Opin Immunol 9: 831-838, 1997. Miller SO, McRae BL, Vanderlugt CL, et al: Evolution of the T-cell repertoire during the cou!'e of experimental immune-mediated demyelinating disease. Immunol Rev 144: 225-244, 1995, Kaufman DL, Clare-Salzler M, TianJ, et al: Spontaneou, 10'5 of T cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabete" Nature 366: 69-72, 1993. Wekerle H: The viral triggering of autoimmune disease. Nature Med 4: 77G-771 , 1998. Holoshitz J, Naparstek Y, Ben-Nun A, et al: Lines of T lymphocyte, induce or vaccinate again't autoimmune arthritis, Science 219: 56-58, 1983, McLaren NK, Atkinson MA: Insulin-dependent diabetes mellitus: the hypothesi, of molecular milnicry between islet cell antigens and microorganisms. Mol Med Today 2: 76-83, 1997, Wucherpfennig KW, Strominger JL: Molecular mimicry in T-cell mediated autoimmunity: viral peptides activate human T cell clone, specific for myelin ba,ic protein. Cell 80: 695-705, 1995, Gmss OM, Forsthuher T, Tary-Lehmann M, et al: Identification of LFA-1 as a candidate autoantigen in treatment-re,i'tant Lyme arthritis. Science 281: 703-706, 1998, Albani S, Key'tone EC, Oilier WER, et al: Positive selection in autoimmunity: abnormal immune responses to a bacterial dna] antigenic determinant in patients with early rheumatoid arthritis, Nat Med 1: 448-452, 1995. Prakken BJ, Samodal R, Le TO, et al: Epitope-specific immunotherapy induces immune deviation of proinflammatory T cell, in rheumatoid arthritis. Proc Nati Acad Sci USA 23: 4228-4233, 2004. Horwitz MS, Bradley LM, Harbertson J, et al: Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat Med 4: 781-785, 1998. Segal BM, Dwyer BK, Shevach EM: An interleukin (ILJ-10/IL-12 immunoregulatory circuit controls su,ceptibility to autoimmune disease. J Exp Med 187: 537-546, 1998. Behar SM, Porcelli SA: Mechanisms of autoimmune disease induction, Arthritis Rheum 38: 458-476, 1995. Robbie-Ryan M, Brown M: The role of mast cells in allergy and autoimmunity. Curr Opin Immunol 1: 728-733, 2002. Brucato A, Franceschini F, Doria A, et al: Pathogenetic a8'ociations of maternal anti-Ro/SSA antibodie,. Lupus 11: 650, 2002. Wada K, Kazukawa I, Someya T, et al: Maternal hypothyroidism in autoimmune thyroiditis and the prognosis of infants. Endocr J 47 (SuppIJ: 5133-S135, 2000, Webert KE, Mittal R, Sigouin C, et al: A retrospective 11-year ana!y'is of obstetric patients with idiopathic thrombocytopenic purpura. Blood 102: 4306-4311, 2003.

169, Martin F, Chan AC: Pathogenic roles of B cells in human autoimmunity; insights from the clinic. Immunity 20: 517-527, 2004. 170. Trende!enburg M, Schifferli JA: Cryoglobulins in chronic hepatitis C viru, infection. Clin Exp Immunol 133: 153-155, 2003, 171. La,smann H, Ransohoff RM: The CD4-Th1 model for multiple sclerosi" a crucial re-appraisal. Trends Immunol 25: 132-137, 2004. 172. Roep BO: The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure, Diabetologia 46: 305-321, 2003. 173. Romagnani P, Annunziato F, Baccari MC, Parronchi P: T cells and cytokines in Crohn's disease, Curr Opin Immunol 9: 793-799, 1997. 174. Panayi GS, Lanchbury JS, Kingsley GH: The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 35: 729-735, 1992, 175. Gattorno M, Facchetti P, Ghiotto F, et al: Synovial fluid T cell clones from oligoarticular juvenile arthritis patients di'pJay a prevalent Thl/ThO patterns of cytokine secretion irrespective to immunophenotype. Clin Exp Immunol 109: 4-11, 1997. 176. Wedderburn LR, Robinson N, Patel A, et 'II: Selective recruitment of polarized T cells expreS'ing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthriti,. Arthritis Rheum 43: 765-774, 2000, 177. Firestein GS: Evolving concepts of rheumatoid arthritis. Nature 423: 356-361, 2003. 178. Takemura S, Braun A, Crowson C, et al: Lymphoid neogenesis in rheumatoid ,ynovitis. J Immunol 167: 1072-1080, 2001. 179. Gebhard JR, Perry CM, Harkins S, et al: Cox,ackievirus B3-induced myocarditis: perforin exacerbates disease, but plays no detectable role in vims clearance. Am J Pathol 153: 417-428, 1998. 180, Alon R, Feigelson S: From rolling to arrest on blood vessels: leukocyte tap dancing on endothelial integrin ligand, and chemokines at sub-second contacts. Semin Immunol 14: 93-104, 2002, 181. Muller WA: Leukocyte-endothelial-cell interaction, in leukocyte transmigration and the inflammatOly respon,e. Trends Immuno! 24: 327-334, 2003, 182. Frenette PS, Wagner DO: Adhesion molecule,: part 1. N Engl J Med 334: 1526-1529, 1996. 183. Patel KD, Cuvelier SL, Wiehler S: Selectins: critical mediators of leukoC}1e recruitment. Semin lnununol 14: 73-81, 2002. 184. Weber C: Novel mechanistic concepts for the control of leukocyte transmigration: specialization of integrins, chemokines, and junctional molecules, Mol Med 81: 4--19, 2003, 185. Pribila JT, Quale AC, Mueller KL, Shintizu Y: Integrins and T cell-mediated immunity, Ann Rev Immunol 22: 157-180, 2004. 186, Alon R, Ka'5ner PO, Carr MW, et al: The integrin VLA-4 supports tethering and rolling in flow on VCAM-l. J Cell Bioi 128: 1243-1253, 1995. 187. von Andrian UH, Engelhardt B: Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med 348: 68-72, 2003, 188. Baggiolini M: Chemokines in patholo!lY and medicine. J Intern Med 250: 91-104, 2001. 189. Campbell OJ, Kim CH, Butcher EC: Chemokines in the systemic organization of immunity, Immunol Rev 195: 58-71, 2003. 190. Gunn MD, Kyuwa S, Tam C, et al: Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 189: 451-460, 1999. 191. Fais S, Malorni W: Leukocyte uropod formation and membranelcytoskeleton linkage in immune interactions. J Leukoc Bioi 73: 556-563, 2003. 192, Gerard C, Rollin, BJ: Chemokines and disease. Nat Immunol 2: 108--115, 2001. 193. Lloyd CM, Delaney T, Nguyen T, et al: CC chemokine receptor (CCRJ3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J Exp Med 191: 265-274, 2000, 194. Proudfoot AE: Chemokine receptors: multifaceted therapeutic targets, Nat Rev Immunol 2: 106-115, 2002. 195. Abbas AK, Lichtman AH: Cytokines. In Abbas AK, Lichtman AH (eds): Cellular and Molecular Inuuunology, 5th ed. Philadelphia, WB Saunders, 2003, pp. 243-274, 196. Feldmann M, Maini RN: Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19: 163-196,2001. 197. O'Shea .l.l, Ma A, Lipsky P: Cytokines and autoimmunity. Nat Rev Immunol 2: 37-45, 2002. 198, Beutler BA, Milsark IW, Cerami A: Cachectin/tumor necrosis factor: production, di'tribution, and metabolic fate in vivo, J Immunol 135: 3972-3977, 1985. 199, Dempsey PW, Doyle SE, He JQ, Cheng G: The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev 14: 193-209, 2003. 200, Lay JD, Tsao q, Chen JY, et 'II: Upregulation of tumor necro,is factor-alpha gene by Ep'tein-Barr virus and activation of macrophages in Ep'tein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome. J Clin Invest 100: 1969-1979, 1997. 201. Dinarello CA: Biologic basis for interleukin-1 in disease. Blood 87: 2095-2147, 1996, 202, Greenfeder SA, Nunes P, Kwee L, et al: Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Bioi Chern 270: 13757-13765, 1995.

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203. Mantovani A, Locati M, Vecchi A, et al: Decoy receptors: a strategy to regulate inflarrunatory cytokines and chemokines. Trends Irrununol 22: 328-336, 2001. 204. Dayer ]M: Evidence for the biological modulation of IL-l activity: the role of IL-IRa. Clin Exp Rheumatol 20(Suppl 27): SI4-S20, 2002. 205. Horai R, Saijo S, Tanioka H, et al: Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in iriterleukin 1 receptor antagonist-deficient mice. ] Exp Med 191: 313-320, 2000. 206. Dinarello CA: The role of the interleukin-l-receptor antagonist in blocking inflammation mediated by interleukin-I. N Engl] Med 343: 732-734, 2000. 207. Hirano T, Yasukawa K, Harada H, et al: Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324: 73-76, 1986. 208. Ishihara K, Hirano T: IL-6 in autoimmune disease and chronic inflarrunatory proliferative disease. Cytokine Growth Factor Rev 13: 357-368, 2002. 209. Taga T, Kishimoto T: Gp130 and the interleukin-6 family of cytokines. Annu Revlrrununol 15: 797-819, 1997. 210. Muller-Newen G: The cytokine receptor gp130: faithfully promiscuous. Sci STKE 201:PE40, 2003. 211. De Benedetti F, Massa M, Pignatti P, et al: Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. ] Clin Invest 93: 2114-2119, 1994. 212. De Benedetti F, Alonzi T, Moretta A, et al: Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I: a model for stunted growth in children with chronic inflarrunation. ] Clin Invest 99: 643-650, 1997. 213. De Benedetti F, Martini A: Is systemic juvenile rheumatoid arthritis an interleukin 6 mediated disease? ] Rheumatol 25: 203-207, 1998, 214. Cazzola M, Ponchio L, De Benedetti F, et al: Defective iron supply to erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood 87: 4824--4830, 1996. 215. Yokota S: Interleukin 6 as a therapeutic target in systemic-onset juvenile idiopathic arthritis. Curr Opin Rheumatol 15: 581-586, 2003. 216. Andersson U, Wang H, Palmblad K, et al: High mobility group 1 protein (HMG:l) stimulates proinflammatory cytokine synthesis in human monocytes. ] Exp Med 192: 565-570, 2000. 217. Ulloa L, Badiwalla FM, Andersson U, et al: High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis. Arthritis Rheum 48: 876-881, 2003. 218. Trinchieri G: Interleukin-12 and the regulation of innate resistance and adaptive immunity, Nat Rev Irrununol 3: 133-146, 2003. 219. Dinarello CA, Fantuzzi G: Interleukin-18 and host defense against infection. ] Infect Dis 187(Suppl 2); S370-S384, 2003. 220. Lankford CS, Frucht DM: A unique role for IL-23in promoting cellular immunity. Leukoc Bioi 73:49-56, 2003. 221. Liew FY: The role of innate cytokines in inflarrunatory response. Irrununol Lett 85: 131-134, 2003. 222. Koch AE: Angiogenesis. Arthritis Rheum 41: 951-962, 1998. 223. Szekanecz Z, Koch AE: Vascular endothelium and immune responses: implications for inflammation and angiogenesis. Rheum Dis Clin North Am 30: 97-114, 2004.

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224. Berse B, Hunt ]A, Diegel R] et al: Hypoxia augments cytokine (transforming growth factor-beta [TGF-~l and IL-l)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin Exp Irrununol1l5: 176-182, 1999. 225. Mioda], Maciewicz R, Kendrew], et al: Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest 80: 1195-1205, 2000. 226. Turini ME, DuBois RN: Cyclooxygenase-2: a therapeutic target. Annu Rev Med 53: 35-57, 2002. 227. Samuelsson B, Dahlen SE, Lindgren ]A, et al: Leukotrienes and Iipoxins: structures, biosynthesis, and biological effects. Science 237: 1171-1176, 1987. 128. Serhan CN, Chiang N: Novel endogenous small molecules as the checkpoint controllers in inflarrunation and resolution: entree for resoleomics. Rheum Dis Clin North Am 30: 69-95, 2004. . 229. Levy BD, Clish CB, Schmidt B, et al: Lipid mediator class switching during acute inflarrunation: signals in resolution. Nat Irrununol 2: 612-619, 2001. 230. Nathan C: Points of control in inflarrunation. Nature 420: 846-852, 2002. 231. Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB] 6: 3051-3064, 1992. 232. Chakravortty D, Hensel M: Inducible nitric oxide synthase and control of intracellular bacterial pathogens. Microbes Infect 5: 621-627, 2003. 233. Babior BM, Lambeth ]D, Nauseef W: The neutrophil NADPH oxidase. Arch Biochem Biophys 397: 342-344, 2002. 234. Edwards SW, Watson F: The cell biology of phagocytes. Irrununol Today 16: 508-510, 1995. 235. Mollinedo F, Borregaard N, Boxer LA: Novel trends in neutrophil structure, function and development. Immunol Today 12: 535-537, 1999. 236. Nagase H, Woessner ]F ]r: Matrix Metalloproteinases. ] Bioi Chern 274: 21491-21494, 1999. 237. Bode W: Structural basis of matrix metalloproteinase function. Biochem Soc Symp 70: 1-14, 2003. 238. Chikanza IC, Grossman AB: Reciprocal interactions between the neuroendocrine and immune systems during inflarrunation. Rheum Dis Clin North Am 26: 693-711, 2000. 239. Cutolo M, Bijlsma ]W, Lahita RG, et al: Altered neuroendocrine irrunune (NEI) networks in rheumatology. Ann N Y Acad Sci 966: xiii-xviii, 2002. 240. Besson ]M: The neurobiology of pain. Lancet 353: 1610-1615, 1999. 241. Niissalo S, Hukkanen M, Imai S, et al: Neuropeptides in experimental and degenerative arthritis. Ann N Y Acad Sci 966: 384-399, 2002. 242. Vottero A, Chrousos GP: Glucocorticoid receptor beta: view I. Trends Endocrinol Metab 10: 333-338, 1999. 243. Chikanza IC: Mechanisms of corticosteroid resistance in rheumatoid arthritis: a putative role for the corticosteroid receptor beta isoform. Ann N Y Acad Sci 966: 39-48, 2002. 244. Vera-Lastra 0, ]ara L], Espinoza LR: Prolactin and autoirrununity. Autoimmun Rev 1: 360-364, 2002. 245. Calandra T, Roger T: Macrophage migration inhibitory factor: a regulator of innate immunity, Nat Rev Irrununol 3: 791-800, 2003. 246. De Benedetti F, Meazza C, Vivarelli M, et al: Functional and prognostic relevance of the -173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 48: 1398-1407, 2003.

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INTEGRATIVE GENOMICS Robert A. Colbert and David N. Glass

When viewed from the perspective of the pediatric rheumatology clinic, few patients with arthritis appear to have genetically determined diseases. Family histories are rarely positive for the more common diseases, including juvenile rheumatoid arthritis ORA), and diseases with a mendelian pattern of inheritance are especially uncommon. Few extended families with chronic pediatric rheumatologic illnesses suitable for traditional linkage studies have been reported. Pediatric rheumatic diseases share this scenario with autoimmune diseases in general, in which the absence of family history is the common experience. One notable exception is spondyloarthritis, particularly ankylosing spondylitis; in some families, the phenotype follows an autosomal dominant inheritance pattern linked to the human leukocyte antigen (HLA) allele HLA-B27, with penetrance as high as 20%. The paradoxical view that diseases without a family history, including the subtypes of JRA, are genetically based is considered in this context; in addition, it is commonly hypothesized that this genetic effect extends not only to a primary predisposition but also to variation in the extent and severity of disease; that is, many, if not all, aspects of the disease phenotype are also genetically determined, whether it be JRA, systemic lupus erythematosus [SLE], scleroderma, or dermatomyositis. The presence of HLA associations in most of these diseases already provides some indication of their genetic nature, although for many years HLAor HLA-linked genes were not necessarily perceived to be central to pathogenesis. It is argued herein that they are a necessary part of genetic predisposition (although only a component) and that other, non-major histocompatibility complex (MHC) genes predispose to the disease in a given individual. This does not exclude an environmental component. It is timely to note that the enormous explosion in knowledge from the Human Genome Project and its related technological advances allows questions to be asked and tested about the role of genes in all diseases, not just those traditionally viewed as having a genetic basis. Current high-throughput molecular technology not only allows screening of DNA polymorphisms but also can track newly identified genes; thus, the traditional approach, starting from a disease phenotype and then identifying the gene, can be reversed. In addition, highthroughput methodology using microarrays is also being applied to gene expression, so that virtually the entire

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expressed genome can be evaluated at the RNA level, and perhaps eventually at the protein level. This socalled functional genomics can be combined with data from DNA polymorphisms to yield comprehensive integrative genomic approaches to human disease. This chapter reviews knowledge of the genome with respect to genes and polymorphic variability before discussing the genetic components of pediatric rheumatic diseases and the extent to which they have or do not have traditional mendelian patterns of inheritance.

THE GENOME The genome can be defined as the individual's (or cell's) total genetic information. The related science of mapping, sequencing, and analyzing genomes is known as genomics. The Human Genome Project, started in 1990, proceeded at an outstanding pace, with a physical and DNA sequence map of the human genome substantially completed well ahead of the original 2003 target. The working draft announced in spring 2000 reported assembled sequences for approximately 85% of the genome.' This map will be the basis for understanding gene function and its pathophysiology. A complete description of this project can be found at the National Human Genome Research Institute Web site, http://www.genome.gov/HGP!

Structure At the DNA level, genetic information consists of more than 3 x 109 base pairs organized into three components: paired autosomal chromosomes, two sex chromosomes, and mitochondrial DNA. A large part of this genetic material is aggregated into repetitive sequences that contribute, as either long or short interspersed sequences, to the familiar banding pattern that characterizes the morphology of chromosomes. The remainder is single copy DNA, about 10% of the whole, which is primarily organized into genes, of which only about 2% overall are protein coding genes and an additional 4% or so contain conserved sequence elements (CSEs) that may include promoter regions.' The human genome most likely encodes 30,000 to 40,000 genes. Experimentally, expressed or functional genes are documented as expressed sequence tags (ESTs), which are partially sequenced complementary DNA

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(cDNA) molecules. A cDNA molecule is synthesized DNA that is complementary to RNA and reflects expressed gene products. The number of these genes expressed is probably different in different organs: A metabolically complex organ such as the liver may have 40,000 expressed genes; the synovium may well have fewer, perhaps 30,000, varying with stage of development. Genes are divided into coding and noncoding compartments (exons and introns, respectively) with additional promoter and flanking sequences that are less well understood. The latter are a major part of the regulatory process, which determines when and where specific genes are expressed. Thus, the gene is a complex unit in both its structure and its regulation.

Polymorphic Elements It is fundamental to the understanding of human diversity and of disease to recognize that, although the genome and gene structure are broadly the same for all persons (99.9% identity), variability is substantial among individuals with respect to ethnicity, and this can give rise to disease-the focus of this review. This variability may be local (Le., gene specific), or it may be part of genome-wide polymorphic elements.

Local Variability Local variability in a given gene or segment of DNA containing several genes can result from a change or mutation in a single nucleotide or from deletions, translocations, or gene conversions. The resulting functional change in even a single expressed gene product can range from deleterious (including fataD, to neutral, or even to beneficial (gain in function). Clearly, the nature and site of the change (e.g., coding regions, regulatory regions) are critical in this regard and can be reflected in changed phenotypes and disease. The use of single nucleotide polymorphisms (SNPs) is a formidable tool to evaluate both the whole genome (see later discussion) and local variability. Examples of individual gene variability of relevance to autoimmunity include complement deficiencies and the chromosome 22 deletion associated with JRA. 3

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small, repetitive sequences of DNA, they are commonly called microsatellites. These polymorphisms can be distinguished by methods based on the polymerase chain reaction (PCR) (see later discussion). Their utility is enhanced by the availability of genome-wide maps and by knowledge of their polymorphic information content (PIC), which allows the selection of those polymorphisms that are likely to optimize any given data set.

Single-Nucleotide Polymorphisms SNPs are much more common than VNTRs.5 Some 4.5 million SNPs were validated by mid-2004, and there may be 10 to 20 million of them in the genome. SNPs form the basis of restriction fragment length polymorphisms (RFLPs), which are SNPs that happen to be located in an enzyme (endonuclease) recognition site. SNPs that are located in a coding region are known as cSNPs. 6 Overall, less is known about the map positions and PICs of SNPs than of VNTRs, although this situation is changing rapidly. With regard to SNPs being a tool for genomics, their number now allows a much greater frequency of markers, offsetting the fact that VNTRs are more polymorphic. Their ubiquitous presence allows their use in association studies, adding greater analytic power than is available through linkage studies, including the use of affected sibling pairs (ASPs). The ability to use SNPs will be enhanced by the new DNA technologies, which may utilize several different platforms, including gene chips, beads, and real-time PCR, although the very great number of SNPs (perhaps 200 or more in some genes) adds complexity to their analysis. 7 However, their utility in the dissection of complex genetic traits can be illustrated by two SNPs that have been associated with components of a disease phenotype. These SNPs involve a mutation that results in a gain of function in the interleukin-4 receptor gene, which is associated with severe asthma, and a mutation in a ~2-adrenergic receptor gene (ADRB2) that is associated with greater resistance to adrenergic drugs. 8,9 Genome-wide maps are being generated, and there are going to be various sources of information for constructing these maps.

Maps Genome-Wide Polymorphlsms A key aspect of research in the genetics of disease is associating sequence variations with heritable phenotypes. One of the consequences of the explosion in knOWledge relating to the genome has been the identification of polymorphic variants that occur throughout the genome in both coding and noncoding elements of DNA. There are two important broad classes of importance with respect to the science of genomics, very numerous tandem repeats (VNTRs) and SNPs.

Very Numerous Tandem Repeats VNTRs were the first genome-wide polymorphisms to be documented; more than 10,000 of them occur throughout the genome. 4 They appear to be randomly distributed in both coding and noncoding regions. Because they are

Chromosome Map Cytochemical approaches have been widely used to generate the familiar chromosome banding patterns. The addition of fluorescent in situ hybridization (FISH) has been a substantial benefit, combining cytochemical and molecular approaches. Although only broad localization is possible, several thousand genes have been mapped by this process to specific chromosomes, albeit with low resolution. Fluorescent tags on intact chromosomes cannot be resolved into separate spots unless they are 2 to 5 million base pairs apart.

Genetic Map Although a genetic map is an extension of the chromosome map described earlier, its creation is a more

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detailed process by which the relationships among individual genes and their eventual assignments to specific chromosome regions and linkage groups becomes possible. Sufficient genes or polymorphic markers are mapped so as to effectively cover the whole genome. Traditionally, extended kindreds are studied for the coinheritance of a particular phenotype, whether physiologic or pathologic. Genes that cosegregate are established by this process; two genes can be shown to be closely linked and, therefore, a component of a linkage group. This sometimes involves genes of like function, the linkage group having arisen by gene duplication, but often a cluster of genes do not have similar or related functions. Examples of functional clusters are the HLA genes and the T-cell receptor genes, each of which each form close linkage groups. The statistical analyses used in such situations are logarithm of the odds Ood) scores; a score of 3.0 or more is the standard for establishing linkage between two genes. A particular linkage group may be inferred from findings in other species, a concept known as !>ynteny. Although clustering of a particular set of genes may be shared across species, the same linkage group may be found on a different chromosome in humans. For example, the MHC linkage group is located on chromosome 6 in humans and on chromosome 17 in the mouse. The recombination rate detected in families is a measure of the closeness of linkage. Recombination may be current or ancestral and translates into map distance, or centimorgans (cM). There are approximately 3500 cM in the human genome. This genetic distance, which depends on recombination frequency, may be different from the physical distance between linkage groups on the same chromosome. The HLA region itself amounts to about 3.5 cM (i.e., about 0.1% of the genome).

allow the definition of linkage disequilibrium throughout the genome and the production of the so-called Hap Map. This is an extension of the Human Genome Project in which the latest high-throughput technology is used to identify tSNPs (or tag SNPs) that identify haplotype blocks. 12 Such a map will provide tSNPs that effectively mark a particular haplotype. These specific SNPs can then be used in genome-wide screens as a surrogate for large stretches of DNA covered by linkage disequilibrium. This may allow an extremely cost-effective screening of at least 80% of the genome. It will limit the number of SNPs that must be used to ensure complete coverage of the genome for wide-scale genomic studies. The physical map will identify the genes and their locations within the total genome but will not determine whether they are functional. There are genes that cannot be expressed because of specific mutations; these genes are known as pseudogenes. Pseudogenes need to be differentiated from genes that, because of mutation, cannot function. The nonfunctioning gene is known as a null gene and is allelic with functioning variants.

Physical Map

Biotechnology and Blolnformatlcs

The advent of DNA sequencing allows definition of individual genes as well as their relationships with each other in terms of intervening DNA structure. Considerable amounts of genetic data have been generated and entered into sequence databanks, much of which is available to investigators (e.g., National Center for Biotechnology Information, http://www.ncbi.nim. nih.gov). This process allows physical mapping of individual stretches of DNA; interim physical maps are based on VNTRs and, more recently, on SNPS. IO ·11 The HLA region, for example, has on the order of 3500 kilobases (kb) of DNA, with approximately 180 genes and perhaps 80 VNTRs, but probably several thousand SNPs. Currently, a major effort is being vested in the identification of SNPs and the establishment of their map positions. Groups of alleles from closely linked genes are known as baplotypes. Some haplotypes are much more common than others, based on the concept of linkage disequilibrium. It has long been recognized that alleles of closely linked genes may not occur at random (Le., they show linkage disequilibrium). This has been most comprehensively documented in the MHC as extended or ancestral haplotypes. The generation of SNP maps will

The Human Genome Project-and with it the potential to establish the genetic basis of disease-would not have been possible without parallel technological advances. One key element is the PCR. This method allows the expansion of specific segments of DNA to make enough of them available for quantitative analysis, including sequencing. With respect to genomics, the widespread availability of polymorphic markers detectable by PCR for every part of the genome and the commercial availability of the appropriate PCR primers have created great opportunities for scientific advances. These primer pairs are organized into sets that allow a genome-wide approach. IS Although substantial work is still involved, marker sets are available that allow multiplexing of primer pairs based on product size and fluorescent tags, permitting up to 15 genotypes to be determined simultaneously on a single lane of a gel or capillary tube. In parallel, high-throughput genotyping/ sequencing machines generate more than 20,000 genotypes per week l6 The newer technologies are now capillary based rather than gel basedY This advance, combined with robotics for the PCR process, allows a laboratory with one or two technical staff members

Functional Map The functional map is based on functional genomics, the analysis of individual gene function, which is itself based on the structural or physical map.13 Through the process of identification of expressed genes (i.e., ESTs), assisted now with technological advances using gene arrays,1'1 it will be possible not only to identify all expressed genes in a given tissue but also to consider their function. Comparisons between developing and developed tissues, as well as disease and normal states, are now ongoing and should progress rapidly. This will result in a functional map.

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to complete up to 1 miJIion genotypes per year. A medium-density genome screen (about every 10 cM) for a given disease may number about 150,000 genotypes. The most recent technology with SNP chips or beads may allow up to 1 miJIion genotypes to be generated per day by two or three staff members, although cost remains a significant issue. In parallel with this enormous flow of data is the development of appropriate software to assign genotypes, to validate the accuracy of the genotyping in the context of the family tree, and then to facilitate the analytic process. Automated processes are particularly important for SNPs, because they are going to be used in lO-fold or greater numbers than VNTRs. The development of software for large databases has been paralleled by conceptual advances in genetic methods. Of particUlar relevance are approaches to linkage analysis that do not depend on large kindreds. Two particularly relevant methods are allele sharing using ASPs and transmission disequilibrium testing (TDT), which uses family-based controls. I8-21 TOT is an alternative approach to establishing linkage that is valid for either simplex or multiplex families (see later discussion). SNPs wiJI promote a shift back to association studies once they are affordable in large numbers.

MONOGENIC DISEASE IN PEDIATRIC RHEUMATOLOGY The diseases inherited in a pattern recognizable as mendelian, primarily autosomal dominant and autosomal recessive, are numerous. More than 10,000 are now listed; of these, hundreds might well involve the musculoskeletal system. A few manifest directly with a form of arthritis, others with musculoskeletal features. These particular disorders make up a very small portion of the referral base for a pediatric rheumatology clinic, but they are well recognized. However, with the increasing capacity to identify particular genes and their mutations, as well as the functional consequences that lead to particUlar phenotypes, molecular analysis has become more practical and necessary-as has awareness of the phenotypes of these disorders. The familial categories of inherited disease (dominant, recessive, and X-linked) proVide patterns of inheritance that are discernible if typically penetrant. A dominant disease should be evident in every generation, shOWing vertical transmission; a recessive disease occurs in approximately one of four children in a family and is more likely to occur in the offspring of consanguineous marriages. X-linked recessive diseases become evident in male children whose mothers are the carriers, although female carriers may show some features of the disease, consistent with the Lyon hypothesis of X chromosome inactivation. In 1997, Chalom and colleagues22 categorized these diseases into three groups: arthritic diseases (e.g., Lesch-Nyhan), those resulting in contractures or stiff joints (e.g., Gaucher's disease), and those causing hypermobility (e.g., Ehlers-Oanlos syndrome) (see Chapter 40). A total of 75 disorders were identified,

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probably only a portion of the whole. 23 It is recognized that not all of these disorders occur in the classic or traditional mendelian manner.

Confounding Variables In the Recognition of Mendelian Inheritance Monogenic effects may be implicated in a given instance but may not be recognizable for a variety of reasons. Transmission anomalies include inheritance of two copies of a whole chromosome from the same parent (uniparental disomy). Other variations in a monogenic disease may have more subtle bases and are summarized in Table 4-1. In addition, modifier genes may alter a specific phenotype, resulting in different levels of expression. A disease caused by a single gene could be modified by the function of other genes on a variable basis. This phenomenon might be distinguished from complex genetic traits in which a number of genes are required to generate the primary disease phenotype, although the distinction is probably relative.

COMPLEX GENETIC TRAITS A complex genetic trait may be defined as one that is dependent on multiple genes and displays nonmendelian inheritance patterns. It is likely that the diseases more commonly encountered in the pediatric rheumatology clinic are the result of complex genetic traits, although the evidence to support this statement is not yet at hand. However, as is evident from the preceding discussion, the genome-wide approaches needed to validate the concept are available, and they have already been tested in insulin-dependent (type 1) diabetes mellitus and many other autoimmune diseases. 24 •25 Examples of complex genetic traits in this category include rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, psoriatic arthritis, scleroderma, and SLE, in addition to type 1 diabetes. 26 Other potential complex genetic traits, including hypertension and osteoarthritis, have a metabolic but nonimmunologic basis. Of most relevance to this discussion is the likelihood that JRA and its various subtypes are complex genetic traits. 27 How are these recognized in the absence of genetic data? Features that suggest a complex genetic trait include a definite but limited family history but with

.~ TABlE 4-1

Variables in 'he Recogni'ion of Monogeni. Disease

Uniparental disomy New mutations Low penetrance Parental imprinting Variable phenotype Mitochondrial genes Parental reproductive choice or fitness From Ostrer H: Non-mendelian genetics in humans. In Oxford Monographs on Medical Genetics No. 35. Oxford. England. Oxford University Press. 1998.

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few or no extended affected kindreds; an increased presence of other autoimmune diseases in the family28; and HLA disease associations that suggest an immunologically related complex genetic trait. Of these features, HLA associations have been extensively documented, and family histories have been reported for the disease affecting the proband, but less commonly for autoimmune diseases in general. Individual components of the phenotype are likely to be regulated separately, such that each component could be called a quantitative trait locus (QTL), with its own genetic basis. For example, vasculitis complicating SLE or uveitis complicating early-onset pauciarticular ]RA may be viewed as an individual QTL. Some patients have these features in their disease phenotype, and others do not. Studies of animal models support this QTL concept in rheumatologic disease. 29 What has also been missing and important to predict is information regarding the likelihood that other non-HLA genes are involved. It is likely that responses to therapy (or failures with therapy) are also QTLs and will prove to be genetically mediated, part of the science of pharmacogenetics.

Quantltatlon of the Family History Genomic screens are time-consuming ventures, and some quantitation of familial risk for a given disease would help to determine the probability that the disease is or is not likely to be a complex genetic trait. The standard measure of risk of affected siblings is As, calculated as the prevalence of the illness in question in sibs of the patient with the disease, divided by the prevalence of the disease in the general population. 18,30 For ]RA, one estimate of A.S is 15, similar to that for type 1 diabetes. Ankylosing spondylitis, with greater penetrance, may have a A.S of about 80.

Dlsease-Spedflc Susceptibility Genes Versus General Autoimmune Genes Mutations in genes with an immunologic function may relate to a variety of immunologic diseases. This can be the experience in both patients and animal models of autoimmunity, one such example being the las gene defects in mice and in humans that effect cell death or apoptosis. 3J.32 This gives rise to the concept that both general autoimmune-predisposing genes and diseasespecific susceptibility confer risk of autoimmunity. The number of genes involved in a particular complex trait is likely to be between 5 and 20; confirmation of this concept is being worked out as genome screens are completed in many autoimmune diseases. Analysis of 22 genome screens identified more than 13 chromosome regions or genes found in common in different autoimmune diseases 33 ; similar evidence is accruing in animal models. 34 Because different autoimmune diseases tend to have different HLA associations, it is likely that disease specificity will partly rest with the HLA region on the short arm of chromosome 6, whereas a general predisposition may be more related to the other, non-HLA susceptibility regions. This concept is a useful generalization and is being tested. There will clearly be exceptions; for

example, both general and disease-specific polymorphisms may be found within the MHC.

Disease Phenotype as a Potential Complex Genetic Trait Two strategies are commonly used in evaluating a disease as a complex trait. One is a candidate gene approach, including selected specific genes or chromosome regions that are tested for disease susceptibility; the other is a comprehensive genome screen. As the growing number of comprehensive or global screens in other autoimmune diseases identify chromosomal loci that confer disease susceptibility, a candidate gene approach for any potential autoimmune complex genetic trait becomes more feasible. The use of candidate genes has the potential to reduce the overall workload but may miss loci or decrease the resolution, whereas the genome-wide screen systematically examines every genetic region, albeit often at low resolution. A conservative approach allows both methods of ascertaining linkage or association to be tried in parallel. As the technology is enhanced, global approaches to association should become feasible.

Candidate Genes With most of the autoimmune diseases, the literature supports the involvement of individual genes or polymorphisms in susceptibility. For ]RA, a recent review 27 identified 30 such potential genes or chromosome regions outside the MHC. Although the data supporting the candidacy of such entities are conflicting at best, the probability that one or more will be involved in disease susceptibility is high, especially in those chromosome regions for which selection is based on meta-analysis of prior genome screens. 33 HLA-B27 is strongly and almost uniformly associated with spondyloarthritis. 35

Genome Screen A genome screen searches systematically throughout the genome for individual chromosome regions of susceptibility. The marker density selected for such approaches has generally been about 10 cM, which necessitates the use of more than 350 markers across the genome. This number being a reasonable compromise between identifying positive areas without excessive workload, a database of 100 ASPs (screened with all parents included) will result in 150,000 genotypes if the DNA quality is sufficient. As noted earlier, the marker sets now available with PCR primer pairs are organized so that multiple PCR products can be run on a given gel, a process known as multiplexing. Appropriately, different fluorescein tags are used to facilitate this process, leading to a high throughput of samples. One marker set has more than 800 marker pairs, substantially increasing the density of the screen.

Strategy for an Individual Genome Screen Although the general approach to genome screening is common to all potential complex genetic traits (i.e., the

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use of multiple markers in all chromosome regions), the strategy selected for any given disease will vary. The level of As, discussed earlier, may be a good indication that "positive" data should result. Some autoimmune and autoinflammatory diseases (e.g., ankylosing spondylitis, SLE) have extensive multiplex kindreds. Most disorders have less extensive kindreds, but almost all autoimmune diseases appear to have ASPs as a common denominator. However, the number of available ASPs differs with each disease, and this also has a bearing on the stratagem to be adopted. Studies with 800 to 1000 ASPs are ongoing in rheumatoid arthritis, and several hundred ASPs are available for ankylosing spondylitis; in pediatric rheumatology, however, the numbers are relatively modest. On the other hand, in pediatric practice, both parents are usually available in a very high proportion of ASPs, which adds considerable analytic power that is unavailable without parental DNA. Normally, ASPs share both haplotypes in 25% of instances and one haplotype in 50%; a deviation from this expected distribution among ASPs indicates linkage. 18 If insufficient ASPs are available, other approaches are needed. An alternative method is the fiT, which requires parents and a single proband (Le., a simplex family). It is considered a test of both association and linkage. 19•2 1,36 An example of the use of familybased control genes is preferential transmission of particular genes to the proband, which is compared with the allelic distribution in genes that are not transmitted. 37 Associations generated through case-control studies have often been confounded by population stratification (founder effects), indicating the importance of familybased studies for assessment of both linkage and association. Unaffected siblings may be used if a stratagem can be devised to work out an individual's potential to contract the autoimmune disease in question. Information on parents is usually necessary, although the absence of one parent can be compensated for if genetic information in the children is sufficient. ASPs may also be used in the fiT (sib-pair fiT); this doubles the power of the test. There is considerable discussion as to the meaning of the TDT; results are not positive in the absence of linkage, although fiT results also depend on linkage disequilibrium and association.

Which Polymorphlsms? In general, microsatellite repeats (VNTRs) have been used most frequently. As noted earlier, they not only have the advantage of being mapped, but their polymorphic content is known, so VNTRs with maximum PIC content can be selected to optimize the available family materials and minimize uninformative genotyping. As an alternative, SNPs are less polymorphic and less commonly· mapped; however, their much greater number and lower cost increasingly offset the advantages of VNTRs. Because use of the fiT in simplex families requires higher-density markers (linkage disequilibrium may rarely extend more than 50 kb), the more densely distributed SNPs are likely to become the method of choice in the TDT. This is especially likely given that the technology is now available to read such polymorphisms

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from DNA-based chips, which adds another automated step to the process and allows increased numbers of genotypes to be more readily processed. 38 Candidate genes can be tested in ASPs or by the TOT, the latter in either simplex or multiplex families. In this situation, association studies using a family-based pool with controls can also reduce the element of population stratification that has made case-control studies problematic.

Replication and Extension of Findings Initial findings suggestive of linkage in any genome study will need replication. For this reason, a second set of DNA on a new population would be an asset. The method of approach, whether through sib pairs or through case-control studies (see later discussion), need not be identical in design to the first study and could be focused on areas of potential interest (chromosome loci or genes) established in the initial study. Fine mapping then becomes possible with high-density markers. For example, 60 to 80 VNTRs might be available for a particular chromosome region and could be applied in multipoint linkage or association studies. In this approach, it is possible to define the point of maximum linkage or association and therefore to map more exactly the gene involved in the disease. Chromosome regions so confirmed will still have the potential to contain many genes (perhaps 20), compared with the larger number in the original region. Such an approach was applied to the mapping of the diastrophic dysplasia and hemochromatosis genes. 39--41 This method allows the gene-hunting phase to be applied with greater precision.

PEDIATRIC RHEUMATIC ILLNESSES AS COMPLEX GENETIC TRAITS To what extent are the common chronic pediatric rheumatic illnesses complex genetic traits? The subtypes of JRA, juvenile dermatomyositis, psoriatic arthropathy, ankylosing spondylitis, SLE, and scleroderma are all candidates. Supportive evidence in children is available (albeit limited) for some diseases but not at all for others; only data in adult patients are available where disease overlap occurs. For pauciarticular JRA with onset in young children, the relatively frequent occurrence of this illness has ensured that enough ASPs are available to demonstrate substantial concordance for diseaseY HLA associations are well documented, although extended multiplex families are not available for linkage studies (see Chapter 11). HLA and JRA have been shown to be linked through two approaches by the TDT in 103 HLA-typed simplex families 43 and through allele sharing in 53 ASPs. 44 Both of these studies used fewer numbers of families than has generally been the case in genomic studies in adults, suggesting that a genome-wide screen using the available number of ASPs would be successful in identifying at least the major susceptibility (if not all of the minor susceptibility) loci. An initial genome-wide screen with eight regions identified with lod scores of 2 or greater has recently been published. 45 These results do depend on

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analyses of subsets. The nonparametric, multipoint linkage for each chromosome is given in Figure 4-1. The numbers required to consider other aspects of all forms of JRA (e.g., development of chronic uveitis as a QTI)

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The selection of candidate genes can be drawn from the literature On JRA, from the literature on other arthropathies, and from candidate loci for other autoimmune diseases in general, the last being especially useful because such data are oriented toward non-HLA genes. The occurrence of autoimmune diseases in JRA families is documented,28,46 as it is in juvenile dermatomyositis, in which, in addition to HLA associations, there is stronger evidence of an increased familial prevalence of autoimmune diseaseY In the instance of juvenile dermatomyositis, the limited occurrence of the disease (approximately 2000 patients in the United States) precludes the possibility of enough ASPs for genome screens, although such pairs do occur. In this instance, simplex families will prove to be the most reliable resource, especially if both parents are available. For the other pediatric rheumatic disorders, studies in adults-both those already reported and those underway, especially for rheumatoid arthritis, SLE, and ankylosing spondylitis-will genelflte candidate genes and loci that can be readily tested for relevance in pediatric populations.48-52

FUNCI10NAL GENONICS Understanding the Expression and Fundlon of Genes For decades, biologists have been interested in the temporal and spatial patterns of expression of individual genes and their protein products, what other gene products mey interact With, and what happens to the cell, organism, or individual when that gene product is mutated or absent. Functional genomics refers broadly to me methods and techniques aimed at answering these questions systematically for all genes encoded in the genome and complements the global approaches to the structure of the genome described earlier. Current estimates of the number of expressed genes in the human genome--those for which messenger RNAs (mRNAs) encode functional proteins-are in the range of 30,000 to 40,000. The number of genes expressed at a given time in a particular cell type depends on a variety of factors but is much smaller. Genes expressed in different cell types overlap, and they also differ considerably depending on the state of differentiation and specialized function of the cell. Gene expression at the level of individual mRNA abundance is generally referred to as the transcriptome, whereas the protein products that result from translation of these mRNAs (i.e., the protein products of the genome) are called the proteome. The ability to measure the transcriptome or proteome of a cell or tissue type has advanced dramatically over the last decade, fueled by the Human Genome Project, advances in microarray technology, and developments in protein chemistry.

Methods to Assess the Transalptome Two .different microarray-based platforms are typically used to Simultaneously assess the abundance of thousands of individual mRNA transcripts. Oligonucleotide microarrays (chips) contain hundreds of thousands of known Single-stranded oligonucleotides synthesized

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in situ on a solid support. For each gene being probed, there are perhaps a dozen oligonucleotide pairs corresponding to perfect and single-base-pair mismatched sequences, proViding a measure of specificity. RNA samples of interest are reverse transcribed (i.e., DNA complementary to the RNA is synthesized in vitro), and then complementary RNA (cRNA) containing fluorescent labeled nucleotides is synthesized. cRNA is hybridized to the chip, and the resulting fluorescent signal intensity is proportional to the abundance of the particular mRNA species in the original sample. The location and intensity of the fluorescent signal on the chip is determined with the use of a high-resolution scanner and is averaged over all of the oligonucleotide pairs for the particular gene, providing a measurement of its relative expression. One commonly used type of oligonucleotide microarray, known as a GeneChip, is manufactured by Affymetrix (Santa Clara, CA). The Ul33 Plus 2.0 human chip provides virtually genome-Wide expression analysis of more than 47,000 transcripts (based on 1.3 x 106 oligonucleotide features on the chip). Most of these represent known and characterized genes (38,500), whereas others remain as ESTs corresponding to unknown or as yet not well characterized genes. The second method of assessing the transcriptome uses double-stranded cDNAs that are created by PCR and spotted onto glass microarray slides, with one probe per gene. Typically, two mRNA samples, representing different experimental conditions, are labeled with distinct fluorescent probes, then combined and hybridized to the chip. The signal intensity ratio for the two fluorescent probes is used as a measure of the relative amount of the mRNA in the two samples. A detailed comparison of the strengths and weaknesses of these two methods is beyond the scope of this review. However, one advantage of the one sample-one chip approach is that multiple cross-wise comparisons can be made. This is particularly important when comparing clinical samples in large data sets.

Data Analysis Analysis of the very large data sets that result from global microarray studies of differential gene expression is an evolving science that remains to be standardized. Even before analysis, one must consider issues of experimental design, such as whether adequate numbers and quality of samples can be obtained that will provide sufficient power to detect statistically significant and biologically meaningful differences. Sample handling is of critical importance, because exposure of cells to "stress" (e.g., heat, cold) during manipulation can dramatically change gene expression patterns. Furthermore, RNA is particularly susceptible to degradation by enzymes that are released during cell death and are present ubiquitously in the external environment. Consequently, quality control analysis must be included in the overall approach. Estimates of sample sizes for microarray experiments depend on the questions being asked, the complexity of the sample (I.e., number of cell or tissue types represented), and variability among samples. To define a relatively homogeneous disease state using peripheral

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blood or tissue, sample numbers can be expected to range from 5 to 40 or more. Higher numbers allow more disease subclasses to be defined, which can be important when dealing with complex phenotypes, such as those often found in autoimmunity. Given the multiple testing bonanza inherent in analysis of data sets that may comprise 40,000 genes from one sample, conservative interpretation of probability values (and/or multiple testing corrections) is often both prudent and the only method through which manageable numbers of differentially expressed genes emerge. In attempting to define subclasses within a large group of samples, one can use supervised (with prior assumptions) or unsupervised (without prior assumptions) approaches. The best designs have a training or exploratory data set and a built-in capacity for replication of findings established through the training set. Several software packages are available for identifying overexpressed and underexpressed genes across multiple samples, recognizing patterns of expression that cluster together, identifying clusters and pathways with functional significance, and estimating overall similarities and differences between patterns of gene expreSSion in complex samples. In interpreting differential gene expression data, it is important to remember that the relative abundance of individual mRNA species does not always correlate with the abundance of the encoded protein. Many genes are regulated at the translational level, where the mRNA remains in high abundance but is translated only under certain conditions. In addition, the turnover of many individual proteins is tightly regulated by ubiquitination and subsequent degradation by intracellular proteases known as proteasomes.

Proteomlcs Proteomics refers to the systematic study of the structure

and function of all proteins in the genome. 53 Goals include the identification and quantitation of all proteins expressed in a particular cell or tissue type and determination of their modifications, subcellular locations, and interaction partners, including RNA, DNA, and other proteins. Systematic attempts to examine the proteome really began with the development of two-dimensional (20) polyacrylamide gel electrophoresis in the mid-1970s,54 predating the development of methods to sequence DNA.5S.56 This methodology was scaled up to provide enhanced resolution and detection of proteins of low abundance, making it possible to visualize as many as 2000 to 3000 proteins on one gel separation. s7 Unfortunately, the methods were cumbersome and had low throughput, and highly reproducible patterns amenable to automated recognition were difficult to obtain. Furthermore, the information obtained from 20 gels was largely descriptive, because methods to identify individual proteins (see later discussion) were not then available. Methods to assess the proteome have lagged significantly behind genomic techniques for a variety of reasons. Proteins are inherently more complex, with 20 amino acid building blocks rather than 4 nucleotides for DNA/RNA, and there are considerable post-translational modifications, such as glycosylation and phosphoryla-

tion, that affect structure and conformation. Differential mRNA splicing and proteolytic processing of translation products further increases the complexity of the proteome. In many cases a single gene locus may give rise to multiple molecular species, suggesting that the proteome is significantly more complex than the transcriptome. Because resolution of proteins based on migration in 20 gels depends primarily on two parameters, relative molecular mass (M) and isoelectric point (pO, there may be considerable overlap in a complex mixture containing thousands of cellular proteins. Methods such as mass spectroscopy (MS), which provides precise mass measurements, are highly sensitive and provide greater resolution than 20 gel separations do, but they have not been automated and can be prohibitively expensive and timeconsuming for high-throughput analyses. The problem of comigrating proteins with any of these methods can be reduced by "upstream" sample fractionation. However, the tradeoff is lower throughput and greater expense. Global detection of expressed proteins presents additional problems. Protein stains are relatively insensitive for low-abundance proteins. Isotope incorporation coupled with PhosphorImaging (Amersham Biosciences, Piscataway, NJ) can enhance detection but favors visualization of proteins with high rates of synthesis. Antibody-based methods of detection are both specific and sensitive, but they are available for only a fraction of the proteome at this time. Furthermore, most antibodies recognize either conformational or linear epitopes, but not both, and therefore are not amenable to either enzyme-linked immunosorbent assay (ELISA)-based methods or immunoblotting. As a consequence of the difficulties in performing global separation and detection of expressed proteins, new gel-independent methods, many of which are based on MS, are being developed.

Protein Identification by Mass Spectroscopy Peptide Fingerprinting One area of significant advance has been the identification of individual proteins separated from complex mixtures. Typically, a single protein spot from a 20 gel separation is removed from the gel and digested with a protease to yield specific peptide fragments, which are subjected to MS analysis. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS is most frequently used because of its sensitivity and availability, and it provides highly precise fragment masses. The masses of the peptide fragments determined experimentally (fingerprint) are matched against a database of calculated peptide fragment masses from "in silico" digested proteins, and if the protein of interest is in the database, one can obtain a match with a high degree of certainty that the proteins are identical. It is also possible to obtain peptide sequence information using tandem MS (MS/MS or MS2), in which peptide ion fragments in a complex mixture are isolated in the machine on the basis of their mass (m!z), and then fragmented in the gas phase. Because peptides fragment in a sequence-dependent fashion, in most cases an unambiguous ordering of the amino acids can be obtained from the MS/MS spectrum. This technology has

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been instrumental in determining the sequences of complex mixtures of peptides derived from HLA class I and class II molecules. 58

Methods for Studying the Proteome Mlcroarray-based Methods Rapid advances in methods for microarray or chip-based analysis of differential gene expression have been possible because of several factors. Probes can be readily synthesized, and, depending on the platform chosen, this can be done in situ. The probes are highly specific, and target recognition does not depend on their secondary structure or that of the target. Targets can also be readily synthesized (copied) and made to incorporate labels that facilitate their detection without significantly changing their properties or ability to be detected. If necessary, targets can be amplified to enhance detection or to facilitate analysis of small amounts of starting material. Essentially none of these factors applies to the global analysis of expressed proteins. For example, proteins cannot be amplified, and they frequently must be in their native conformation to be properly detected. Tagging methods, which can enhance detection, run the risk of altering conformation or the structure of the region being probed. As a consequence of these limitations, there have been few Itlicroarray-based proteomic analyses identifying differentially expressed proteins in complex samples such as peripheral blood, inflammatory lesions, or synovial fluid. Protein or "antigen" arrays have been used successfully to assess autoantibody profiles from patients with various autoimmune diseases. Essentially, protein or peptide autoantigens have been attached to planar surfaces using robotic microarrayers. Up to 1152 features representing 196 distinct antigenic targets of known autoantibodies have been used to screen sera from patients with rheumatoid arthritis, SLE, and other rheumatologic diseases.59 Antibody binding is visualized with anti-human secondary antibodies conjugated to fluoroprobes, and this is followed by scanning and quantitation. The arrays are more sensitive than conventional ELISAs and offer parallel screening for multiple autoantibodies. Results so far have been encouraging, revealing high concordance with results from more conventional methods and a high degree of antigen target specificity. Studies using MS-based or 2D gel methods have also revealed differences in proteins expressed in the synovial fluid or peripheral blood of patients with rheumatoid arthritis, compared with control subjects with reactive arthritis or osteoarthritis. 6o.61

Genetk-based Methods Protein-protein interactions can be detected with the use of genetic methods known as yeast two-hybrid screens. Using molecular biologic tools, a known or "bait" protein can be expressed as a fusion product with the DNAbinding domain of a transcriptional activator. A different protein ("prey") is expressed as a fusion product with the activation domain of the transcription factor. If the bait

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and prey interact when expressed in the yeast, the result is activation of transcription of a reporter gene that can easily be detected. This method can be used to study protein-protein interactions of known gene products or to screen entire libraries to discover interaction partners. Like any method, the yeast two-hybrid system has its limitations, but it has been used successfully for a number of important applications.

Functional Genomlcs In Pediatric Rheumatic Diseases Functional and integrative genomics approaches are currently being applied to the etiology and pathogenesis of complex rheumatologic diseases, including those that primarily affect children. Studies using oligonucleotide microarrays to examine differential gene expression in peripheral blood mononuclear cells (PBMC) from patients with juvenile-onset SLE62 found prominent granulopoiesis and type I interferon (IFN)-response "signatures, " with the latter correlating with SLE Disease Activity Index (SLEDAI) scores. Furthermore, high-dose glucocorticoid treatment, which suppresses disease flares, significantly suppressed the IFN signature. These findings confirmed a role for IFN-a. in SLE pathogenesis. 63 The granulopoiesis signature was more surprising, and further analysis of cell populations led to the identification of highly granular cells in early stages of granulocyte development that were purified together with mononuclear cells during the isolation of PBMC. These were not related to corticosteroid treatment, and they were present in new, untreated patients. Similar evidence for upregulation of IFN-inducible genes in the peripheral blood of patients with adult-onset SLE was noted by Baechler and colleagues,64.65 who also found correlation between the IFN signature and disease severity, particularly with renal and hematologic involvement. These studies have reinforced the potential for targeting type I IFNs in SLE and have led to new ideas about pathogenesis. Furthermore, new biomarkers have been identified that may help investigators and eventually clinicians to monitor disease activity and, potentially, even to predict severity in SLE. Notably, in the studies of Bennett and associates,62 patients with juvenile chronic arthritis (European League Against Rheumatism [EULAR] criteria) who were used as disease controls had very different gene expression patterns from those of the SLE patients. Barnes and associates 65 recently described gene expression differences in PBMC from patients with polyarticular JRA (American College of Rheumatology [ACR] criteria) that readily distinguished them from healthy controls. Results from this pilot study revealed possible differences between the polyarticular and pauciarticular JRA subtypes, as well as juvenile-onset ankylosing spondylitis; however, more patients need to be studied for more definitive distinctions to be made. This work also revealed differential expression of CXCL chemokines, with angiogenic and angiostatic activities in peripheral blood and synovial fluid that may have relevance to disease course and the extent of joint involvement. In addition, Jarvis and coworkers66 found differentially expressed genes in the peripheral blood of patients with polyarticular JRA that

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tended to normalize when the patients responded to treatment. Although functional genomics studies in the pediatric rheumatic diseases are in their infancy, these papers higWight several important points. First, it is striking that peripheral blood is such a rich source of information. Although this might have been expected in active SLE, it is perhaps more surprising in JRA, and it supports the concept that joint inflammation might represent an end result of immune dysregulation, rather than simply a site where joint antigens drive a cross-reactive local inflammatory process. Second, analysis of cell mixtures such as those present in peripheral blood and synovial fluid can provide useful information, despite the complexity of the sample. For example, differences in RNA abundance as detected by microarray analyses can reflect differences in cell populations rather than upregulation or downregulation of genes. Cell type-specific genes can indicate the presence of certain cell populations, such as the early granulocytes in patients with SLE. Third, the comprehensive nature of microarrays affords several advantages, including the ability to simultaneously measure multiple gene products in a pathway (e,g., those responsive to type I IFNs). This can be a more sensitive approach than analyzing the expression of individual genes, or even levels of the cytokines responsible for the signature. For example, it has been difficult to consistently measure increases in IFN-Cl in SLE patients, yet strong evidence for the presence of IFN-Cl (and/or IFN-~) at some point comes from the detection of an IFN signature in peripheral blood. Finally, regardless of the actual identities of the differentially represented genes, so long as there are consistent differences between the groups being compared (e.g., pauciarticular versus polyarticular JRA), it may be possible to identify biomarkers that help distinguish these individuals. In many cases, this can already be done based on clinical features, but there are also many instances in which it is impossible. For example, which patients with new-onset pauciarticular JRA are likely to develop severe erosive arthritis involving multiple joints? Which patients with arthritis, enthesitis, and HLA-B27 will develop ankylosing spondylitis? There are currently few good predictors for these outcomes, but the combination of genotyping for known susceptibility alleles, combined with differential gene expression analyses, may provide clues to some of these questions in the near future.

CONCLUSIONS It seems highly likely that the autoimmune diseases most

commonly encountered by pediatric rheumatologists are complex genetic traits that can be read from an individual's genome. Eventually, diagnosis and prognosis will be based on such traits. It is also evident that genomic polymorphisms will be used to predict responsiveness to therapy. Ultimately, therapy will be matched to an individual's genomic findings, a science known as pharmacogenetics. The methods now being developed to evaluate genomes will also allow gene therapy to be applied to chronic pediatric rheumatic illnesses.

REFERENCES 1. Collins FS, Patrinos A, ]orda E, et al: New goals for the V.S. Human Genome Project: 1998-2003. Science 282: 682-689, 1998. 2. Dermitzakis ET, Reymond A, Scamuffa N, et al: Evolutionary discrimination of mammalian conserved non-genic sequences (CNGs). Science 302: 1033-1035, 2003. 3. Sullivan KE, McDonald-McGinn OM, Driscoll DA, et al: Juvenile rheumatoiu arthritis-like polyarthritis in chromosome 22qll.2 deletion syndrome (DiGeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome). Arthritis Rheum 40: 430--436, 1997. 4. Weber ]L, May PE: Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am] Hum Genet 44: 388-396, 1989. 5. Kruglyak L: The use of a genetic map of biallelic markers in linkage studies. Nat Genet 17: 21-24, 1997. 6. Beaudet AL: 1998 ASHG presidential address. Making genomic medicine a reality. Am] Hum Genet 64: 1-13, 1999. 7. Pennisi E: A closer look at SNPs suggests difficulties. Science 281: 1787-1789, 1998, 8. Martinez FD, Graves PE, Baldini M, et al: Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. ] Clin Invest 100: 3184-3188, 1997. 9, Hershey GK. Friedrich MF, Esswein LA, et al: The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl] Med 337: 1720-1725, 1997. 10. Dib C, Faure S, Fizames C, et al: A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380: 152-154, 1996. 11. Cohen 0, Chumakov I, Weissenbach]: A first-generation physical map of the human genome. Nature 366: 698-701, 1993. 12, The Internationl HapMap Consortium: The International HapMap Project. Nature 426: 789-796, 2003. 13. Strachan T, Abitbol M, Davidson 0, Beckmann ]S: A new dimension for the human genome project: towards comprehensive expression maps. Nat Genet 16: 126--132, 1997. 14. Heller RA, Schena M, Chai A, et al: Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc Nat! Acad Sci V S A 94: 2150-2155, 1998. 15. Reed PW, Davies ]L, Copeman]B, et al: Chromosome-specific microsatellite sets for nuorescence-based, semi-automated genome mapping. Nat Genet 7: 390-395, 1994. 16. Ziegle ]S, Su Y, Corcoran KP, et al: Application of automated DNA sizing technology for genotyping microsatellite loci. Genomics 14: 1026--1031, 1992. 17. Simpson PC, Roach 0, Woolley AT, et a1: High-throughput genetic analysis using microfabricated 96-sample capillary array electrophoresis microplates. Proc Nat! Acad Sci USA 95: 2256--2261, 1998. 18. Risch N: Linkage strategies for genetically complex traits: n. The power of affected relative pairs. Am] Hum Genet 46: 229-241, 1990. 19. Spielman RS, McGinnis RE, Ewens W]: Transmission test for linkage uisequilibrium: the insulin gene region and insulin-dependent diabetes melHtus (IDDM), Am] Hum Genet 52: 506--516, 1993. 20. Spielman RS, McGinnis RE, Ewens W]: The transmission/disequilibrium test detects cosegregation and linkage. Am ] Hum Genet 54: 559-560; author reply 560-563, 1994. 21. Spielman RS, Ewens W]: A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am ] Hum Genet 62: 450-458, 1998. 22. Chalom EC, Ross ], Athreya BH: Syndromes and arthritis. Rheum Dis Clin North Am 23: 709-727, 1997. 23. Prahalad S, Colbert RA: Genetic diseases with rheumatic manifestations in children. Curr Opin Rheumatol 10: 488-493, 1998. 24. Lander ES, Schork N]: Genetic dissection of complex traits, Science 265: 2037-2048, 1994. 25. Risch N, Merikangas K: The future of genetic studies of complex human diseases. Science 273: 1516--1517, 1996. 26. Davies ]L, Kawaguh Y, BenneU, et al: A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371: 130-136, 1994. 27. Rosen P, Thompson S, Glass 0: Non-HLA gene polymorphisms in juvenile rheumatoid artluitis. Clin Exp Rheumatol 21: 650-656, 2003. 28. Prahalad S, Shear ES, Thompson SO, et al: Increaseu prevalence of familial autoin1fnunity in simplex and multiplex families with juvenile rheumatoid arthritis, Artllfitis Rheum 46: 1851-1856, 2002. 29. Weis II. McCracken BA, Ma Y, et al: Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease. ] Immunol 162: 948-956, 1999. 30. Risch N: Linkage strategies for genetically complex traits: 1. Multilocus mouels. Am] Hum Genet 46: 222-228, 1990. 31. Adachi M, Watanabe-Fukunaga R, Nagata S: AbelTant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc Nat! Acad Sci V S A 90: 1756--1760, 1993. 32. Fisher GH, Rosenberg ], Straus SE, et al: Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune Iymphoproliferative syndrome. Cell 81: 935-946, 1995.

C HAP T E R 33. Becker KG, Simon RM, Bailey-WilsonjE, et aI: Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diSeases. Proc Nat! Acad Sci USA 95: 9979-9984, 1998. 34. Kawahito Y, Cannon GW, Gulko PS, et al: Localization of quantitative trait loci regulating adjuvant-induced arthritis in rats: evidence for genetic facto~s common to multiple autoimmune diseases. J Immunol161: 4411--4419, 1998. 35. Gonzalez-Roces S, Alvarez MY, Gonzalez S, et al: HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. Tissue Antigens 49: 116--123, 1997. 36. Cleves MA, Olson JM, Jacobs KB: Exact transmission-disequilibrium tests with multiallelic markers. Genet Epidemiol 14: 337-347, 1997. 37. Thomson G: Mapping disease genes: family-based association studies. Am J Hum Genet 57: 487--498, 1995. 38. SL'Ott WK, Pericak-Vance MA, Haines ]L: Genetic analysis of complex diseases. Science 275: 1329-1330, 1997. 39. AjiPka RS, Yu P, Gnten JR, et al: Recombinations defining centromeric and telpmeric borders for the hereditary haemochromatosis locus. J Med Genet 34: 28-33, 1997. 40. Gandon G, Jouanolle AM, Chauvel B, et al: Linkage disequilibrium and extended haplotypes in the HLA-A to D6SI05 region: implications for mapping the hemochromatosis gene (HFE). Hum Genet 97: 103-113, 1996. 41. Hasthacka J, de 1a Chapelle A, Mahtani MM, et al: The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-stntcture linkage disequilibrium mapping. Cell 78: 1073-1087, 1994. 42. Moroldo MB, Chaudhari M, Shear E, et al: Juvenile rheumatoid arthritis affected sibpairs: extent of clinical phenotype concordance. Arthritis Rheum 50: 1928-1934, 2004. 43. Moroldo MB, Donnelly P, Saunders J, et al: Transmission disequilibrium as a test of linkage and association between HLA alleles and pauciarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum 41: 1620-1624, 1998. 44. Pf'~halad S, Ryan MH, Shear ES, et al: Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs. Arthritis Rheum H: 2335-2338, 2000. 45. Thompson S, Moroido MB, Guyer L, et al: A genome-wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage. Arthritis Rheum 50: 2920-2930, 2004. 46. Rossen R, Brewer EJ, Sharp RM, et al: Familial rheumatoid arthritis: linkage of HLA to disease susceptibility locus in four families where proband presented with juvenile rheumatoid arthritis. J Clin Invest 65: 629-642, 1980. 47. Ginn LR, Lin JP, Plotz PH, et al: Familial autoimmunity in pedigrees of' idiopathic inflammatory myopathy patients suggests common genetic ri~k factors for many autoimmune diseases. Arthritis Rheum 41: 400--405, 1998. 48. Jawaheer 0, Seldin MF, Amos CI, et al: Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. Arthritis Rheum 48: 906--<)16, 2003.

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49. Tsao BP, Cantor RM, Kalunian KC, et al: Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest 99: 725-731, 1997. 50. Wordsworth P: Genes in the spondyloarthropathies. Rheum Dis Clin North Am 24: 843-862, 1998. 51. Moser KL, Neas BR, Salmon JE, et al: Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci USA 95: 14869-14874, 1998. 52. Gaffney PM, Keams GM, Shark KB, et al: A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Nat! Acad Sci USA 95: 14875-14879, 1998. 53. Patterson SO, Aebersold RH: Proteomics: the first decade and beyond. Nat Genet 33 (Suppl): 311-323, 2003. 54. O'Farrell PH: High resolution two-dimensional electrophoresis of proteins. J Bioi Chem 250: 4007--4021, 1975. 55. Sanger F, Nick/en S, Coulson AR: DNA sequencing with chain-terminating inhibitors. Proc Nat! Acad Sci USA 74: 5463-5467, 1977. 56, Maxam AM, Gilbert W: A new method for sequencing DNA, Proc Natl Acad Sci USA 74: 560-564, 1977. 57, Young DA, Voris BP, Maytin EV, Colbert RA: Very-high-resolution twodimensional electrophoretic separation of proteins on giant gels. Methods Enzymo191: 190-214, 1983, 58. Hunt OF, Henderson RA, Shabanowiz J, et al: Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 255: 1261-1263, 1992. 59. Robinson WH, Steinman L, Utz PJ: Protein arrays for autoantibody profiling and fine-specificity mapping. Proteomics 3: 2077-2084, 2003. 60. Sinz A, Bantscheff M, Milckat S, et al: Mass spectrometric proteome analyses of synovial fluids and plasmas from patients suffering from rheumatoid arthritis and comparison to reactive arthritis or osteoarthritis. Electrophoresis 23: 3445-3456, 2002. 61. Dotzlaw H, Schulz M, Eggert M, Neeck G: A pattern of protein expression in peripheral blood mononuclear cells distinguishes rheumatoid arthritis patients from healthy individuals. Biochim Biophys Acta 1696: 121-129, 2004, 62. Bennett L, Palucka AK, Arce E, et al: Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197: 711-723, 2003. 63. Blanco P, Palucka AK, Gill M, et al: Induction of dendritiC cell differentiation by IFN-alpha in systemic lupus erythematosus, Science 294: 1540-1543, 2001. 64. BaecWer EC, Batliwalla FM, Karypis G, et al: Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Nat! Acad Sci USA 100: 2610-2615, 200365, Barnes M, Aronow BJ, Luyrink LK, et al: Gene expression in juvenile arthritis and spondyloarthropathy: pro-angiogenic ELR+ chemokine genes relate to COurse of arthritis, Rheumatology (Oxford) 43: 973-979, 2004. 66, Jarvis IN, Dozmorov 1, Jiang K, et al: Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis. Arthritis Res Ther 6: RI5-R32, 2004.

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P HARMACOLOGY D RUG T HERAPY

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Ronald M. Laxer

The previous edition of this textbook described the tremendous progress that had been made over the preceding decade in the treatment of patients with inflammatory arthritis and other rheumatic diseases. Since that time, the development of new agents has continued, extensive clinical experience with the use of the new biologic agents has been gained, and the clinical indications for the use of these agents have been expanded. All this has resulted in better outcomes for patients with rheumatic diseases. The principal drugs used in pediatric rheumatology are those that suppress the inflammatory and immune responses. The targets of their therapeutic effects are predominantly the arachidonic acid metabolic pathways and the cells of the immune system and their products. This chapter outlines some of the most important general principles relating to use of these medications, particularly as they apply to children. The treatment of specific rheumatic disorders is detailed in the chapters dealing with each disease.

CONCEPTS IN PHARMACOLOGY Although often incomplete, knowledge of the pharmacokinetics of drugs used to treat childhood rheumatic diseases contributes to understanding of their clinical applications. This brief overview can be supplemented by referring to standard works in the field.1–3

Drug Absorption and Bioavailability Most drugs are given by the oral route and are absorbed through the mucosa of the gastrointestinal (GI) tract, particularly that of the small intestine. GI absorption may be influenced by a number of factors, including the presence or absence of food in the gastric lumen, luminal pH, gastric emptying time, and the coadministration of other drugs. Drug bioavailability, the net result of these factors, is usually determined by sequential measurement of plasma drug concentrations. Three parameters are routinely considered: peak drug concentration, the time necessary to reach peak concentration, and the area under the time-concentration curve. The area under the

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curve after intravenous administration is considered equivalent to complete absorption after oral administration. Because the effects of many repeatedly administered drugs are cumulative, except with drugs of extremely short half-life given at infrequent intervals, bioavailability is best determined at the mean steady-state concentration of the drug—that is, the point at which drug intake is equal to drug elimination.

Volume of Distribution The volume of distribution is the volume of fluid into which a drug would need to be distributed to achieve a concentration equal to the concentration ultimately measured in plasma. If the drug stays in the plasma, its volume of distribution is smaller than if it is distributed widely in tissues. Drugs in the body are either free or bound to plasma proteins or tissue lipids. The extent and nature of binding affect the volume of distribution of the drug, the rate of renal clearance (because only free drug is filtered by the glomerulus), the drug half-life, and the amount of free drug that reaches the target tissue or receptor. Most acidic drugs are bound to plasma albumin, whereas the basic drugs are bound to lipoproteins, α1-acid glycoproteins, and globulins. In inflammatory states, plasma albumin concentration falls and α1-acid glycoproteins increase, although the extent of the decrease usually does not require any change in drug therapy. Drugs that are highly protein-bound tend to stay within the vascular compartment and have a relatively limited volume of distribution. Those that are widely bound to lipids in tissues have large volumes of distribution.

Half-Life and Clearance The half-life of a drug is the time necessary for the serum concentration to fall by 50% during the elimination phase of a time-concentration curve. Clearance is a measure of the removal of a drug from the body as a whole or from a specific part of the body, such as liver or kidney. It is expressed as the volume of body fluid from which a drug is removed per unit of time.

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The first-pass effect refers to the rapid breakdown of a drug when it passes through the intestinal mucosa or enters the liver for the first time. In this case, the drug reaches the systemic circulation predominantly in the form of metabolites that may be pharmacologically inactive. Avoidance of this effect requires intravenous administration. When the rate of elimination of a drug is directly proportional to its concentration in the body, the drug is said to have first-order kinetics. Drugs that are eliminated at a constant rate, unrelated to the amount of the agent in the body, are said to follow zero-order kinetics. Some drugs obey capacity-limited kinetics: at low concentrations, first-order kinetics are observed; at higher concentrations, the enzymes used in metabolism of the drug are saturated, and zero-order kinetics is approached. Salicylate and its metabolites demonstrate this phenomenon. Time-dependent kinetics may be altered by the effect of drug metabolites. For most drugs, a steady state is not reached until the passage of five half-lives. Blood levels measured before that time may be erroneous.

Drug Biotransformation Drug biotransformation or metabolism principally occurs in the liver, kidney, skin, and GI tract. In the liver, biotransformation involves hydrolysis, oxidation, reduction, or demethylation and conjugation of the metabolite with glycine, glucuronide, sulfate, or hippurate with subsequent secretion into the bile. In the kidney, drugs may be filtered, filtered and secreted, filtered and passively reabsorbed (e.g., acetaminophen), or filtered or actively secreted and passively reabsorbed (e.g., salicylates).4 Many drugs used to treat rheumatic diseases are active in the form in which they are administered; exceptions include sulindac, salsalate, prednisone, cyclophosphamide, and azathioprine, which require biotransformation before they exert their principal effects. Because the liver and kidney play such key roles in drug metabolism, dysfunction of these organs may require alteration in drug dose. In general, however, additional toxicity caused by drugs that totally depend on the kidney for their elimination is not a danger unless renal function is diminished by more than 50%.2 In patients with significant renal or hepatic disease, monitoring of drug levels and attention to the potential of drug toxicity become more critical.

5 PHARMACOLOGY TABLE 5–1

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D RU G T H E R A P Y

Agents Used to Treat Rheumatic Diseases

Nonsteroidal anti-inflammatory drugs Disease-modifying antirheumatic drugs/slow-acting anti-inflammatory drugs Glucocorticoids Cytotoxic or immunosuppressive drugs Biologic immunomodulators

connective tissue diseases. They provide symptomatic anti-inflammatory relief and are recommended for the majority of patients with juvenile rheumatoid arthritis (JRA). In the United States, only acetylsalicylic acid (aspirin, ASA), tolmetin, naproxen, ibuprofen, and indomethacin are approved for use in young children. In Australia, only aspirin, naproxen, and ibuprofen are licensed for use in children. The range of actual NSAID use in childhood is broader in these and many other areas of the world and usually extends beyond the range of drugs approved for use in children and the manufacturer’s recommendations in terms of dosage and minimum age for use.5 In general, ASA is now used much less often because it is associated with a greater frequency of adverse effects (including Reye’s syndrome, discussed later) and is without any demonstrated superiority in

COOH OC

CH3

O

CO

ASPIRIN (acetylsalicylic acid)

CI

N CH3 CH2COOH

CH3O OH

INDOMETHACIN

COO⫺ CH2 CHOLINE MAGNESIUM COO

F

COOH

OOC

CH3

HO

OH

H

CHOLINE MAGNESIUM TRISALICYLATE

H3C

CHCH2

CH3

S

CHCOOH

CH3

H3C

O

SULINDAC IBUPROFEN

O CH3

C

H3C

CH3COONa

N

CHCOOH

CH3 O

TOLMETIN SODIUM

ANTIRHEUMATIC DRUGS

CO2Na

FENOPROFEN

The pharmacologic agents used to treat children with rheumatic disorders are grouped into five categories: the nonsteroidal anti-inflammatory drugs (NSAIDs), diseasemodifying or slow-acting antirheumatic drugs, glucocorticoids, cytotoxic or immunosuppressive agents, and biologic response modifiers (Table 5–1).

CH3 CI

CH3 NAPROXEN

MECLOFENAMATE SODIUM CH2COONa

O

KETOPROFEN

■ Figure 5–1

O

OH

C

NH

NH CI

N CI

C

The NSAIDs (Fig. 5–1) remain the mainstay of the initial treatment of the chronic arthropathies of childhood and have a role in management of some aspects of the other

CI

CH3O

CH3CHCOOH

Nonsteroidal Anti-inflammatory Drugs

NH

CHCOOH

N S

CH3

O O DICLOFENAC

PIROXICAM

Structures of nonsteroidal anti-inflammatory drugs (NSAIDs).

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C H A P T E R

H2N

AND

D RU G T H E R A P Y

O

Mechanism of Action

S

O N

N

CF3

H3C CELECOXIB

O O

O S H3N

O ROFECOXIB

■ Figure 5–2

Structures of cyclooxygenase 2 (COX-2) inhibitors.

terms of efficacy compared with other NSAIDs for the treatment of arthropathies; however, it continues to have a major role in the treatment of Kawasaki disease. ASA is also less convenient to use because of the need for more frequent dosing, its poor solubility in liquid form, and the necessity of monitoring serum levels. Since the last edition of this textbook, the role of Cox-2 inhibitors (Figure 5–2) has evolved tremendously. Recently, the COX-2 inhibitor rofecoxib was reported to be safe and effective in children with JRA.6 However, the role of the Cox-2 inhibitors is currently under review as recent data have suggested an increased incidence of cardiovascular events in adults with long-term use.6a-6c

NSAIDs inhibit pro-inflammatory pathways that lead to chronic inflammation. The major anti-inflammatory effect of NSAIDs is mediated by inhibition of the COX enzyme in the metabolism of arachidonic acid to prostaglandins, thromboxanes, and prostacyclins7 (Fig. 5–3) (see Chapter 3). Currently available NSAIDs (except diclofenac and indomethacin) have little effect on the lipoxygenase pathway, the other major pathway of arachidonic acid metabolism.8 The discovery of two related but unique isoforms of the COX enzyme, COX-1 and COX-2, has resulted in a greater understanding of the mechanism of action of NSAIDs.9–12 These enzymes are structurally very similar but are encoded by distinct genes and differ in their distribution and expression in tissues. The COX-1 isoenzyme has a wide tissue distribution and is constitutively expressed under basal conditions. It appears to have a “housekeeping” function and is associated with the production of prostaglandins resulting in diverse physiologic effects such as gastric cytoprotection, platelet aggregation, vascular homeostasis, and maintenance of renal blood flow (see Fig. 5–3). In contrast, COX-2 is an inducible enzyme that is upregulated at sites of inflammation by various pro-inflammatory mediators, including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), bacterial endotoxins, and various mitogenic and growth factors. It also appears to be expressed in the central nervous system (CNS) and to have a role in the central mediation of pain and fever. After the discovery of COX-2 in the early 1990s,13 it was hypothesized that COX-1 mediated uniquely physiologic prostaglandin production whereas COX-2 mediated uniquely pathologic prostaglandin production; consequently, the anti-inflammatory effects of NSAIDs were considered to result from COX-2 and the adverse effects from COX-1 inhibition. However, this appears to have been an oversimplification.14 COX-2 may also have a

■ Figure 5–3 Synthesis of prostaglandins and leukotrienes. Sites of action of anti-inflammatory agents and cytokines are highlighted by arrows (–, downregulation; +, upregulation). COX, cyclooxygenase.

MEMBRANE PHOSPHOLIPIDS Phospholipase A2 ARACHIDONIC ACID

Cyclo-oxygenase

Lipoxygenase

⫹ LEUKOTRIENES

COX-1 Constitutive

COX-2 Inducible ⫺

⫺

• NSAIDs (reversible) • Aspirin (irreversible) May also be induced at sites of inflammation

“PHYSIOLOGICAL PROSTAGLANDINS” • gastrointestinal cytoprotection • renal blood flow • platelet aggregation • vascular homeostasis

• endotoxins • cytokines • growth factors

⫺ • COX-2 inhibitors • Corticosteroids

“PATHOLOGICAL PROSTAGLANDINS”

May also have physiological role in:

• sites of inflammation • central mediation of pain and fever

• kidney • brain • ovary and uterus • cartilage and bone • healing of gastrointestinal inflammation or ulcers

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physiologic function in certain tissues; it is expressed constitutively in structures such as the ovary, uterus, brain, kidney, cartilage, and bone.12 COX-2 knockout mice have severe renal dystrophy, suggesting an important role for this isoenzyme in early renal development. Conversely, COX-1 may have nonphysiologic functions and, like COX-2, may be upregulated at sites of inflammation. Therefore, the two isoforms of COX each appear to have a role in both physiologic and pathologic prostaglandin production and to have more broad and complex functions than originally thought. Currently available NSAIDs inhibit both isoforms of COX, but most inhibit COX-1 preferentially, resulting in undesirable adverse effects such as GI toxicity while producing desirable anti-inflammatory effects through concurrent inhibition of COX-2. Existing NSAIDs are known to differ in the degree of inhibition of COX-2, compared with COX-1, that they produce. This has been found to correlate with their adverse-effect profiles: NSAIDs that are more selective for COX-2 appear to have more favorable adverse effect profiles.10 In light of the differences between the COX-1 and COX-2 isoenzymes and their binding sites for NSAIDs, there has been a profusion of research into a “safer” class of drugs that selectively bind to and inhibit COX-2 activity: the COX-2 inhibitors.9 However, the degree of COX-2 suppression needed to produce an anti-inflammatory and analgesic effects in vivo is uncertain—a threshold degree of COX-2 inhibition that must be achieved with no associated COX-1 suppression cannot be clearly defined at this time.11,15 A number of additional concerns remain about specific COX-2 inhibitors. Because COX-1 may also be induced at sites of inflammation, a specific COX-2 inhibitor may be less effective as an anti-inflammatory or analgesic agent.9,10,14 Recent data from several trials not yet published examining the Cox-2 inhibitors in the prevention of colonic disease (cancer and recurrent polyposis) have shown an increased incidence of cardiovascular events. As a result, the production of rofecoxib has been halted entirely by the manufacturer.15a Similar concerns have arisen with the use of valdecoxib, and although studies suggest that celecoxib appears to be safer, long-term use at high doses may also be associated with an increased risk of CVS events.15b Whether the events are unique to one, several or all drugs from the COX-2 class is still unclear and requires further study.15c Similarly, it is not known whether the increased cardiovascular risk is related to co-morbid cardiovascular risk factors. Until further data are available, many feel that Cox-2 inhibitors have little role to play in the treatment of children with JRA. Surprisingly, 440 mg/day of naproxen was associated with an increased cardiovascular risk in a recent study (data not yet published). The mechanism by which COX-2 inhibitors are thought to lead to increased risk relate to relatively unopposed inhibition of vasodilator and platelet inhibitory prostaglandins, without inhibiting vasoconstrictor and platelet activating prostaglandins. Currently, it is believed that COX-2 inhibitors should be administered with low-dose aspirin in patients with cardiac risk factors.16 The consequences of specific COX-

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2 inhibition in tissues wherein the COX-2 isoenzyme appears to have a physiologic role, such as the renal medulla, ovary, and uterus, is also unknown.9,10 Renal toxicity may occur with COX-2 inhibitors. Three COX-2 inhibitors (celecoxib, rofecoxib, and valdecoxib) have been launched in the United States, and others are in various stages of development. The doses of existing NSAIDs that are required to reduce inflammation are generally higher than those needed to inhibit prostaglandin formation, suggesting the existence of other mechanisms by which their antiinflammatory effects are mediated (Table 5–2). In addition to inhibiting prostaglandin production, current NSAIDs inhibit specific proteinases involved in degradation of proteoglycans and collagens of cartilage17 and inhibit the generation of oxygen radicals, particularly superoxide.18–20 NSAIDs also have been shown to interfere with bradykinin release, response of lymphocytes to antigenic challenge, phagocytosis, and chemotaxis of granulocytes and monocytes.21 Individual NSAIDs may have additional specific mechanisms of action. Indomethacin blocks the action of phosphodiesterase, thus increasing intracellular cyclic adenosine monophosphate.22 This effect leads to a decrease in the generation of superoxide and hydroxyl radicals.22–24 Indomethacin also inhibits the mobility of polymorphonuclear neutrophils in inflammatory sites. Like ASA and ibuprofen, indomethacin uncouples oxidative phosphorylation and decreases the synthesis of mucopolysaccharides.25 Diclofenac and indomethacin also limit the availability of the substrate for prostaglandin and leukotriene synthesis by facilitating incorporation of arachidonic acid into triglycerides.8,26 Piroxicam at high concentrations inhibits neutrophil migration, phagocytosis, lysosomal enzyme release,27 and oxygen radical production by neutrophils.28 Meclofenamate sodium may inhibit prostaglandin binding at its receptor and inhibits phospholipase A2.29 Meclofenamate also inhibits the lipoxygenase pathway of arachidonic acid metabolism.30 Other differences in the mechanism of action of various NSAIDs have been reviewed.8,31

TABLE 5–2

Processes Influenced by NSAIDs

Prostaglandin production Leukotriene synthesis Superoxide generation Lysosomal enzyme release Neutrophil aggregation and adhesion Cell-membrane functions Enzyme activity (NADPH oxidase, phospholipase C) Transmembrane anion transport Oxidative phosphorylation Uptake of arachidonate Lymphocyte function Rheumatoid factor production Cartilage metabolism NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; NSAIDs, nonsteroidal anti-inflammatory drugs. From Brooks PM, O’Day RO: Nonsteroidal antiinflammatory drugs: differences and similarities. N Engl J Med 324: 1716–1725, 1991. Copyright © 1993 Massachusetts Medical Society. All rights reserved.

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Pharmacology The pharmacokinetic evaluation of NSAIDs in children with JRA has been variable, ranging from extensive for the salicylates to minimal or none with the newer agents; the interested reader is referred to reviews on the subject.32,33 However, studies in adults indicate that most NSAIDs share similar pharmacokinetic properties. They are weakly acidic drugs that are rapidly absorbed after oral administration, with most of the absorption taking place in the stomach and upper small intestine. Circadian rhythms in gastric pH and intestinal motility may lead to variability in NSAID absorption, with reduced absorption of a dose given at night compared with that given in the morning.34 The majority of NSAIDs are strongly protein bound, primarily to albumin, leading to a potential for drug–disease and drug–drug interactions. Hypoalbuminemia may occur as a manifestation of disease activity in JRA, especially in patients with systemic-onset disease, and may be one of the most important factors influencing the pharmacokinetics of NSAIDs in these children. Because clinical effects are determined by unbound or free drug levels, states of hypoalbuminemia may be associated with a corresponding increase in the unbound fraction and hence with a potential for increased toxicity. However, most of the studies of NSAID pharmacokinetics in children do not report the level of disease activity.35 Protein binding may also be reduced with renal or hepatic disease. Although the strong plasma protein binding of NSAIDs also makes possible drug–drug interactions with other highly protein-bound drugs, significant clinical interactions are rare.36,37 Furthermore, children rarely need to be prescribed drugs that have a potential for interacting with NSAIDs. However, NSAIDs may potentially interact with methotrexate (MTX) through several mechanisms, including displacement from plasma protein–binding sites, competition for renal secretion, and impairment of renal function. Although the impact of NSAIDs on MTX clearance varies widely and the potential for clinically significant interactions exists in some children,38 MTX–NSAID interactions are rarely of clinical significance. The kinetics of NSAIDs at their anti-inflammatory sites of action (e.g., synovial fluid) may be more clinically relevant than their kinetics in plasma. The comparative kinetics of NSAIDs in plasma and synovial fluid are related to the half-life of the drug and to differences in protein binding at these sites. Studies in adults indicate that NSAIDs with short half-lives have less fluctuation in synovial fluid concentrations than in plasma concentrations over a given dosage interval.36 This phenomenon may partially account for the fact that the dosage interval of these drugs is longer than their plasma half-life. In addition, because synovial fluid albumin concentrations are lower than plasma concentrations, the free fraction of NSAIDs in synovial fluid can be significantly higher than in plasma and has been shown to correlate with clinical effectiveness.34 This may account for clinical effects observed with relatively low plasma drug levels. Except for naproxen and ASA, plasma concentrations correlate poorly with anti-inflammatory activity.39

NSAIDs are eliminated predominantly by hepatic metabolism; only small amounts are excreted unchanged in urine. Some NSAIDs, such as sulindac or indomethacin, are also secreted in significant amounts in bile and undergo enterohepatic recirculation.36 Most NSAIDs are metabolized by first-order or linear kinetics, whereas salicylate is metabolized by zero-order or nonlinear kinetics. For this reason, dosage adjustments are frequently required with ASA therapy, and small changes in dose may lead to large fluctuations in serum levels of ASA at the higher end of the therapeutic range.33 Naproxen may also demonstrate nonlinear pharmacokinetics at doses greater than 500 mg/day in adults because of the saturation of plasma protein–binding sites and associated increase in clearance.33,34 Interpatient differences in the metabolic clearances of individual NSAIDs may be marked, resulting in considerable variation in the extent of their accumulation at all sites throughout the body.36 In children, NSAIDs may be eliminated more rapidly than in adults; therefore, children may require more frequent doses to maintain a clinical response.35 Differences in pharmacokinetics between short- and long-term administration may be significant, but this has not been studied systematically.32 Abnormalities of hepatic function are common in children with JRA, particularly those with systemic-onset disease. Because hepatic metabolism plays a major role in NSAID elimination, it is necessary to assess hepatic function before institution of NSAID therapy in these children. NSAIDs should not be started if there is significant elevation of transaminase levels (e.g., three times normal or higher).

General Principles of NSAID Therapy The NSAIDs are generally good analgesic and antipyretic drugs and weak anti-inflammatory agents. They provide good symptomatic relief but have traditionally not been considered to influence the underlying disease process or to significantly affect long-term outcomes. The analgesic effect of NSAIDs is rapid, but the anti-inflammatory effect takes longer and requires doses up to twice as large as those needed for analgesia.40,41 NSAIDs are relatively safe for long-term use. Toxicity, although not infrequent, especially for GI side effects, is seldom serious.42–44 Given the wide variety of available NSAIDs, a few general principles can be applied in the selection of a particular NSAID for therapy in an individual patient (Table 5–3).

TABLE 5–3

General Principles of NSAID Use

A specific diagnosis should be established. The objectives of therapy (analgesia or suppression of inflammation) should be understood. The objectives of therapy must be balanced against the risks of toxicity and cost of the drug. An adequate trial (appropriate dose for at least 6–8 wk) is needed before assessing efficacy. Use of combinations of NSAIDs should be avoided. Clinical and laboratory evidence of effect and toxicity should be objectively monitored. NSAIDs, nonsteroidal anti-inflammatory drugs.

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First, according to empirical evidence from clinical experience and some studies in adults, response to NSAIDs appears to have some disease specificity. Indomethacin, one of the more potent NSAIDs, may be more useful in treating manifestations of systemic JRA, such as fever and pericarditis, and in managing the spondyloarthropathies. Ibuprofen is also a very effective antipyretic agent in systemic-onset JRA. Sustained-release preparations of naproxen or, in the older child, indomethacin, given at night may be effective in reducing night pain or prolonged morning stiffness. However, studies suggest that differences in the effectiveness of NSAIDs are small but that some NSAIDs, such as ASA or indomethacin, are more toxic than others.40 Second, individual patient response to NSAIDs is variable and often relatively unpredictable; a child may fail to respond to one drug and yet respond to another. Similarly, the frequency of toxicity may vary widely. A favorable initial response occurs in more than 50% of patients on the first NSAID chosen; of those showing an inadequate response to the first NSAID, a further 50% improve when given another drug of the same class.33 Therefore, for the child whose condition has not responded to one NSAID or who is experiencing significant toxicity, a subsequent trial with another agent is usually warranted. An adequate trial of any NSAID should not be less than about 8 weeks5,45; although about 50% of children who respond favorably to an NSAID do so by 2 weeks of therapy, the mean time to therapeutic response can be 4 weeks, and up to 25% may not respond until after approximately 12 weeks of therapy.46 Third, additional factors such as availability in liquid form, frequency of dosing, cost, and tolerability of any given NSAID may influence patient preference. These factors can have a major impact on patient adherence to a particular treatment regimen and should be carefully evaluated when making therapeutic choices. A reasonable initial approach is to choose an NSAID that has a favorable toxicity–efficacy profile, can be taken on a convenient schedule (such as once or twice daily), is not too expensive, and, for young children, is available in a liquid formulation that is palatable. For these reasons, naproxen has become the initial drug of choice for children with arthritis. It is generally well tolerated and safe, is administered twice daily, and is available in a palatable liquid form.47 A recent open-label study of nabumetone in children with JRA reported an excellent safety profile with no loss of efficacy compared with previously used NSAIDs. The drug was administered at a dose of 30 mg/kg/day, in a single dose, and can be given as a liquid slurry.48 Generally, therapy should commence with the NSAID of choice at the lowest recommended dose, which can then be titrated to the patient’s clinical response. Use of multiple NSAIDs is not recommended, because this approach has no documented benefit in terms of efficacy and can be associated with a greater potential for drug interactions and organ toxicity. The dose range and schedule of administration vary with the individual NSAID (Table 5–4). Patients who are receiving long-term NSAID therapy should have their liver and renal function

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monitored, and a complete blood count should be obtained at least every 6 months. Patients with active systemic disease should have more frequent monitoring of liver function, including serum albumin, particularly with any changes in dose. Once a patient has responded and is considered to be in clinical remission, withdrawal of NSAID therapy can be considered. Although there are no good studies of NSAID discontinuation in children with JRA to guide recommendations, most pediatric rheumatologists consider it reasonable to attempt gradual withdrawal of therapy after remission has been maintained for at least 6 months. Adherence to NSAID regimens may be improved by a variety of behavioral interventaions.49,50

Toxicity Serious toxicity associated with the use of NSAIDs appears to be rare in children.41 However, much of the available information is derived from case reports, case series, or retrospective cohort studies, making it difficult to derive accurate figures for the incidence and prevalence of various toxicities. Prospective studies using standardized approaches to measuring drug-related toxicities are needed to allow a better quantification of the magnitude of risk for the various adverse effects associated with NSAID therapy. In general, however, most toxicities are shared to a greater or lesser degree by all NSAIDs (Table 5–5), although individual patients may have fewer side effects with one drug than with another.23,42,43,51,52

Gastrointestinal Toxicity GI tract toxicity is common to all NSAIDs. The pathogenesis of gastroduodenal mucosal injury involves multiple mechanisms with both local and systemic effects due to NSAIDs.53 The systemic effects appear to have a predominant role and are largely the result of inhibition of prostaglandin synthesis, which leads to impairment of many cytoprotective actions such as epithelial mucus production, secretion of bicarbonate, mucosal blood flow, epithelial proliferation, and mucosal resistance to injury.53 The associated symptoms range from mild epigastric discomfort immediately after taking the medication to symptomatic or asymptomatic peptic ulceration.54 The incidence of symptomatic ulcers and potentially life-threatening ulcer complications, such as upper GI bleeding, perforation, and gastric outlet obstruction, is about 2% to 4% in adults taking NSAIDs for 1 year.55 The relative risk of upper GI bleeding and perforation associated with current NSAID use is estimated to be 4.7 overall, with variability in the magnitude of risk associated with individual NSAIDs.56 Complication-related hospitalization and death rates are estimated to be less than 1.5% per annum in adults.57 However, many of the studies on which these figures are based have limitations in ascertainment as well as attribution of adverse effects to NSAIDs, resulting in the potential for substantial underestimation or overestimation of NSAID adverse effects. Furthermore, differences in patient populations, drugs

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TABLE 5–4

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NSAIDs Commonly Used in Children Maximum Dose (mg/day)

Doses per day

Anti-inflammatory dose: 80–100 (<25 kg) 2500 mg/m2 (>25 kg) Antiplatelet dose: 5

4900

2–4

Kawasaki disease: high dose for initial and low dose for subsequent treatment Therapeutic serum levels (for anti-inflammatory therapy): 15–25 mg/dL (measure 5 days after initiation of therapy or alteration of dose) Nonlinear (zero-order) kinetics (see text) LFT abnormalities common (stop ASA is LFT more than three times normal) Association with Reye’s syndrome (see text) Watch for salicylism

Naproxen*

10–20

1000

2

Ibuprofen*

30–40

2400

3–4

Ketoprofen Fenoprofen

2–4 35

300 3200

3–4 4

Most frequently used initial NSAID Overall favorable toxicity/efficacy profile Pseudoporphyria in fair-skinned children (see text) May have nonlinear pharmacokinetics at higher doses Most favorable toxicity/efficacy profile Association with aseptic meningitis in patients with SLE Least favorable toxicity/efficacy profile Significant risk of nephrotoxicity

Drug

Dose (mg/kg/day)

Comments

Salicylates Acetylsalicylic acid (ASA)

Propionic Acid Group

Acetic Acid Derivatives Indomethacin*

1.5–3.0

200

3

Tolmetin

20–30

1800

Sundilac

4–6

400

2

Diclofenac

2–3

150

3

Meloxicam

0.25

15

1

Piroxicam

0.2–0.3

20

1

Nabumetone

30

2000

1

3–4

Useful in spondyloarthropathies and treatment of fever or pericarditis in systemic-onset JRA Less favorable toxicity profile Headache common at initiation and may diminish with continuation of therapy Least favorable toxicity/efficacy profile May cause false-positive result for urinary protein Absorbed as a prodrug and converted to active metabolite Significant enterohepatic recirculation May be less nephrotoxic than other NSAIDs Similar potency to indomethacin Reports of significant hepatotoxicity

Oxicams Once-daily dosing possible Relatively new agent Least favorable toxicity/efficacy profile Once-daily dosing possible—may be useful in older children or adolescents with poor medication compliance; little experience in young children Once-daily dosing possible Tablets can be mixed in water to create a slurry

JRA, juvenile rheumatoid arthritis; LFT, liver function tests; NSAIDs, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus. *Available in liquid form.

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TABLE 5–5 Relative Toxicities of NSAIDs Toxicity

ASA

Ibuprofen

Fenoprofen

Naproxen

Indomethacin

Sulindac

Tolmetin

Meclofenamate

GI irritation Peptic ulcer CNS Tinnitus Hepatitis Asthma Renal function Bone marrow

+++ ++ + +++ ++ ++ + −

+ + ± + + + + +

++ + ++ +++ + + + +

++ ++ + + + + + +

++++ +++ ++++ + + + ++ +

++ + + + + + ± +

++ + + + ? + ++ +

++ + ± ± + + + +

ASA, acetylsalicylic acid; CNS, central nervous system; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs.

used, dosages, and periods of exposure add to the variability in estimates of prevalence. Data from a randomized, placebo-controlled study of the efficacy of a cytoprotective agent, misoprostol, in 8843 patients with rheumatoid arthritis treated with NSAIDs determined that the incidence of definite serious GI complications was 0.95% in the placebo group over the 6-month trial period.58 Possible risk factors for GI complications during NSAID therapy include advanced age, past history of GI bleeding or peptic ulcer disease, and cardiovascular disease.58 However, most patients who have a serious GI complication requiring hospitalization have not had prior GI side effects.53,54 Additional risk factors may include longer disease duration, higher NSAID dose, the use of more than one NSAID, longer duration of NSAID therapy, concomitant glucocorticoid or anticoagulant use, and serious underlying systemic disorders.53,54 Many of the studies on which these conclusions are based do not account for the interaction of multiple factors or confounding by coexisting conditions.53 It appears that infection with Helicobacter pylori increases the risk of gastroduodenal mucosal injury associated with NSAID use only minimally, if at all.59 The magnitude of this problem in children is poorly documented but has traditionally been thought to be considerably less than in adults, partly because of the absence of the associated risk factors identified in the adult population. H. pylori has not been reported to be an important pathogen in children with JRA treated with NSAIDs.60 Studies in children confirm that, although mild GI disturbances are frequently associated with NSAID therapy, the number of children who develop clinically significant gastropathy appears to be low.44 In many children who develop GI symptoms while receiving NSAIDs, alternative causes, such as the underlying disease process, psychosocial factors, and other concomitant medications, could account for their symptoms. The rigor with which these factors have been systematically evaluated and the definition of “clinically significant” gastropathy have varied considerably among studies, resulting in variability in reported rates for this complication. A retrospective study of a cohort of 702 children receiving NSAID therapy for JRA who were monitored for at least 1 year found 5 children (0.7%) with clinically sig-

nificant gastropathy defined as esophagitis, gastritis, or peptic ulcer disease.61 The retrospective nature of this study may have resulted in a substantial underestimation of the prevalence of NSAID-associated gastropathy. A prospective study of a cohort of 203 children found that, although 135 children (66.5%) had documented GI symptoms at some stage during NSAID therapy, only 9 (4.4%) had endoscopically detected ulcers or erosions; the most commonly reported GI symptoms were abdominal pain (49.7%) and appetite loss (32.0%).62 A more recent prospective study reported on 45 children who underwent routine endoscopy (in association with general anesthesia for joint injections). Nineteen patients, or 42%, had normal gastric and duodenal mucosa, and 20 had histologically mild gastritis. A clear association was seen between abdominal pain and gastroduodenal pathology, but the severity of gastric inflammation did not correlate with the duration of NSAID therapy.63 Factors frequently associated with clinically significant gastropathy in children are abdominal pain at night, melanotic stools, and a previous history of gastropathy.61 Endoscopic studies in very small numbers of highly selected groups of children with JRA receiving NSAIDs have reported a higher frequency of abnormalities.64,65 However, these endoscopic lesions, which are usually mild, have not been found to correlate well with symptoms, and their clinical significance is not clear.64,65 Further prospective studies are needed. A number of studies have shown differences in rates of serious GI complications associated with different NSAIDs. Systematic reviews have found ibuprofen to be associated with the lowest risk; indomethacin, naproxen, sulindac, and aspirin with moderate risk; and tolmetin, ketoprofen, and piroxicam with the highest risk.56,66 A recent report comparing rofecoxib (0.3 to 0.6 mg/kg/day, maximum 25 mg/day) with naproxen (7.5 mg/kg twice daily) showed equivalent efficacy but significantly fewer GI adverse events with rofecoxib.6 In adults, endoscopic studies have shown that COX-2 inhibitors induce significantly fewer ulcers than traditional NSAIDs do.67 Studies in children have also found that tolmetin may be associated with higher risk.61,62 A reasonable approach to therapy is to choose initially an NSAID with a lower risk of GI complications. GI symptoms can be further minimized by ensuring that NSAIDs are always given with food.

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Although some studies in healthy volunteers suggest that enteric coating may reduce acute gastric mucosal injury,68 the use of enteric-coated preparations and parenteral or rectal administration of NSAIDs aimed at preventing topical mucosal injury have not been shown to prevent gastric ulceration.53 The development of “safer” NSAIDs, such as the highly selective COX-2 inhibitors, offers considerable promise, but the clinical utility of these agents in children remains to be determined. Two large studies assessed the gastroprotective effects of celecoxib and rofecoxib. In the Celecoxib Long-term Arthritis Safety Study (CLASS),69 celecoxib was compared with diclofenac or ibuprofen in 8059 patients with rheumatoid arthritis or osteoarthritis; only at higher than clinically indicated doses did celecoxib demonstrate a lower incidence of GI-related adverse events. In the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, rofecoxib (50 mg/day) was compared with naproxen (500 mg twice daily) in 8076 patients with rheumatoid arthritis.70 Significantly fewer clinically important GI adverse events occurred in the rofecoxib group. However, given the relative infrequency of clinically significant GI adverse events in patients with JRA, COX-2 inhibitors should not be the anti-inflammatory agent of first choice. Their role in the treatment of JRA remains to be determined. The utility of antacids and histamine 2 (H2)-receptor antagonists for prophylaxis against serious NSAIDinduced GI complications is controversial. Although these medications suppress symptoms, they do not prevent significant GI events such as endoscopically documented gastric ulcers. In fact, asymptomatic patients on acid-reduction therapies appear to be at greater risk for serious GI complications than are patients not taking these medications, so their routine use in asymptomatic patients taking NSAIDs cannot be recommended.53,54 Sucralfate also does not appear to offer any significant benefit in the prophylaxis of NSAID-induced gastric ulcers.71 Misoprostol, a synthetic prostaglandin E1 analogue, has been shown in adults to be effective in both prophylaxis58,72 and treatment of NSAID-induced gastroduodenal damage, allowing continuation of NSAID therapy while achieving ulcer healing.73,74 Studies of misoprostol cotherapy in children are limited but also suggest that it may be effective in the treatment of GI toxicity symptoms in children receiving NSAIDs.64,75 Misoprostol may also be associated with a protective effect on hemoglobin values in NSAID-treated patients.76,77 Omeprazole, a proton pump inhibitor, has been shown to be superior to ranitidine and misoprostol for the prevention and treatment of NSAID-related gastroduodenal ulcers in adults.77,78 Prospective studies are needed to further evaluate the role of misoprostol and omeprazole cotherapy in children. Recommendations for the treatment of established dyspeptic symptoms or active gastroduodenal ulceration, with or without continuation of NSAIDs, differ from those for the prophylaxis of gastroduodenal injury. Symptoms of active gastroduodenal ulceration after discontinuation of NSAIDs can be treated empirically with an H2-receptor antagonist or a proton pump inhibitor. If an ulcer develops,

discontinuation of the NSAID is preferred, but if NSAID therapy needs to be continued, proton pump inhibitors are recommended.53

Hepatotoxicity Hepatitis with elevation of transaminase levels can occur with any NSAID but has most commonly been reported in children with JRA receiving ASA; up to 50% of these children may have some elevation of enzyme levels,79 and up to 15% may require discontinuation of therapy for this reason.42 In one retrospective study, transaminase levels were increased in 6% of children receiving naproxen.42 One of the confounding factors is that transaminases can be elevated in untreated JRA, particularly in the systemic-onset subtype, and in systemic lupus erythematosus (SLE). Elevated transaminase levels are rarely of clinical significance and often resolve spontaneously, but they may necessitate lowering of the dose or temporary cessation of therapy. Rarely, hepatotoxicity is severe; NSAIDs have been associated with a poorly understood severe multisystem disorder, now called the macrophage activation syndrome, which consists of macrophage activation, hepatic involvement, consumptive coagulopathy, and neurologic manifestations.80,81 Therefore, liver function should be carefully monitored in children taking NSAIDs, particularly those with systemic-onset JRA.

Renal Toxicity Several types of renal complications have been associated with NSAID therapy. These include reversible renal insufficiency and acute renal failure; acute interstitial nephritis; nephrotic syndrome; papillary necrosis; and sodium, potassium, and water retention.82–85 Although these complications are more often reported in the adult population, with an estimated prevalence of 1% to 2%, a number of cases have been described in children.82,86–89 The limited data on the prevalence of these complications in children indicate that it is considerably lower than that reported in adults. A 4-year prospective study of 226 children with JRA treated with NSAIDs found the prevalence of renal and urinary abnormalities attributable to NSAID therapy to be only 0.4%90; an even lower prevalence of 0.2% was reported in another cohort of 433 children.91 Several studies demonstrated subclinical abnormalities of renal glomerular or tubular function in children with JRA receiving NSAIDs by measuring the urinary excretion of selected glomerular proteins (albumin, transferrin, immunoglobulin G [IgG]) and tubular proteins (α1- and β2-microglobulin) or enzyme markers (N-acetyl-βglucosaminidase).92,93 However, the clinical relevance of these abnormalities as potential markers for the development of more serious renal complications is not yet clear, because no long-term data are available to correlate these abnormalities with important clinical outcomes. The various renal syndromes associated with NSAID therapy differ in their pathophysiologic basis, clinical presentation, frequency, and predisposing risk factors. The most commonly reported complication is reversible

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renal insufficiency, mediated through the effect of NSAIDs on prostaglandin synthesis. Inhibition of renal prostaglandin synthesis has little effect on renal function in healthy persons. However, in states of hypovolemia or salt depletion, the adrenergic and renin-angiotensin system is activated, resulting in renal vasoconstriction. Prostaglandins are needed to maintain renal perfusion under such conditions by producing local vasodilatation. Inhibition of prostaglandin synthesis with NSAID therapy may suppress this protective autoregulatory mechanism, resulting in unopposed vasoconstrictor activity and renal hypoperfusion.83,84 This type of renal insufficiency is usually reversible within 24 to 72 hours.82 Risk factors include underlying renal disease (e.g., SLE) or states of hypovolemia and salt depletion with high plasma renin activity (e.g., gastroenteritis, sepsis, congestive cardiac failure, cirrhosis, diuretic treatment) in normal persons. Indomethacin is the NSAID most often implicated with this complication.83,94 In addition to impairment of renal function, some children show signs of fluid retention, such as congestive heart failure, edema, or hypertension, when treated with NSAIDs. A modest drop in hematocrit value with ASA or other NSAIDs may result from mild degrees of sodium retention and hemodilution rather than from anemia related to GI bleeding.41 Acute interstitial nephritis with nephrotic syndrome is far less commonly reported with NSAIDs. It occurs sporadically and is thought to represent a hypersensitivitytype reaction.84 It typically has an abrupt onset with hematuria, heavy proteinuria, and flank pain. In contrast to classic drug-induced allergic nephritis, however, fever, rash, eosinophilia, and eosinophiluria usually are not present. Onset may be from 2 weeks to 18 months after initiation of NSAID therapy, and resolution may take from 1 month to almost 1 year after discontinuation of the NSAID.84 Renal failure may be severe enough to require temporary dialysis support. Glucocorticoids have been used to treat this complication, but their efficacy is unproven. Interstitial nephritis with and without nephrotic syndrome has also been described in a small number of children.41 This complication is more commonly reported with propionic acid (naproxen, fenoprofen) and acetic acid (tolmetin, indomethacin, sulindac) derivatives.84,85 Papillary necrosis is a chronic renal injury that has been most commonly associated with long-term analgesic abuse, particularly with phenacetin.84,95 It has also been reported to occur with several NSAIDs, including ibuprofen, fenoprofen, phenylbutazone, and mefenamic acid. Medullary ischemia is thought to be the initiating factor in the production of papillary necrosis.84 The syndrome is usually characterized by painless leukocyturia and hematuria, without impairment of renal function, and by demonstration of changes on the intravenous pyelogram.84,87,88,96–100 Combination NSAID therapy appears to be a risk factor in both adults and children.82,100

Central Nervous System Effects Three general categories of CNS side effects have been reported in association with NSAID therapy in adults:

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aseptic meningitis, psychosis, and cognitive dysfunction.101 The NSAID most commonly reported to cause aseptic meningitis has been ibuprofen; susceptibility appears to be greater in patients with SLE. However, there does not seem to be any cross-reactivity between NSAIDs for this complication. Indomethacin and sulindac have been reported to induce psychotic symptoms, including paranoid delusions, depersonalization, and hallucinations, in a small number of patients.101 More subtle CNS effects, such as cognitive dysfunction and depression, can also occur and are probably under-recognized and under-reported. Tinnitus may occur with any NSAID, but particularly with ASA.41 A prospective study of 203 children with JRA found that CNS symptoms occurred in 55% of patients taking NSAIDs; the most common symptom was headache, which occurred in about one third of children.102 Other reported symptoms included fatigue, sleep disturbance, and hyperactivity. Seizures were noted in two patients, both of whom were taking indomethacin.

Cutaneous Toxicity A diverse group of skin reactions, including pruritus, urticaria, morbilliform rashes, erythema multiforme, and phototoxic reactions, have been described.41,103 Initially described in Australia,104 the syndrome of pseudoporphyria occurring in association with naproxen therapy in children with JRA has now been reported in several case series.104–109 It is a distinctive photodermatitis marked by erythema, vesiculation, and increased skin fragility characterized by easy scarring of sun-exposed skin (Fig. 5–4). Porphyrin metabolism is normal. All findings except scarring resolve with discontinuation of naproxen, but

■ Figure 5–4 Distant and close-up views of the face of an 8-year-old boy with pseudoporphyria who was taking naproxen. Note a blistered lesion adjacent to a superficial scar. Superficial scars are also visible on the nose.

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the vesiculation may persist for several months.110 Children with fair skin and blue eyes are particularly susceptible; one study reported a relative risk of 2.96 if the child had blue-gray eyes and was taking naproxen.109 Pseudoporphyria appears to be a common side effect even in geographic areas without high sun exposure; a 6-month prospective study of children seen in a rheumatology clinic in Halifax, Nova Scotia, reported a prevalence of 12% among those treated with naproxen107; similarly, there was a 10.9% incidence among NSAIDtreated children with juvenile idiopathic arthritis (JIA) in Edinburgh.109 Although this complication has most often been reported with naproxen, many other NSAIDs have also been implicated.

Effects on Coagulation The NSAIDs decrease platelet adhesiveness by interfering with platelet prostaglandin synthesis, such as that of thromboxane B2, which promotes platelet aggregation. This inhibition is reversible in the case of all NSAIDs except ASA, which irreversibly acetylates and inactivates COX (see Fig. 5–3), an effect that persists for the life of the platelet; bleeding time returns to normal only as new platelets are released into the circulation.41 The NSAIDs also displace anticoagulants from protein-binding sites, thereby potentiating their pharmacologic effect. These effects of NSAIDs must be considered when any surgical procedure is planned.

Reye’s Syndrome Reye’s syndrome was first described in Australia in 1963 as a distinct clinicopathologic entity by Reye and associates.111 An association with salicylate therapy was later demonstrated in the early 1980s.112 Reye’s syndrome is an acute illness characterized by encephalopathy and fatty degeneration of the liver that occurs almost exclusively in children and usually in association with a viral-like prodromal illness, the most common being influenza or other respiratory illnesses, varicella, or gastroenteritis.113 The onset of the illness is characterized by profuse vomiting and varying degrees of neurologic impairment. Initially, there may be fluctuating personality changes and deterioration in consciousness, followed by extreme irritability, agitation, confusion, delirium, and coma as the encephalopathy progresses. Associated metabolic abnormalities include hyperammonemia and increased levels of hepatic transaminases, with consequences of hepatic dysfunction such as prolongation of the prothrombin time and severe hypoglycemia. Characteristic liver histopathologic abnormalities include microvesicular fat accumulation in hepatocytes on light microscopy and mitochondrial disorganization and proliferation of smooth endoplasmic reticulum on electron miscroscopy.113 The illness can be fatal, with an overall case-fatality rate of 31%; rates are significantly higher in children younger than 5 years of age and in those with a serum ammonia level greater than 45 μg/dL.113 Reye’s syndrome appears to be a heterogeneous condition; in recent years, a proportion of children presenting with Reye-like illnesses have been found to have various inborn metabolic

disorders. This subgroup is characterized by features such as younger age, recurrent episodes, family history of similar illness, frequent hypoglycemia, cardiac enlargement, muscle weakness, and lack of mitochondrial disorganization in liver tissue.113 The association between Reye’s syndrome and salicylate therapy was first reported in a small case-control study.114 Although this study initially was a source of controversy, its findings were later confirmed by larger and more rigorously designed studies.112 The association between salicylate use and Reye’s syndrome is consistent and is very strong, with odds ratios as high as 35 to 40 in the larger studies.115,116 Although demonstration of an epidemiologic association alone is not sufficient to prove causation, there is further evidence in support of an etiologic role for salicylates in Reye’s syndrome: The finding of a dose-response relationship, with higher doses of salicylate used in case subjects than in controls, and more recent epidemiologic evidence from the United States and United Kingdom indicate that there has been a dramatic decline in the incidence of Reye’s syndrome concurrent with a decline in the use of salicylates in children since public health warnings were issued in the mid1980s.113,117 In a large epidemiologic study in the United States, 14 of 361 patients with Reye’s syndrome for whom data on aspirin use were available had taken salicylate-containing medications for illnesses such as JRA and Kawasaki disease.113 Other studies have reported higher rates of Reye’s syndrome in children taking salicylates for JRA.118,119 None of the studies to date has reported any association with other NSAIDs.112 Physicians and others caring for children requiring long-term salicylate therapy should be aware of the risk of Reye’s syndrome and be able to recognize the early symptoms so that salicylate therapy can be promptly withdrawn. These children should be offered varicella vaccine and annual vaccination against influenza in accordance with the recommendations of the Advisory Committee on Immunization Practices.120

Hypersensitivity and Miscellaneous Effects The precipitation of asthma or anaphylaxis with NSAIDs has been reported in adults as a unique syndrome associated with nasal polyps; 15% to 40% of patients with nasal polyps may experience bronchospasm when given aspirin.121,122 Although this syndrome can theoretically be provoked by any NSAID, it has most commonly been reported with ASA or tolmetin; cross-reactivity between NSAIDs may occur.41 However, there appears to be a correlation with the strength of COX inhibition: More potent NSAIDs such as indomethacin induce bronchospasm at smaller doses than do less potent ones such as ibuprofen.123 Although “allergy” to ASA is often reported by patients or parents, true hypersensitivity to the drug is exceedingly rare in childhood. ASA hypersensitivity occurs in about 0.3% to 0.9% of the general population, in 20% of patients with chronic urticaria, and in 3% to 4% of patients with chronic asthma and nasal polyps.124–126 It should be noted that such patients are often hypersensitive to the other NSAIDs as well.127

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Effects on the bone marrow, including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia, have been reported but are rare.41 Mild anemia occurs in about 2% to 14% of children42 and may be partly due to hemodilution, hemolysis,128 or occult GI blood loss due to NSAID therapy.75

Salicylates The salicylates, a group of related drugs that differ by the nature of the substitutions on the carboxyl or hydroxyl groups of the molecule, include ASA (ASA), salsalate, choline salicylate, magnesium salicylate, and sodium salicylate. They are hydrolyzed in vivo to salicylic acid. Related compounds such as salicylamide and diflunisal are not hydrolyzed to salicylic acid and therefore are not considered to be salicylates.129 ASA is the oldest NSAID and has been used to treat the articular manifestations of rheumatic diseases for many years. Although newer NSAIDs have largely replaced ASA as the mainstay of anti-inflammatory drug therapy in pediatric rheumatology, ASA continues to have a role in the management of Kawasaki disease (see Table 5–4) and in the treatment of patients who are predisposed to thromboses. The general principles of NSAID mechanism of action and pharmacology, as well as the principles of therapy and the spectrum of known adverse effects, have already been addressed with reference to salicylates where relevant. However, the salicylates differ from other NSAIDs in a number of specific aspects; these are addressed in the following paragraphs.

Mechanism of Action ASA exerts its anti-inflammatory, analgesic, and antipyretic effects in part by irreversibly acetylating and inactivating COX, thus inhibiting biosynthesis and release of the prostaglandins (see Fig. 5–3; see Chapter 3).120,130,131 Other salicylates also inactivate this enzyme, but not irreversibly. A dose-dependent effect of ASA on the inhibition of prostacyclin (prostaglandin I2) production by endothelial cells and of thromboxane A2 production by platelets has also been noted and may be relevant in the management of Kawasaki disease or other types of vasculitis in children (see Chapter 24).132,133 Large doses of ASA increase urinary excretion and lower the serum concentration of urate; low doses have the opposite effect.134 This phenomenon must not be confused with hyperuricemia or with gout, which is extremely rare in children.

Pharmacology The plasma level of salicylate (ASA and salicylate ion) peaks 1 to 2 hours after a single dose, and the drug is virtually undetectable at 6 hours. ASA itself is bound very little to plasma protein, but salicylic acid binds extensively to albumin and erythrocytes. Salicylic acid is found in most body fluids (including the cerebrospinal fluid, saliva, synovial fluid, and breast milk), and it crosses the placenta. ASA is metabolized by hepatic microsomal enzymes by conjugation with glycine to form salicyluric acid and, to a lesser extent, by conjugation with the phenolic and acyl glucuronides, which are in turn excreted by the kidneys. Renal clearance of these metabolites, which have longer half-lives than the parent drug, is augmented by alkalinization of the urine.

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Administration ASA is quickly absorbed from the stomach and proximal small intestine.135,136 Some salicylates (methyl salicylate, salicylic acid) are well absorbed through the skin. The systemic anti-inflammatory effects of ASA are maximal, and in most cases they are achieved only if serum steady-state levels are 15 to 25 mg/dL (1.09 to 1.81 mmol/L).137,138 With levels less than 15 mg/dL, ASA does not function effectively as an anti-inflammatory agent; at greater than 30 mg/dL (2.17 mmol/L), it is likely to be toxic. The dosage necessary to reach these concentrations is usually 75 to 90 mg/kg/day, divided into four doses given with food. Lower doses suffice in the child weighing more than 25 kg. The plasma half-life of salicylate increases as the plasma concentration of the drug increases (capacity-limited kinetics). For example, at a plasma concentration of 26 mg/dL, the half-life of ASA can be as long as 16 hours, whereas at a plasma level of 4 mg/dL, it may be as short as 2.5 hours.33 Consequently, the drug need not be given as frequently once plasma concentrations are high, and toxic concentrations of the drug take much longer to decrease than would otherwise be anticipated. Therapeutic levels are not reliably attained before 2 to 5 days of administration. Serum salicylate and serum liver enzyme levels should be checked 5 days after initiation of therapy or after any dose adjustment. Although it is the author’s practice to monitor salicylate concentrations in serum taken 2 hours after the morning dose, one study indicated that the timing of blood sampling was not critical if the interval between doses was 8 hours or less and a steady state had been achieved after 5 days of therapy.139

Toxicity: Salicylism Salicylism (acute or chronic salicylate intoxication) can occur rapidly in the young child, and early signs such as drowsiness, irritability, or hyperpnea can easily be overlooked. In the very young child, metabolic acidosis and ketosis occur, whereas the older child may first experience respiratory alkalosis by direct action of ASA on the hypothalamus. Abdominal pain or vomiting may occur in some children. The child with fever and dehydration is prone to salicylism: In the child with intercurrent illness and nausea, vomiting, or diarrhea, the drug should be immediately discontinued. Symptoms of salicylism include tinnitus, deafness, nausea, and vomiting (Table 5–6). Early on, there is CNS stimulation (hyperkinetic agitation, excitement, maniacal behavior, slurred speech, disorientation, delirium, convulsions). Later, CNS depression (stupor and coma) supervenes. Because the young child, in whom there is a narrow margin between therapeutic and toxic levels,140,141 may not effectively communicate symptoms of salicylism, the family must be thoroughly schooled in the signs of overdose.

TABLE 5–6

Toxicity of Salicylates

Symptom

Frequency

Gastric irritation Tinnitus and/or diminished hearing Hepatotoxicity Reye’s syndrome Hypersensitivity (in asthma) Salicylism Mild: Lethargy, dizziness, headache, diaphoresis, nausea Moderate: Confusion, hyperpnea, metabolic acidosis, respiratory alkalosis Severe: Hyperpyrexia, convulsions, cardiovascular collapse

50% 15% 2% Rare Rare

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Mild salicylate toxicity requires no treatment and often only a minor decrease in salicylate dose. If the child has persisting symptoms, evidence of CNS stimulation, or depression, the drug must be discontinued. The child should be monitored for evidence of acute salicylate toxicity: fever, acute renal failure, CNS depression, pulmonary edema, bleeding, and hypoglycemia. In situations of severe chronic salicylism or acute overdose, the stomach contents should be emptied, and activated charcoal (0.5 to 1.0 g/kg) should be administered. Urine output, body temperature, serum electrolytes, and glucose should be monitored, and glucose-containing intravenous fluids should be given as required. Alkaline diuresis induced with sodium bicarbonate and furosemide increases the rate of salicylate excretion in the urine but must be carefully titrated in the presence of rapidly changing metabolic or respiratory function. Peritoneal dialysis or hemodialysis may be necessary. The reader is referred to the recommendations of Mofenson and Caraccio142 for details of the management of severe salicylate poisoning.

Contraindications ASA leads to hemolysis in children who have the enzyme defect glucose-6-phosphate dehydrogenase deficiency or pyruvate kinase deficiency. It should be avoided in children who have bleeding disorders, such as hemophilia or von Willebrand’s disease, and in patients receiving thrombolytic agents or anticoagulants. ASA should not be given during the last trimester of pregnancy because of its effects on coagulation and platelet function.

Drug Interactions ASA should be used with caution in children taking certain other drugs. Levels of MTX,38 valproic acid,143 phenytoin,144 and other NSAIDs (tolmetin, diclofenac)139,145 may be increased in children who are also receiving aspirin. ASA decreases the bioavailability of other NSAIDs by 20% to 50%142 and increases the digitalis concentration by 30%,144 although the clinical significance of this interaction is uncertain. Glucocorticoids increase the rate of excretion of ASA,146 and salicylism may occur if glucocorticoid drugs are abruptly discontinued in a child taking therapeutic amounts of ASA.

Disease-Modifying Antirheumatic Drugs A number of drugs used to treat JRA and certain other rheumatic diseases do not produce an immediate analgesic or anti-inflammatory effect but exert their beneficial effects weeks to months after initiation of therapy. These compounds, called disease-modifying antirheumatic drugs (DMARDs) or slow-acting antirheumatic drugs (SAARDs), currently include MTX, the antimalarials, sulfasalazine, leflunomide, gold compounds, and D-penicillamine. Historically, there was reluctance to start DMARD treatment until relatively late in the course of disease. Standard practice had been to use one, two, or even three NSAIDs sequentially (or occasionally even in combination) before starting DMARD therapy. Much of this delay had to do with the potentially serious toxicities of DMARDs (principally gold and D-penicillamine), the fact that JRA was not a fatal disease and therefore thought not to warrant treatment with drugs of such potentially significant toxicities, and a belief that most children would eventually “outgrow” the disease. However, there has

been a philosophical shift in therapeutic approach, based on an appreciation that irreversible damage occurs early; that active disease, leading to deleterious long-term effects, persists for many years147; and that MTX, the most frequently prescribed drug in this class, is both safe and effective.148–151 Therefore, there has been a tendency to pursue a more aggressive approach than in the past and to start DMARDs early in the course of the disease to prevent irreversible joint damage, rather than wait for significant damage to declare itself. Furthermore, experience with combination therapy in adult rheumatoid arthritis has led to use of a variety of combinations in JRA as well. MTX is the most commonly used DMARD for JRA. Gold and D-penicillamine now are rarely used for JRA. Several DMARDs are also used to treat other rheumatic diseases (e.g., hydroxychloroquine in the management of SLE and, occasionally, juvenile dermatomyositis [JDM]; sulfasalazine in treatment of the spondyloarthropathies). In the treatment of arthritis, DMARDs are usually given in addition to an NSAID. The goal of treatment is to achieve disease control with drugs from this class and then to stop other treatments (e.g., NSAIDs, prednisone).

Methotrexate Low-dose weekly MTX has emerged as one of the most useful agents in the therapeutic armamentarium for the management of rheumatic diseases in children. It is one among only a small number of agents that have been demonstrated to be efficacious in a randomized controlled trial in children; this drug is now often the firstchoice second-line agent in childhood arthritis. Although it has been most extensively studied in adult rheumatoid arthritis and in children with JRA, its use is also growing in many other chronic inflammatory disorders.152

Mechanism of Action MTX (Fig. 5–5) is a folic acid analogue and a potent competitive inhibitor of dihydrofolate reductase (DHFR) (Fig. 5–6). It may also inhibit thymidylate synthase and interfere with the metabolic transfer of single carbon units in methylation reactions, especially those involved in synthesis of thymidylate and purine deoxynucleosides, which are essential components of DNA.153 It also interferes with de novo purine biosynthesis by inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, an enzyme in the purine biosynthetic pathway. MTX-induced inhibition of AICAR transformylase N

N

H2N

O N

N

CH2

NH2

N

C

CH3

NH CHCOOH CH2 CH2 COOH

■ Figure 5–5

Structure of methotrexate.

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Intracellular Purine synthesis (guanine, adenine)

D-Ribose 5P (pentose cycle)

A

A

10 - Formyl- THF THF GAR

Guanine

FGAR

10 - FormylTHF

THF

AICAR

MTX

89

Extracellular

Cell membrane

C H A P T E R

FAICAR

IMP

AMP AMP deaminase

MTX

5’–nucleo– tidase

B

C Inosine

CD73 ⫽ ecto– 5’–nucleotidase

Adenosine

ADA (Adenosine deaminase)

Uric acid

AMP

C

D

Adenosine

Adenine GTP

Immunosuppression

A2a A2b

G␣? cAMP

G

F

G␤

G␥

cAMP

E A1

GTP G␣? G␤

G␥

■ Figure 5–6 Steps in methotrexate intracellular metabolism and possible sites of action. AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; dUMP, deoxyuridylate monophosphate; MTX, methotrexate; TMP, thymidylate monophosphate. (From Cutolo M, Sulli A, Pizzorni C, Seriolo B. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 60: 729–735, 2001.)

and secondary inhibition of adenosine deaminase leads to accumulation and enhanced release of adenosine, a potent inhibitor of neutrophil adherence.154,155 It is believed that the effects of MTX are in fact mediated primarily through the anti-inflammatory action of adenosine acting through a variety of receptors.156 The mechanism of action of MTX in JRA or adult rheumatoid arthritis is not clearly elucidated, although MTX is known to act at a number of intracellular levels. In addition to its action as an antimetabolite, it is an antiinflammatory and immunomodulatory agent. MTX modulates the function of many of the cells involved in inflammation and affects the production of a variety of cytokines, including reducing the production of TNF-α, interferon-γ (IFN-γ), IL-1, IL-6, and IL-8, thus acting as a potent inhibitor of cell-mediated immunity.153,156 By reducing the endothelial cell production of adhesion molecules, MTX may reduce the permeability of the vascular endothelium. In addition, adenosine inhibits adherence of stimulated neutrophils to endothelial cells, thereby protecting the vascular endothelium from neutrophil-induced damage.153,157 It may also have more direct effects in inflamed joints by inhibiting the proliferation of synovial cells and synovial collagenase gene

expression.158 Although the exact mechanism of action is the subject of intense study, it is not yet possible to clearly distinguish which of the many cellular and immune effects demonstrated in vitro and in vivo are of particular relevance to MTX’s clinical effects. The reader is referred to reviews that explore this issue in greater detail.153,157 The widespread biologic effects of MTX may in fact account for its observed efficacy in a wide variety of diseases with disparate pathogeneses, such as cancer, psoriasis, and the various rheumatic and other chronic inflammatory diseases.

Pharmacology There is significant intraindividual and interindividual variability in the absorption and pharmacokinetics of MTX after oral administration.159 Although the average oral bioavailability is about 0.70 (compared with intravenous dosing), the range can be quite wide (0.25 to 1.49), with 25% of subjects in one study absorbing less than half their dose.160 Factors such as age-related differences, the influence of food, and the effects of concurrently administered medications contribute to this variability. The effect of food on the oral bioavailability

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Serum concentration, molar

of MTX has been controversial.161 However, a pharmacokinetic study demonstrated that factors such as age, body weight, creatinine clearance, sex, dose, and fed versus fasted state significantly influenced the disposition of MTX in adults with rheumatoid arthritis.162 The bioavailability of MTX has also been demonstrated to be greater in the fasting state in children with JRA.163 The author currently recommends that MTX be given on an empty stomach with water or clear citrus beverages. In general, oral bioavailability is about 15% less than after intramuscular administration. Bioavailability of intramuscular and subcutaneous administration is similar,164 with the latter being generally more acceptable for children who require parenteral MTX. After a single dose of MTX, the drug is present in the circulation for a relatively short period before it is redistributed to the tissues (Fig. 5–7). Peak serum levels are reached in approximately 1.5 hours (range, 0.25 to 6 hours), with elimination half-life being approximately 7 hours in subjects with normal renal function.165 Circulating levels fall rapidly as the drug is distributed into tissue and eliminated. The predominant route of elimination is renal, with more than 80% of the drug eliminated unchanged via glomerular filtration and tubular secretion within 8 to 48 hours. A smaller but significant route of elimination is the biliary tract. The pharmacokinetics of MTX are triphasic. The initial rapid phase represents tissue distribution and renal clearance; the second phase is prolonged because of slow release from tissues, tubular reabsorption, and enterohepatic

10⫺6

Cmax Toxicity likely

MTX 10⫺7

7-OH-MTX

10⫺8

10⫺9

Tmax

% excreted in urine

12

24

36

48

MTX 100 75 50 25

7-OH-MTX 12

24

36

48

recirculation; the third phase is flat between weekly doses, reflecting the gradual release of tissue MTX.165 Most MTX is delivered to cells as the parent compound and enters cells via active transport by reduced folate carriers. MTX competes with leucovorin for these carriers. Folic acid enters cells through a different set of receptors, the folate receptors. Their expression may be upregulated in inflamed synovium, allowing for more efficient transport of MTX into cells. These receptors are expressed variably, most likely under genetic control, and the interindividual variability may explain some of the differences in efficacy and toxicity. Similarly, removal of MTX from cells occurs via multidrug resistance–associated proteins, which may be enhanced in some patients and could again explain some interindividual variability in MTX response. Between 3% and 11% of the parent drug is hydroxylated in the liver to 7-hydroxymethotrexate (7-OH-MTX). A portion of intracellular MTX and 7-OH-MTX is metabolized to MTX polyglutamates by the enzyme folyl-polyglutamyl synthetase. This enzyme also polyglutamates folic acid and folinic acid, which at high levels may overwhelm this enzyme system, preventing MTX polyglutamation and allowing it to efflux from cells.153 MTX polyglutamates are long-lived derivatives that retain biochemical and biologic activity within the cell.165 These intracellular, polyglutamated MTX derivatives may in fact be the active anti-inflammatory agents,156 and levels of polyglutamates in red blood cells have been shown to correlate with efficacy in patients with rheumatoid arthritis.166 Plasma drug levels do not correlate well with clinical effects and therefore are not useful in routine monitoring of MTX therapy.159 Measurement of MTX levels in saliva also has not been helpful.165,167 The pharmacokinetics of oral MTX in JRA appear to be age dependent, with more extensive metabolism of MTX in younger children.168 This difference may account for the observation that children require higher doses of MTX than adults do to obtain similar therapeutic effects.169,170 At low doses, MTX is only moderately protein bound (11% to 57%), so the potential for interactions with other protein-bound drugs is small and usually is not clinically significant.165 Studies in adults have not shown a consistent or clinically important interaction between MTX and NSAIDs. However, several studies in children have demonstrated an interaction between MTX and NSAIDs that may be clinically significant in individual patients, particularly those with any renal dysfunction.38,171 It is thought that this interaction may be mediated through competition for protein-binding sites and through alteration of renal clearance.152 The combination of MTX and trimethoprimsulfamethoxazole should be avoided, because it may lead to hematologic toxicity through the synergistic effects of these drugs on DHFR. Although the potential for interaction between MTX and various other drugs (e.g., sulfasalazine, glucocorticoids, folate supplementation) exists, current clinical data do not support general avoidance of these combinations (see later discussion).165

Time after ingestion (h)

■ Figure 5–7 Time course of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) after an oral dose of 15 mg. (From Hillson JL, Furst DE: Pharmacology and pharmacokinetics of methotrexate in rheumatic disease: practical issues in treatment and design. Rheum Dis Clin North Am 23: 757–778, 1997.)

Efficacy The short- to medium-term efficacy of MTX in children with JRA is now well established.152,172 Benefits in initial

retrospective and uncontrolled studies were subsequently confirmed in a combined USA-USSR placebo-controlled, randomized controlled clinical trial.148 In this 6-month study of 127 children with resistant JRA (mean age, 10.1 years; mean disease duration, 5.1 years), 63% of the group treated with 10 mg/m2 of MTX improved, compared with only 32% of those treated with 5 mg/m2 and 36% of the placebo group. The assessment of efficacy was based on a composite of clinical and laboratory parameters and subjective global assessment by physician and parent but did not include any functional assessments or radiographic examinations. A Cochrane Database Systematic Review, based on only two studies of 165 patients, concluded that MTX had minimal clinically significant effects (greater than 20%) on patient-centered disability in patients with JIA.173 Various investigators have tried to determine whether MTX is more effective in some JRA subgroups than others. A randomized, controlled study from the United Kingdom concluded that MTX, at doses up to 20 mg/m2, produced significant improvement in patients with extended oligoarticular JIA but was much less effective in patients with systemic-onset JIA.174 Ravelli and associates175 studied the effects of MTX in patients with polyarticular, extended oligoarticular, and systemic-onset JIA (20, 23, and 37 subjects, respectively) and determined that the extended oligoarticular subtype was the best predictor of short-term clinical response. These patients also relapsed more quickly on discontinuation of MTX, supporting the conclusion that MTX may be most effective in patients with extended oligoarticular disease. Finally, a study from Saudi Arabia of 18 patients with systemic-onset JIA treated with MTX for a mean of 18 months found that systemic features resolved in all of the 10 patients who had such features at the start of treatment; the active joint count and functional class improved in 16 patients, and there was an overall reduction of the need for corticosteroid treatment.176 However, some children with systemiconset JRA had worsening of their disease with MTX treatment.177

Several subsequent studies suggested that MTX may also slow the radiologic progression of disease in JRA, although the available data are not conclusive.178,179 Some authors suggested that earlier treatment with MTX, possibly before the appearance of radiographic changes, may favorably influence the outcome of MTX treatment in children with systemic-onset disease.180 Similar results were found with early “aggressive” treatment in adults with recent-onset rheumatoid arthritis.181 The longer-term efficacy of MTX in JRA and its impact on function and quality of life need further study. There is also accumulating experience with the use of MTX in many other pediatric rheumatic disorders, including SLE,182 some vasculitides,183,184 sarcoidosis,185 systemic sclerosis,186 localized scleroderma,187 and uveitis.188 However, the evidence for the efficacy of MTX in these conditions is less strong and often is based on open, uncontrolled studies or extrapolated from the larger experience in adults, which is not always valid. The reader is referred to the chapters dealing with these conditions for a fuller discussion of the role of MTX in their overall management.

Dosage, Route of Administration, and Duration of Methotrexate Therapy Standard effective doses of MTX in children with JRA are in the range of 10 to 15 mg/m2/week or 0.3 to 0.6 mg/kg/week (Table 5–7). Improvement is generally

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TABLE 5–7

Guidelines for Use of Methotrexate in the Treatment of Juvenile Idiopathic Arthritis Dose Initially, 10 mg/m2, once per week; give on an empty stomach with water, citrus, or carbonated beverage Increase dose as tolerated or as needed to 15 mg/m2 Administer subcutaneously once per week for doses >15 mg, intolerance, or nonadherence Administer with folic or folinic acid (see text) Clinical Monitoring Improvement should be seen by 6–12 wk Monitor every 3–6 mo, depending on course Reduce dose or discontinue and monitor for clinical or laboratory adverse events Laboratory Monitoring CBC with WBCC, differential, and platelet count; MCV; AST, ALT, albumin every 4–6 wk (see also Table 5–9) ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; MCV, mean cell volume; WBCC, white blood cell count.

seen by about 6 to 8 weeks on effective doses, but may take up to 6 months. Children seem to tolerate much higher doses than adults, and some series have described using up to 20 to 25 mg/m2/week or up to 1.1 mg/kg/week in children with resistant disease with relative safety in the short term.169,170 The efficacy of the use of higher doses was not supported by a randomized controlled trial.151 Furthermore, the longer-term safety of MTX therapy at these doses is not known. Parenteral MTX administration should be considered in those children who (1) have a poor clinical response to orally administered MTX (this may be due to poor compliance or to reduced oral bioavailability for a variety of reasons); (2) need a dose in excess of about 10 to 15 mg/m2/week in order to achieve maximum clinical response (oral MTX absorption is a saturable process, whereas subcutaneous administration is not) (Fig. 5–8)189,190; or (3) develop significant GI toxicity with 24 20

AUC (␮M.h)

C H A P T E R

ou

16

ut bc u S

12

s

e an

8

Oral

4 0 0

10

20

30

40

50

60

Dose (mg/m2)

■ Figure 5–8 Bioavailability of oral and subcutaneously administered methotrexate. AUC, area under the curve. (Adapted from Wallace CA: New uses of methotrexate. Contemp Pediatr 11: 43–53, 1994.)

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orally administered MTX (because there is some anecdotal experience that patients complain of less GI irritation when the drug is given parenterally).152,191 Studies in adult rheumatoid arthritis suggest that oral absorption of MTX is considerably reduced at doses of 15 mg or more and therefore should be administered parenterally.192,193 Furthermore, bypassing the enterohepatic circulation may also reduce hepatotoxicity. Some pediatric rheumatologists even advocate using parenteral MTX at initiation of treatment to ensure complete absorption and achievement of early disease remission.152,194 The issue of when, how, and by what criteria to attempt withdrawal of MTX therapy in JRA is currently undecided. There have been a number of studies in children treated with variable doses of MTX for variable periods in whom discontinuation of MTX was attempted after clinical “remission” of variable length was achieved.195–197 The criteria for “remission” or “relapse” have usually not been well defined or standardized among various studies, and the assessment of outcomes has been nonblinded. Given these limitations, no firm conclusions can be drawn about the optimal time and mode of MTX discontinuation in children with JRA. MTX withdrawal may result in disease flare in more than 50% of patients; this rate may be even higher in younger children.195,197 A longer period on MTX treatment after remission may not prolong the duration of improvement after stopping treatment, but the duration of clinical remission may be predicted by the degree of subclinical synovial inflammation at the time of stopping MTX.198 There are conflicting data about the ease with which remission can be reestablished when MTX is restarted after disease relapse, which may be related to the different doses of MTX used and the differing lengths of follow-up in the studies reported to date. Prospective studies with more standardized assessments of outcome and durations of follow-up are needed to address these issues.

Safety MTX is currently considered the second-line agent with the best toxicity/efficacy profile for the treatment of various rheumatic diseases in children and adults.172 Although MTX is associated with a number of potential toxicities, the documented overall frequency and severity of adverse effects in children with arthritis have been low (Table 5–8).150,152,199 Most side effects are mild and reversible and can be treated conservatively. The two areas of greatest concern and debate, especially in children, have been the potentially increased risk of hepatic cirrhosis in patients exposed to large cumulative doses of MTX and a possible increased risk of malignancies. Although the precise mechanism of all MTX-related toxicities is not yet clearly understood, at least some of its adverse effects are directly related to its folate antagonism and its cytostatic effects.200 This is especially evident in tissues with a high cell turnover rate, such as the GI tract and bone marrow, which have a high requirement for purines, thymidine, and methionine. Supplementation with folic or folinic acid may diminish these but not other types of toxicities which, along with MTX efficacy, may be mediated by different mechanisms (see later discussion).200

Gastrointestinal Toxicity Abdominal discomfort and nausea, the most frequently reported symptoms, occur in about 12% of children with JRA who receive MTX. Stomatitis or oral ulcers are reported in about 3% of children.152 Higher rates are reported in adults, with up to 60% of patients taking low-dose MTX developing GI adverse events in the form of stomatitis, anorexia, abdominal pain, indigestion, dyspepsia, nausea, vomiting, weight loss, or diarrhea.201,202 MTX-related abdominal discomfort, anorexia, nausea, or oral ulcers usually occur within 24 to 36 hours after administration of the weekly dose and can be diminished by the addition of folic acid supplementation (see later discussion), by dose reduction, or, in some troublesome cases, by conversion to subcutaneous MTX administration, although the evidence for the effectiveness of the latter strategy is only anecdotal.152 Liver Toxicity The effect of MTX on liver function and the development of hepatic fibrosis remains a major concern and has been extensively reviewed.203 MTX is associated with the potential for both acute and chronic hepatotoxicity. Mild acute toxicity, with elevations of transaminases, is common, occurring in about 9% of MTX-treated children with JRA.152 These elevations are usually transient and resolve with either MTX discontinuation or lowered dose after a brief interval off treatment.148,150 In some of these cases, concurrent administration of NSAIDs may be contributing to the elevation in transaminases, and discontinuation of NSAID treatment may allow normalization of liver function.204 The issue of greatest concern with the long-term use of low-dose MTX in children has been the potential for significant liver fibrosis or cirrhosis. However, the risk of this complication in children with JRA may differ from that in adults with rheumatoid arthritis or psoriasis treated with low-dose MTX. Long-term studies of MTX use in adult patients with rheumatoid arthritis have found a much lower incidence of liver fibrosis and cirrhosis than that initially reported in psoriatic patients; one retrospective study of 16,000 patients with rheumatoid arthritis reported a 5-year cumulative incidence of liver cirrhosis or failure of 1 in 1000 MTX-treated patients.205 Another study suggested that the incidence may be higher, with a 5-year cumulative incidence of cirrhosis of 9.4 in 1000 MTX-treated patients with rheumatoid arthritis.206 A meta-analysis of patients with rheumatoid arthritis and psoriasis found that higher cumulative dose of MTX, heavy alcohol consumption, and the presence of psoriasis were associated with higher risk of progressive liver histologic abnormalities.207 Other risk factors include preexisting liver disease, obesity, insulin-dependent diabetes mellitus, and renal insufficiency.203,208 The American College of Rheumatology has suggested guidelines for monitoring liver toxicity in patients with rheumatoid arthritis based on regular measurement of liver enzymes and performance of liver biopsy in selected cases with persistent abnormalities of liver enzymes (Table 5–9).209 These guidelines were developed by expert consensus and subsequently evaluated for their usefulness; they were found to be cost-effective

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TABLE 5–8 Reported Adverse Effects in Children Treated with Methotrexate* Study 1

Study 2

Study 3

Study 4

Study 5

Study 6

Study 7

Study 8

Totals

19

23

12

19

30

62

86

27

277

10.5 4–10

19.2 6–52

6 6

18.5 8–39

— 6–30

27 19–65

6 —

— 6–72

— 4–72

4–17 —

— 0.1–0.6

8–25 —

5–15 —

— 0.4–0.8

5–20 —

5 or 10 —

10–15 —

— —

2

0

1

2

6

14

8

0

33

0 1 1 0 ND 0 0 1 0 3

0 0 0 0 0 0 0 0 ND 10

ND ND 1 ND ND ND ND 0 1 1

0 1 0 0 0 0 ND 0 ND 1

0 0 2 ND ND ND ND 1 ND 3

4 0 0 0 2 ND 4 1 ND 9

0 2 1 1 0 0 0 0 0 1

1 1 0 0 0 1 ND ND ND 4

5 5 4 1 2 1 4 3 1 25

0 0 0 3

0 0 0 0

0 0 0 0

0 0 0 0

0 1 0 0

0 0 1 0

0 0 0 0

0 0 0 0

0 1 1 3

Patients (n) Treatment Duration (mo) Mean Range Methotrexate Dose mg/m2/wk mg/kg/wk

Adverse Effects (no. patients) Gastrointestinal symptoms Peptic ulcer Stomatitis Mouth ulcers Rashes Alopecia Jaundice Bacterial infections Herpes zoster Mood changes Liver function test elevations Hematuria Leukopenia Anemia Proteinuria

*Studies cited: Study 1: Truckenbrodt H, Hafner R: Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study. Arthritis Rheum 29: 801–807, 1986. Study 2: Wallace CA, Bleyer WA, Sherry DD, et al: Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis. Arthritis Rheum 32: 677–681, 1989. Study 3: Speckmaier M, Findeisen J, Woo P, et al: Low-dose methotrexate in systemic onset juvenile chronic arthritis. Clin Exp Rheumatol 7: 647–650, 1989. Study 4: Rose CD, Singsen BH, Eichenfield AH, et al: Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 117: 653–659, 1990. Study 5: Halle F, Prieur AM: Evaluation of methotrexate in the treatment of juvenile chronic arthritis according to the subtype. Clin Exp Rheumatol 9: 297–302, 1991. Study 6: Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM: Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 120: 468–473, 1992. Study 7: Giannini EH, Brewer EJ, Kuzmina N, et al: Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N Engl J Med 326: 1043–1049, 1992. Study 8: Huang JL: Methotrexate in the treatment of children with chronic arthritis—long-term observations of efficacy and safety. Br J Clin Pract 50: 311–314, 1996. ND, not determined. Modified from Singsen BH, Goldbach-Mansky R: Methotrexate in the treatment of juvenile rheumatoid arthritis and other pediatric rheumatic and nonrheumatic disorders. Rheum Dis Clin North Am 23: 811–841, 1997.

and clinically useful, with a sensitivity of 80% and a specificity of 82% but a low positive predictive value of 27%.208 Although a similar level of consensus does not exist for monitoring MTX-treated JRA in children, most pediatric rheumatologists tend to follow these guidelines or a variation of them.152 A study examining the relationship between hepatotoxic risk factors and liver histopathology in MTX-treated JRA found that serial biochemical abnormalities were significantly associated with Roenigk grade and the presence of liver fibrosis, suggesting that the guidelines for monitoring MTX hepatotoxicity in rheumatoid arthritis may also be applicable to patients with JRA.210 It must be remembered, however, that even close monitoring of liver function tests does not eliminate the possibility of progressive hepatic fibrosis. Erickson and colleagues208 reported one patient in a series who developed cirrhosis despite normal results on liver function tests. Furthermore, these guidelines may

not apply to patients receiving more than 25 mg/week or a cumulative dose of greater than 10 g; surveillance liver biopsies may be indicated for these patients.203 In a number of small studies in children, liver biopsies were performed after cumulative doses of up to 3000 mg had been reached; none showed any cirrhosis.150,211,212 A cross-sectional study213 reported on results of liver histology in children exposed to even higher cumulative doses of MTX (more than 3000 mg or more than 4000 mg/1.73 m2), with the mean duration of treatment being about 6 years (and some children treated for up to 10 years); no significant fibrosis or cirrhosis was found. However, 13 (93%) of 14 biopsies showed some histologic abnormality, with only 1 graded as Roenigk grade II. In addition, higher weekly doses of MTX (20 mg/m2/week or more) were not associated with significant hepatic fibrosis in 10 patients who underwent liver biopsy.214

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TABLE 5–9 Recommendations for Monitoring for Hepatic Safety in Patients with Rheumatoid Arthritis Receiving Methotrexate (MTX) A. Baseline 1. Tests for all patients a. Liver blood tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies b. Other standard tests, including complete blood cell count and serum creatinine 2. Pretreatment liver biopsy (Menghini suction-type needle) only for patients with a. Prior excessive alcohol consumption b. Persistently abnormal baseline AST values c. Chronic hepatitis B or C infection B. Monitor AST, ALT, albumin at 4- to 8-wk intervals C. Perform liver biopsy if 1. Five of nine determinations of AST within a given 12-mo interval (6 of 12 if tests are performed monthly) are abnormal (defined as an elevation above the upper limit of normal) 2. There is a decrease in serum albumin below the normal range (in the setting of well-controlled rheumatoid arthritis) D. If results of liver biopsy are 1. Roenigk grade I, II, or IIIA: resume MTX and monitor as in B, C1, and C2 above 2. Roenigk grade IIIB or IV: discontinue MTX E. Discontinue MTX in patient with persistent liver test abnormalities, as defined in C1 and C2 above, who refuses liver biopsy From Kremer JM, et al: Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arthritis Rheum 37: 316–328, Copyright © 1994 Wiley-Liss, Inc. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Although these data are encouraging, their interpretation requires some caution: First, the number of children studied is small, so the statistical power for detection of infrequent events, such as cirrhosis, is low (type II error); second, only 58% of eligible MTX-treated patients underwent biopsy, so selection bias may have occurred; and third, the clinical significance, if any, of the minor histologic abnormalities detected in most of the biopsies is not known, and there were no control biopsies to help distinguish the effects of disease (e.g., systemiconset JRA) or concomitant medications (e.g., NSAIDs) on liver histology. A follow-up study from the same group reported the results of 33 liver biopsies in 25 patients; 27 biopsies (82%) were classified as Roenigk grade I; 4 (12%) as grade II; and 2 (6%) as grade IIIA; none demonstrated significant fibrosis. The frequency of biochemical abnormalities and body mass index were the only risk factors found to significantly relate to the Roenigk grade.210 However, the same limitations as with the earlier study apply, particularly with respect to the small number of patients studied (possibility of type II error) and the unknown significance of the minor histologic abnormalities observed in most patients. Further longterm, prospective studies in larger numbers of MTXtreated children are needed to define more accurately the risk of MTX-related liver fibrosis or cirrhosis and to develop appropriate guidelines for monitoring therapy in JRA.

Infection Although MTX may potentially increase the risk for common bacterial infections, herpes zoster, and opportunistic infections, these complications are infrequently reported in treated patients. One study of 62 children with JRA treated for a mean of 161 weeks reported only 2 cases of recurrent cellulitis, 1 of osteomyelitis, and 1 of an infected Hickman catheter site; there were 8 viral infections, including 1 case of herpes zoster, 1 case of mononucleosis, and 6 cases of primary varicella. Many of the patients with varicella infection were also concurrently receiving glucocorticoids.150 The randomized controlled clinical trial of MTX treatment in JRA did not document an increased frequency of infection in children treated with MTX compared with placebo.148 Although the overall risk of infection appears to be low, it has not been precisely quantitated in adults or in children. Infections in MTX-treated patients are usually common bacterial infections (e.g., lungs, skin) or herpes zoster. The development of hypogammaglobulinemia in MTX-treated patients may predispose to infection.215 Opportunistic infections associated with MTX treatment are rare unless there is concurrent treatment with highdose glucocorticoids.216 Immunization with inactivated vaccines is not contraindicated in MTX-treated children, but immunization with live attenuated vaccines should be avoided.217 There are currently no generally accepted guidelines regarding varicella immunization in these children. However, active varicella immunization of susceptible children and family members may need to be considered before initiation of MTX therapy.205 Family members of MTX-treated patients who require polio immunization should receive inactivated vaccine. Hematologic Toxicity Hematologic toxicity includes macrocytic anemia, leukopenia, thrombocytopenia, and pancytopenia. In adult patients with rheumatoid arthritis, pancytopenia has been reported in about 1% to 2% of MTX-treated patients.218 Identified risk factors in this population include impaired renal function, advanced age, concurrent viral infection, alcohol ingestion, folate deficiency, hypoalbuminemia, and drug interactions (e.g., trimethoprim-sulfamethoxazole). MTX-associated pancytopenia has not been reported in children, and hematologic toxicity is uncommon overall; a 1997 review of published studies, including a total of 277 MTX-treated children, found only 1 case of leukopenia and 1 case of macrocytic anemia.152 Although supplemental folate treatment results in lowering of the mean corpuscular volume in MTX-treated patients, whether this will prevent pancytopenia is not yet known. Spontaneous recovery is usual within 2 weeks after withdrawal of MTX in patients with mild bone marrow suppression. Patients with moderate to severe bone marrow suppression may require folinic acid rescue and supportive therapy (e.g., colony-stimulating factors).202 MTX may have triggered the macrophage activation syndrome in one patient with systemic-onset JIA.219 Reversible asymptomatic eosinophilia has also been described.220 Malignancy The issue of whether MTX treatment is an independent risk factor for various malignancies is controversial and remains unresolved. Although in vitro

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studies have shown that MTX has mutagenic and carcinogenic potential, in vivo studies in animal models (mice, rats, hamsters) have failed to demonstrate any carcinogenicity. In humans, low-dose weekly MTX therapy has not been convincingly linked to malignancy.221 However, there have been a number of case reports of an association between MTX treatment and lymphoproliferative diseases in adult patients with rheumatoid arthritis.222,223 It has not been possible to determine whether these observations were merely coincidental or were causally linked to MTX or to the underlying disease process.221 Rheumatoid arthritis is known to be associated with an increased risk of hematologic malignancy.224 There have been several cases of Epstein-Barr virus (EBV)–associated lymphoma manifesting during the course of MTX treatment for rheumatoid arthritis or dermatomyositis that regressed with discontinuation of MTX.225 Some of the reported cases demonstrated features typical of immunosuppression-induced lymphoproliferation, including extranodal location, large cell or polymorphous histology, geographic areas of necrosis, and the presence of EBV.226 The association of MTX with reversible lymphoproliferation suggests a causative role. However, MTX has not been shown to increase the risk of lymphoproliferative disorders when used in the treatment of other diseases such as psoriasis227,228 or in bone marrow transplantation.221 Several cases of both Hodgkin’s lymphoma229–231 and non-Hodgkin’s lymphoma232,233 have been reported in children with JRA treated with MTX. In two of these, EBV was implicated.231,233 Long-term prospective cohort studies, with appropriate controls, are needed to define the risk of hematologic or other malignancies in MTX-treated patients.

Pulmonary Toxicity Significant pulmonary toxicity occurring during the course of treatment with low-dose weekly MTX has been described in adult patients with rheumatoid arthritis; reported prevalence rates in published studies range from 0.3% to 18%, with a mean prevalence of 3.3%.234 However, the actual frequency of this complication is difficult to estimate, because the literature has not been clear in defining toxicity related to the drug itself rather than to secondary problems associated with MTX therapy (e.g., opportunistic lung infections). The issue is clouded further by the fact that rheumatoid arthritis itself is associated with interstitial lung disease. The mechanism of this toxicity and the risk factors for its development are poorly defined, although a number of studies implicate preexisting lung disease as an important predisposing factor in the development of MTX pneumonitis.202,234,235 Interestingly, MTX-associated pneumonitis is rarely reported in psoriatic patients. In 1998, the first pediatric case of possible MTX-induced pneumonitis was reported in an 11-year-old girl with rheumatoid factor (RF)–positive, antinuclear antibody–negative polyarticular JRA.236 However, the clinical course of lung disease in this case was not typical of that described in adults with MTX pneumonitis, clinical and laboratory information was insufficient to satisfactorily exclude alternative causes, and no biopsy was performed. Prospective studies of lung function in children with

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various types of JRA have not demonstrated any significant abnormalities in pulmonary function test results in those treated with MTX.149,150,237–239

Accelerated Nodulosis MTX has been associated with a syndrome of “accelerated nodulosis,” with an estimated prevalence of 8% in adult patients with rheumatoid arthritis.201 This association was described in two teenagers with RF-positive JRA240 and in one 3-year-old girl with systemic-onset JRA.241 The nodules were similar in distribution and size to those reported in adults and developed within 6 months after the initiation of MTX treatment in these children. Although discontinuation of MTX is associated with regression of nodulosis, some patients have been successfully treated with hydroxychloroquine240 or colchicine,242 allowing stabilization of nodulosis with continued MTX treatment of the underlying disease. Although the exact mechanism of MTX-associated nodulosis is not known, it is thought to be mediated by MTX-enhanced adenosine production; therapies that inhibit adenosine production or interfere with adenosine A1 receptor function may be effective in treating MTX-associated nodulosis.201

Other Adverse Effects Central Nervous System Various CNS symptoms, including headaches, mood alterations, change in sleep patterns, irritability, fatigue, and impaired academic performance, have been reported by some pediatric rheumatologists to occur transiently in the 12 to 48 hours after the weekly dose of MTX.152 These problems may be subtle and need to be differentiated from effects of underlying disease and from various psychosocial issues that may coexist. Osteopathy Animal studies have shown that prolonged administration of low-dose MTX is associated with suppression of osteoblast activity and stimulation of osteoclast recruitment, resulting in increased bone resorption and osteopenia.243 Similar effects have been described in a small number of case reports in adults with rheumatoid arthritis or psoriasis treated with lowdose weekly MTX.244,245 Although leg pain and spontaneous fractures attributed to MTX therapy in pediatric oncology have been recognized for some time, this phenomenon has been described in only one patient with polyarticular JRA and a disease duration of 25 years recently treated with low-dose MTX.246 Teratogenicity MTX therapy is associated with spontaneous abortions.247 In 1997, a case of multiple congenital abnormalities in a baby whose mother was treated with low-dose MTX for JRA was reported.248 Although it is difficult to quantitate the risk of teratogenicity with lowdose weekly MTX treatment, women of child-bearing age should be counseled to practice effective contraception during the course of treatment. Patients should be informed that past MTX use does not predispose to congenital abnormalities and that, ideally, MTX should be discontinued before attempts at conception. There have not been any reports of azoospermia due to low-dose MTX treatment of JRA.152 MTX is excreted in breast milk

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in low concentrations, but it is not known whether this affects the newborn. Women taking MTX should be advised not to breast-feed.249

N CI CHOHCH3

Folate Supplementation A number of studies have examined the issue of minimizing MTX toxicities with the use of concurrent folic or folinic acid (leucovorin) supplementation in adults with rheumatoid arthritis.250–253 These studies have evaluated the effect of folate supplementation on both the efficacy and the toxicity of low-dose weekly MTX therapy. Although the doses and regimens of folic and folinic acid used in the various trials, the doses of concurrent MTX therapy, and the assessment of “toxicity” have not been standardized, there is evidence for overall effectiveness of folate supplementation. A 1998 systematic review of all published clinical trials found that folic acid supplementation was associated with a significant reduction in mucosal and GI toxicity in MTX-treated adults with rheumatoid arthritis.254 There was no adverse effect on efficacy except with high-dose folinic acid supplementation. Currently, data are insufficient to assess the effect of long-term folate supplementation on hepatic or hematologic toxicities. It also is not clear whether folate supplementation should be commenced as prophylaxis with initiation of MTX therapy in all patients or as treatment if specific toxicities develop. There has not been any formal cost-benefit study to address this issue. Folic acid is cheaper and has a greater margin of safety in dosing compared with folinic acid. However, the two agents have not been directly compared for their clinical effectiveness and cost. Studies in children are limited. A short-term, randomized, double-blind, placebo-controlled, crossover trial of folic acid (1 mg/day) added to a stable dose of MTX (mean, 9–9.7 mg/week) in 19 children with JRA showed no effect on clinical efficacy.255 There were no observable abnormalities of liver function, but no information about other toxicities is available from this small study. Folinic acid administered 24 hours after the weekly dose of MTX at doses of approximately one-third of the MTX dose has been used effectively to treat manifestations of MTX toxicity in children with JIA,256 but at high doses this treatment was associated with disease flares.257 At present, it is not possible to make firm recommendations about routine folate supplementation in MTX-treated children. However, based on the information from adult studies and the small trial in children with JRA, it appears that low-dose (1 mg/day) folic acid supplementation does not have any detrimental effect on disease control and confers a beneficial effect in terms of GI and mucosal toxicities associated with low-dose weekly MTX treatment. Folic acid supplementation should be considered at least in symptomatic patients. High-dose folinic acid rescue should be reserved for those with severe, life-threatening toxicity (e.g., aplastic anemia).

Antimalarials Hydroxychloroquine sulfate (Fig. 5–9) is the least toxic of the 4-aminoquinolone drugs and has generally supplanted chloroquine in rheumatologic practice,258–260 although other antimalarial agents are occasionally used for recalcitrant skin disease in SLE. Hydroxychloroquine is rapidly absorbed from the intestine. Equilibrium concentrations

NH

CH(CH2)3 CH3

■ Figure 5–9

N CH2CH3

Structure of hydroxychloroquine.

are reached after 2 to 6 months of a constant daily dose, and the half-life exceeds 40 days.261 Tissue levels are much greater than plasma concentrations, and there is increased affinity of the drug for melanin as well as for the liver, pituitary, spleen, kidney, lung, and adrenals. Excretion is primarily via the kidney, although hepatic oxidative deamination accounts for part of the excretion. The antimalarial drugs inhibit the synthesis of DNA, RNA, and protein by interacting with nucleic acid.258 These drugs alter lysosomal pH, thereby interfering with ligand-receptor dissociation and antigen processing; stabilize lysosomal membranes262; inhibit antigen–antibody reactions263; suppress lymphocyte responses to mitogens; act as antioxidants262; inhibit phospholipase activity264; and inhibit neutrophil chemotaxis and phagocytosis.258 They may also antagonize the action of some of the prostaglandins.265 Antimalarials interfere with IL-1 release by monocytes263; interfere with production of TNF-α, IL6, and IFN-γ266; inhibit natural killer activity267; and induce apoptosis.268 They also have antiplatelet and antihyperlipidemic effects that are extremely important in patients with SLE.269 Antimalarials are important in many rheumatic diseases. In JRA, the therapeutic efficacy has never been established, and the only placebo-controlled study did not prove these agents to be better than placebo.270 However, recent work in adult rheumatoid arthritis has demonstrated them to be effective, especially in early disease.271 Antimalarials are also effective in combination with other DMARDs in adult rheumatoid arthritis.272 Hydroxychloroquine reduces some MTX-related toxicity, such as elevated liver enzymes and nodulosis.273,274 Studies in adult SLE have also provided proof of efficacy for hydroxychloroquine, especially in preventing flares of disease.275 Its role in SLE is primarily for treatment of dermatitis, arthritis, and serositis. It may have particular benefit as a result of its lipid-lowering effect in steroid-treated SLE patients.276–278 It has also been used in dermatomyositis, especially for skin disease, but the results are not clear.279,280

When used at recommended doses, the antimalarials are considered extremely safe. However, at least four young children have died from respiratory failure after accidental ingestion of large doses (1 to 3 g) of chloroquine,281 and it is recommended that antimalarials be used with great caution in the very young child because there is no antidote. GI intolerance occurs in 10% of adults but is probably less common in children. Antimalarials occasionally cause bleaching of the skin and hair. Rarely, neuropathy or myopathy occurs. CNS side effects are common, may be reversible with dose reduction, and may remit spontaneously. These include headache, lightheadedness, tinnitus, insomnia, and increased nervousness. Myasthenia and muscle weakness have been described.282

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The major side effect of concern is retinal toxicity.283–285 Antimalarials accumulate in the pigmented cells of the retina and persist for long periods after they have been discontinued; however, the binding to melanin may not be predictive of ocular damage. Retinal toxicity, although rare, can cause blindness, even after the medication has been stopped. Retinitis is sometimes, but not always, reversible.284 Evidence in adults suggests that retinal toxicity will not occur if the dose of hydroxychloroquine is maintained at less than 6.5 mg/kg/day, even for as long as 7 years.286 Early detection of pre-maculopathy prevents visual loss if the medication is discontinued and forms the basis for routine ophthalmologic monitoring (every 6 months) with visual field testing, color vision testing, corneal examination, and visual acuity testing. A progressive loss of color vision may signify early retinopathy and is an indication for stopping the drug. Corneal deposits are not visually limiting but are also probably an indication to lower the dose. Debate continues as to the necessity of an initial ocular examination, or of biannual examinations. The author’s current policy is to continue to perform these examinations every 6 months but not to perform a baseline examination. Recommendations differ somewhat in adults.287 Each examination should include visual acuity, color vision testing, visual field corneal examination,286,288 and retinoscopy. Retinal abnormalities or interference with vision, especially with foveal recognition of red,289 is an absolute indication for discontinuing the medication. Use of hydroxychloroquine in children younger than 7 years of age may be limited by difficulty in obtaining satisfactory evaluation of color vision in this age group.

The dose of antimalarials is limited by retinal toxicity. For hydroxychloroquine, the recommended dose is less than or equal to 6.5 mg/kg/day to a maximum of 400 mg/day.290 The overall retinal toxicity seems to be related to daily dose rather than to cumulative dose. One study of children with JRA did correlate outcome with serum levels of hydroxychloroquine,291 but levels are not measured in clinical practice. Hydroxychloroquine crosses the placenta but is considered safe to use during pregnancy.292 Hydroxychloroquine does appear in breast milk, but the amount ingested per day by the breast-feeding infant would be very low.293 It seems reasonable for the mother taking hydroxychloroquine to breast feed if she had taken hydroxychloroquine during pregnancy.

Sulfasalazine Sulfasalazine is an analogue of 5-aminosalicylic acids linked by an azo bond to sulfapyridine, a sulfonamide (Fig. 5–10). Its development was based on the concept that rheumatoid arthritis might be an infectious disease and would respond to combination therapy with an anti-

COOH N HO

N

N

SO2NH

■ Figure 5–10 Structure of sulfasalazine.

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bacterial agent and an anti-inflammatory drug.294,295 Sulfasalazine has become a primary therapeutic choice in the treatment of mild to moderate inflammatory bowel disease, and it has been reported to be beneficial in the management of childhood arthritis,296–303 psoriatic arthritis,304 and reactive arthritis.305 Its role in ankylosing spondylitis is controversial,306–308 although it does seem to be effective for the peripheral arthritis.309 Sulfasalazine is poorly absorbed from the GI tract.310–312 Peak serum concentrations are reached after 5 days of therapy. The half-life of the drug is 10 hours. Approximately one third of the dose is absorbed in the small intestine and excreted unchanged in the bile. The remaining 70% enters the colon intact, where the azo linkage is split by bacterial enzymes to sulfapyridine, which is absorbed and excreted in the urine, and 5-aminosalicylate, which reaches high concentrations in the feces. Approximately 90% of the sulfapyridine is absorbed from the colon. Sulfapyridine is tightly protein bound and acetylated, hydroxylated, and conjugated with glucuronic acid in the liver. Both sulfasalazine and sulfapyridine reach synovial fluid in concentrations comparable to those in serum. About one third of the 5-aminosalicylic acid is absorbed, acetylated, and excreted in the urine. The rest is eliminated unchanged in the stool. The small amount of salicylate absorbed is not sufficient to reach anti-inflammatory levels in the plasma. Several mechanisms of action may explain the antiinflammatory effect of sulfasalazine. Bacterial growth is reduced by sulfasalazine and sulfapyridine, and thus the bacterial antigenic load delivered to the gut-associated lymphoid tissue may be reduced. This may be important for patients with spondyloarthropathies, in whom bacteria may gain access through inflamed gut mucosa and stimulate the immune system. Sulfasalazine interferes with a number of enzymes that are important in inflammation, in the formation of leukotrienes and prostaglandins.313 Sulfasalazine is a potent inhibitor of AICAR transformylase; as a result, there is an accumulation of extracellular adenosine with a consequent reduction in inflammation via occupancy of A2 receptors on inflammatory cells.314 Levels of matrix metalloproteinase 3 (MMP3) are decreased in patients with early rheumatoid arthritis responsive to sulfasalazine.315 Sulfasalazine reduces the release of IL-1, IL-2, TNF-α, IL-6, and IFN-γ.316–318 This effect is most likely mediated by inhibition of the degradation of I-κB (inhibitor of nuclear factor-κB [NF-κB]), which results in an inhibition of NF-κB upregulation of gene transcription,319 and by the induction of apoptosis through the activation of caspase 8.320 Sulfasalazine decreases natural killer cell activity and induces neutrophil apoptosis in vitro.321 In vitro effects on macrophages include suppression of production of IL-12, production of nitric oxide, and expression of major histocompatibility complex (MHC) class II molecules.322 Sulfasalazine may also have anti-angiogenic properties.322,323 Intolerance and toxic reactions occur in approximately 20% of sulfasalazine-treated adults with rheumatoid arthritis (range, 5% to 55%).324–348 In a placebo-controlled study of children with JRA, 29% of 35 patients developed adverse effects that led to discontinuation of the drug.299

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Toxicity may be more common in patients with a slow acetylator phenotype, but there is no clinical indication to document a patient’s acetylator status before starting sulfasalazine.349 Enteric-coated preparations probably cause fewer GI side effects (anorexia, nausea, vomiting, dyspepsia, diarrhea). Rashes occur in 1% to 5% of patients. A maculopapular rash occurring within 2 days after institution of therapy, especially on sun-exposed skin, is the most common dermatologic complication.324 In patients who develop hypersensitivity reactions (usually early), desensitization protocols can be carried out. Oral ulcers325 and the Stevens-Johnson syndrome326 are uncommon but important complications. Neutropenia occurs in up to 4.4% of patients treated with sulfasalazine.327 Sulfasalazine-induced thrombocytopenia has also been reported,328 and pancytopenia329 and macrocytic anemia330 may occur. It is important to note that serious hematologic toxicity can develop many months after starting treatment. Drug-induced SLE,331 Raynaud’s phenomenon,332 interstitial pneumonitis, fibrosis, alveolitis,333,334 and hepatitis (granulomatous hepatitis, elevated transaminases)335 are rare complications of sulfasalazine therapy. Hypogammaglobulinemia and IgA deficiency have been reported,350 and immunoglobulin levels should be monitored. However, serious infections have not been reported. A reversible decrease in sperm count has been observed,336 but there are no reports of increased fetal wastage or abnormalities. The drug should not be used in infants or in those with known hypersensitivity to sulfa drugs or salicylates, impaired renal or hepatic function, or specific disease contraindications (e.g., porphyria, glucose-6-phosphate dehydrogenase deficiency). Most authors also believe that sulfasalazine is contraindicated in patients with systemic-onset JRA because of an apparent increased risk of diffuse intravascular coagulation (DIC)–like reactions,298,351 as well as in patients with adult-onset Still’s disease.352 The suggested dosage in children is 30 to 50 mg/kg/day in two to three divided doses, usually taken with food or milk.296,353 Treatment is initiated at a lower dose (10 to 15 mg/kg/day) and increased weekly over 4 weeks to achieve maintenance levels. A satisfactory clinical response may occur within 4 to 8 weeks. Sulfasalazine should probably be continued for at least 1 year after disappearance of clinical disease before tapering is begun (Table 5–10). It has been reported that sulfasalazine can be used safely during pregnancy354 and that women can breast feed while taking sulfasalazine.355

Leflunomide Leflunomide (Fig. 5–11) is an immunomodulatory agent that, through its active plasma metabolite, A77-1726, inhibits de novo pyrimidine synthesis by inhibiting the enzyme dihydro-orotate dehydrogenase.356 Activated lymphocytes require de novo pyrimidine synthesis for proliferation. As a result of the inhibition, p53 in the cytoplasm translocates to the nucleus and initiates cellular arrest in the G1 phase of the cell cycle. It also inhibits tyrosine kinase,357 inhibits leukocyte-endothelial

TABLE 5–10

Guidelines for Use of Sulfasalazine

Dose Initially, 12.5 mg/kg/day (maximum, 500 mg), given in one dose; increase to maintenance dose over 4 wk Maintenance dose: 50 mg/kg/day to a maximum of 2 g/day for 1 yr or longer Clinical Monitoring After first month, then every 2–3 mo to follow disease course; discontinue if rash appears Laboratory Monitoring CBC with WBCC differential, and platelet count; hepatic enzymes; and urinalysis every week until maintenance dose is achieved, then monthly for 2 mo, then every 3 mo. Immunoglobulin levels every 6 mo. Discontinue if persistent neutropenia, thrombocytopenia, elevated hepatic enzymes, or decreased immunoglobulins CBC, complete blood count; WBCC, white blood cell count.

CF3 O N H N O

CH3

■ Figure 5–11 Structure of leflunomide.

adhesion,358 and affects cytokine production leading to immunosuppression.359 Because its actions are similar to those of MTX, it might be better classified as a DMARD. In vitro, leflunomide inhibits the production of prostaglandin E2, MMP1, and IL-6 and modulates various tyrosine kinases and growth factor receptors.360 Leflunomide is rapidly converted to A77-1726, which is highly protein bound and has a prolonged half-life of up to 18 days.361 As a result, loading doses have been recommended for the first 3 days of administration to rapidly achieve steady state. Another result of this prolonged half-life is that the metabolite remains in the circulation for prolonged periods (Table 5–11). Initial studies in adults with rheumatoid arthritis showed that, after a 3-day loading dose of 100 mg/day, daily doses of 10 and 25 mg of leflunomide were more effective than placebo361,362 as effective as sulfasalazine over 24 weeks363 and as effective as MTX at 1 year364 and at 2 years.365 After a 3-day loading dose of 100 mg/day, daily doses of 10, 20, and 25 mg have shown benefit as early as 4 weeks and continuing improvement for up to 20 weeks, after which the clinical improvements are maintained. The major side effects from leflunomide have been related to the liver, with elevation on liver function tests occurring in approximately 5% of patients with rheumatoid arthritis. However, the risk of serious hepatic disease appears to be minimal and, as with MTX, associated with preexisting liver disease, viral hepatitis, or heavy alcohol consumption. More significant hepatotoxicity was observed when MTX was combined with leflunomide.366 Side

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TABLE 5–11

Guidelines for the Use of Leflunomide in the Treatment of Juvenile Idiopathic Arthritis Dose 10–20 mg/day, based on weight (usual adult dose = 20 mg/day) Clinical Monitoring Improvement should be seen by 6–12 wk Monitor every 3–6 mo, depending on course Reduce dose or discontinue and monitor for clinical or laboratory adverse events Laboratory Monitoring CBC with WBCC, differential and platelet count; AST, ALT, albumin every 4–6 wk ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; WBCC, white blood cell count.

effects from leflunomide have been mild and doserelated. These include GI side effects (abdominal pain, dyspepsia, anorexia, diarrhea, gastritis), allergic rash, reversible alopecia, mild weight loss, and elevation of liver function test results.363,367 No increase in infection has been reported. Silverman et al reported on 27 patients with polyarticular course JRA who had failed treatment with or were intolerant of methotrexate and were treated with leflunomide.368 After an initial loading dose of ~100 mg/1.73 m2, patients received 10 mg/1.73 m2; the dose could be increased to 20 mg/1.73 m2 after week 8 for a poor response. After 26 weeks, 14 patients (52%) had improved according to the ACR Pedi 30 criteria; 44% and 19% met criteria for an ACR Pedi 50 and 70 respectively. Forty-four percent of patients responded as early as 4 weeks, and all who responded did so by 12 weeks. Seventeen of 27 patients entered an extension phase during which 65% of patients achieved an ACR Pedi 30, 47% an ACR Pedi 50 and 35% an ACR Pedi 70. Adverse events led to discontinuation in two. Other adverse events reported in at least 30% of patients were transient elevation of liver function tests, headache, alopecia, abdominal pain, nausea, diarrhea and dizziness. In a subsequent study, Silverman et al also compared the safety and efficacy of leflunomide with methotrexate in the treatment of patients with polyarticular course JRA in a multinational, randomized controlled trial.368a The dose of leflunomide was dependent on the weight of the child. A loading dose of 100 mg for 1, 2 or 3 days for a weight <20 kg, 20–40 kg, >40 kg, respectively, was followed by a dose of 10 mg every other day, 10 mg daily, or 20 mg daily for a weight <20 kg, 20–40 kg, >40 kg, respectively. Methotrexate was given at a dose of 0.5 mg/kg/week (maximum 25 mg per week). In addition, pharmacokinetic studies were performed at week 16. At week 16, 68% of patients receiving leflunomide showed an ACR Pedi 30, versus 89% of patients treated with methotrexate; the improvements achieved were maintained at a similar rate in a 32 week extension study. The median time to an ACR 30 did not differ between the two groups (52 days in leflunomide, 56 days in methotrexate). Body weight was a significant determinant of response, and patients weighing less than 20 kg showed the greatest discrepancy between the two groups. The incidence of treatment related adverse events was similar in both groups. The clinically active metabolite of leflunomide, M1, was lower in patients weighing less than 40 kg than those associated with clinical responses in adult rheumatoid arthritis, which may have

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explained the discrepancy between responses in the patients weighing less than 40 kg.

Leflunomide is teratogenic.369 Because of the very long half-life of this drug, it has been recommended that cholestyramine be administered and then that drug levels lower than 0.02 mg/L be verified on two separate tests at least 2 weeks apart, in both men and women.369 In addition, women of child-bearing potential must have a negative pregnancy test before starting leflunomide and must practice contraception. The place of leflunomide in the treatment of patients with JRA is not yet established. At the moment, it should be considered for patients who do not tolerate MTX. A loading dose is recommended in adults with rheumatoid arthritis to rapidly achieve steady state but is not necessary and may lead to significant GI upset. The usual daily dose for adults is 20 mg, which may be reduced to 10 mg in the face of adverse effects.

Gold Compounds The use of gold and penicillamine has waned dramatically since the introduction of MTX and the newer biologic agents, and the descriptions included here are primarily for historical interest and importance. Sulfhydryl-containing organic gold compounds have been prescribed for treatment of rheumatoid arthritis since the observations of Forestier370,371 in the 1920s. In the management of JRA, they have essentially been replaced by MTX and sulfasalazine, except perhaps for patients with RF-positive disease.

Pharmacology The mechanisms of action of gold compounds are not entirely clear372 but appear to depend on the sulfhydryl bond, which is also thought to be responsible in part for the beneficial effects of D-penicillamine. Gold compounds may diminish vascular permeability, reduce the number of inflammatory cells in rheumatoid foci, and impair phagocytosis. They stabilize lysosomal membranes and suppress enzymatic activity in general. They may prevent denaturation of proteins induced by free oxygen radicals. In vitro lymphocyte responses to mitogens and specific antigens are inhibited, and monocyte interaction in cell-mediated immune function is impaired.373–375 The intramuscular preparations are 50% gold by weight (Fig. 5–12).376 The oral gold compound auranofin is 30% gold by weight and is lipid soluble. With aurothiomalate, the gold is predominantly bound to serum albumin; however, with auranofin, approximately 50% of the gold is bound to leukocytes and erythrocytes. Gold compounds are excreted in both urine and stool. They cross the placenta in substantial concentrations, apparently without harm to the fetus, and the level in breast milk is low. The gold concentration in synovial fluid is approximately half of that in blood. Gold is concentrated in organs rich in mononuclear phagocytes and in synovial type A cells. The initial half-life of intramuscularly administered gold is approximately 7 days but increases with chronic administration. After discontinuation of gold injections, plasma concentration falls to undetectable levels by 40 to 80 days, but gold is still excreted in the urine for up to 1 year.377 Auranofin is more hydrophobic than the intramuscular gold compounds and is readily absorbed orally.378,379 The tissue halflife of gold is approximately 80 days. Plasma gold concentrations in patients treated with auranofin take longer to reach

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AU

TABLE 5–12

Guidelines for Use of Aurothiomalate or Aurothioglucose

HC HC

Initial Course

OH

HCOH

0.75–1.0 mg/kg/wk Test doses of 5 mg, then 10 mg, then 25 mg weekly; maximum of 50 mg/wk for at least 20 wk

HCO

Maintenance

HOCH

1 mg/kg (maximum, 50 mg) every 2 wk for 3 mo; then every 3 wk for 3 mo, then every 4 wk thereafter

CH2OH AUROTHIOGLUCOSE

Clinical Monitoring Clinical evaluation before every injection: dermatitis, pruritus, stomatitis, vasomotor (nitritoid) reaction

CH2COONa Au

S

Laboratory Monitoring

CHCOONa

Weekly before each dose: CBC, WBCC, differential, and platelet count; urinalysis. Monthly: hepatic enzymes, BUN, creatinine Discontinue drug if WBCC <3500/mm3 (<3.5 × 109/L), platelet count <100,000/mm3 (<100 × 109/L), persistent proteinuria (>0.5 g/24 hr) or hematuria

AUROTHIOMALATE

O CH2OCCH3 O CH3CO

O S

Au

O O CCH 3

P(C2H5)3

OCCH3 O AURANOFIN

■ Figure 5–12 Structure of gold compounds.

plateau levels and are only 20% of those achieved with aurothiomalate.379–381 However, no direct relationship has been observed between plasma gold concentrations and either clinical benefit or toxicity with any gold compound. The drug is principally excreted in the urine.

Intramuscular Gold Administration and Toxicity Two intramuscular gold preparations are available in North America: aurothioglucose and sodium aurothiomalate.381 Neither preparation has a clear-cut advantage over the other. Aurothioglucose is more viscous and requires a larger-bore needle for administration. Hypersensitivity reactions after aurothioglucose administration are sometimes related to the oil vehicle. Aurothiomalate may rarely induce a nitritoid reaction (flushing, tachycardia, occasionally transient hypotension). Although intramuscular gold compounds are reasonably safe (Table 5–12),382,383 a complete blood count and urinalysis should be obtained before each injection, to detect early signs of toxicity. Toxicity requiring discontinuation of the drug occurs in 25% of children,385–394 pruritic dermatitis in approximately 15%, and stomatitis in approximately 5% to 10%. Pigmentation (chrysiasis) of the skin and mucous membranes may occur. Although rashes and mouth ulcers are the most common side effects of gold therapy, the greatest difficulty encountered in maintaining children with JRA on gold may be the development of an abnormal urinary sediment,395,396 which is related to damage to the proximal tubules or, rarely, to glomerulonephritis. Because children with JRA may have minimal, transient microscopic hematuria and proteinuria

BUN, blood urea nitrogen; CBC, complete blood count; WBCC, white blood cell count.

unrelated to drug intake, a thorough renal evaluation is important before gold therapy is initiated. During gold therapy, renal function should remain normal, and microscopic hematuria should be minimal and intermittent at most and unaccompanied by significant proteinuria (300 mg/24 hours or less). If any question of toxicity arises, the drug should be discontinued and the child should be re-evaluated 1 week later before readministration of the drug is considered, perhaps at a lower dose. An immune complex–mediated membranous glomerulonephritis, heralded by proteinuria, accounts for 10% to 20% of renal toxicity and may result in the nephrotic syndrome.397 Significant proteinuria is an absolute contraindication to reinstitution of gold therapy. Hematologic abnormalities, including leukopenia, eosinophilia, and thrombocytopenia, occur in only 1% to 2% of gold-treated patients; aplastic anemia is rare but may be fatal.398 The risk of mucocutaneous, hematologic, or renal toxicity from gold compounds in adults with rheumatoid arthritis is increased in patients with the human leukocyte antigen allele HLA-DR3.399 Other toxic reactions that have been reported specifically in children with JRA include DIC,80,400 intrahepatic cholestasis and liver disease,401,402 and hypogammaglobulinemia.403 Pulmonary injury induced by gold compounds is uncommon and evidently has not been reported in children.404,405 In adults, pulmonary toxicity is characterized by cough, dyspnea, fever, pleuritic pain, eosinophilia, and skin rash. Neurologic complications of gold therapy include psychiatric syndromes and focal, central, and peripheral nerve abnormalities.406 Occasionally, glucocorticoids or chelating agents are prescribed for severe gold-induced reactions such as neutropenia or exfoliative dermatitis. 406 Reports of accidental overdose of injectable gold compounds (500 mg twice in 1 week) noted no significant ill effects,407 but other reports of acute toxicity have been published,408 including one in a child with JRA.409 One study indicated that 7 surviving infants of 10 pregnancies (there were 2 abortions and 1 stillbirth) exposed in utero to maternal gold administration had no long-term adverse effects.410 No teratogenic or embryopathic effects were encountered.

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Oral Gold Administration and Toxicity

TABLE 5–13

Triethylphosphine gold, auranofin, was effective in the treatment of adults with rheumatoid arthritis.411 Preliminary openlabel, noncontrolled studies in children with JRA indicated that almost all patients sustained some improvement after 6 months at dosages between 0.1 and 0.2 mg/kg/day.412–416 However, a subsequent double-blind trial demonstrated no significant advantage of auranofin over placebo.417 Orally administered gold appears to be better tolerated than the injectable compounds. Auranofin therapy is associated with loose stools in approximately 10% of patients, a side effect that can often be controlled by decreasing the dose. Proteinuria and hematologic toxicity appear to be less common than with intramuscularly administered gold. Stomatitis and dermatitis are about equally frequent with both the oral and the injectable compounds. D-Penicillamine D-Penicillamine

(D-β,β-dimethylcysteine) (Fig. 5–13) is now rarely used in the treatment of JRA because safer and more effective agents have replaced it. Its role in the treatment of scleroderma has been questioned.418 It has three major biochemical effects.419 It influences the formation of disulfide bonds with other sulfhydryl compounds by either an oxidation or an exchange reaction; it undergoes condensation with aldehydes and ketones to give substituted thiazolidinedione carboxylic acids, causing inhibition of collagen cross-linking and dissociation of macroglobulins; and it chelates, or forms complexes with metals. D-Penicillamine has been used in the treatment of rheumatic diseases (rheumatoid arthritis, scleroderma),420,421 in Wilson’s disease to reduce tissue concentrations of copper, in lead and mercury poisoning, and in patients with cystinuria. D-Penicillamine is absorbed orally, with peak blood levels achieved by approximately 1 to 4 hours. Absorption of the drug is significantly diminished by food, antacids, and iron. Oxidation of D-penicillamine in the presence of transition metals such as copper results in the formation of poorly absorbed disulfides. The D-penicillamine–albumin disulfide bond is quantitatively the most important during chronic therapy, because the drug tends to accumulate in this form and only slowly dissociates from albumin.422 The disulfide metabolites are excreted in urine and stool. Little unmetabolized drug can be detected in the blood 2 days after a dose. D-Penicillamine is usually started at a low dose and increased as tolerated according to a schedule such as the one presented in Table 5–13. The mechanisms whereby D-penicillamine and its metabolites influence inflammation in chronic arthritis or scleroderma are uncertain.423 D-Penicillamine–induced reduction of sulfhydryl groups on macrophages, and possibly other cells, may influence their function. Oxidation of D-penicillamine results in the production of reactive oxygen species that inhibit the reactivity of T cells. D-Penicillamine also directly inhibits myeloperoxidase, thereby reducing the production of hypochlorite, which is toxic to tissue.424 By complexing with trace metals such as copper, D-penicillamine may interfere with the action of superoxide dismutase and may thereby influence the production and scavenging of oxygen-derived free radi-

C

D RU G T H E R A P Y

CH

COOH

SH NH2

■ Figure 5–13 Structure of penicillamine.

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Guidelines for Use of D-Penicillamine

Dose Initially 5 mg/kg/day (maximum, 250 mg/day) for 3 mo; then 10 mg/kg/day for 3 mo; then 15 mg/kg/day (maximum, 1 g/day) for 1–3 yr Clinical Monitoring Clinical evaluation every month: dermatitis, pruritus, bruising Laboratory Monitoring CBC with differential WBCC, platelet count, and urinalysis every 2 wk until dose is stable, then monthly Discontinue drug if WBCC <3500/mm3 (<3.5 × 109/L), platelet count <100,000/mm3 (<100 × 109/L), persistent proteinuria (>0.5 g/24 hr), or hematuria CBC, complete blood count; WBCC, white blood cell count. Copyright © 1998 John Wiley & Sons, Inc. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

cals.425,426 It also inhibits carboxypeptidase and angiotensin II converting enzymes, which are involved in the kinin pathways,427 although the concentrations required to achieve this effect considerably exceed those achieved in vivo. It may interfere with immune complex formation428,429 and may block the replication of viral RNA.419,430 The toxicity of D-penicillamine is usually similar to that of gold,431–437 and monitoring should be carried out in the same manner as for gold toxicity. However, autoimmune diseases, including SLE, polymyositis, Goodpasture’s syndrome, and myasthenia gravis, may develop after D-penicillamine therapy.438–440 A child who has a toxic reaction to a gold compound may develop toxicity to D-penicillamine, in many cases even with the same manifestations. In adults, at least, this predisposition may be associated with HLA-DR3 (DW33) and the C4 null allele.398,441

Other Disease-Modifying Drugs Colchicine The primary use of colchicine (Fig. 5–14) in pediatrics is for treatment of familial Mediterranean fever (FMF), wherein it has been shown to reduce not only the frequency of attacks but also the development of amyloidosis. Colchicine is also occasionally used for recurrent aphthous stomatitis, Behçet’s disease, and cutaneous vasculitis. Peak plasma levels are reached 1 to 3 hours after oral administration. The drug is metabolized extensively in the liver by the cytochrome P-450 system.442 Its halflife after oral administration is 9 ± 4 hours.443 Its action is thought to depend on binding of two of its rings to

CH3O NHCOCH3

CH3O

CH3 CH3

AND

CH3O O OCH3

■ Figure 5–14 Structure of colchicine.

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cellular microtubules, inhibiting the movement of intracellular granules and preventing secretion of various components to the cell exterior.444,445 Interaction with endothelial cells and neutrophils is inhibited by reducing the expression of adhesion molecules on the neutrophil membrane.446 The drug is present in granulocytes to a much greater extent than in lymphocytes or monocytes, perhaps because of reduced activity of the p-glycoprotein efflux pump in these two cell types.444 Drug interactions may occur either at the level of the intestine (reduced absorption447) or through the cytochrome P-450 system. Agents that inhibit this system may lead to colchicine toxicity; alternatively, drugs that are metabolized by this system may compete with colchicine, leading to a buildup of both agents. The effect of colchicine on microtubules has raised concern about chromosomal and gonadal aberrations. In a group of patients with FMF receiving long-term treatment with colchicine, there were no differences between patients and controls in lymphocyte mitotic rate, percentage of tetraploidy, or chromosomal breakage.448 The amount of colchicine needed to reduce sperm motility is much greater than that used with standard therapy.449 Azoospermia and oligospermia are more common in patients with Behçet’s disease than in those with FMF, which suggests that genetic makeup or the underlying disease may contribute to reduced sperm production.450 Concerns regarding growth delay in children are unfounded.451,452 The therapeutic dose of colchicine ranges from 0.5 to 2.0 mg/day as needed to prevent or significantly reduce the frequency of FMF attacks. Toxicity is extremely rare with oral administration and is generally limited to the GI tract (nausea, vomiting, abdominal pain, diarrhea). In the case of serious overdose, treatment with colchicine-specific Fab could be considered.453 However, severe toxicity can result in dehydration, multiorgan failure, and a DIC-like syndrome.444

Thalidomide Thalidomide (N-α-phthalimidoglutarimide) has acquired a well-deserved reputation as a major teratogen. However, it has been shown to be effective in a variety of immune-mediated disorders. Its immunosuppressive effects include inhibition of neutrophil chemotaxis,454 decreased monocyte phagocytosis,455 decrease in the ratio of helper T cells to suppressor T cells,456 inhibition of expression of TNF-α and IL-6 messenger RNA (mRNA),457 and inhibition of angiogenesis.458,459 Its structure includes two ring systems (Fig. 5–15). Mean peak plasma concentrations occur 4.39 ± 1.27 hours after a

O C N C O

C C

O

NH

O

■ Figure 5–15 Structure of thalidomide.

200-mg dose.460 It is metabolized primarily by spontaneous hydrolysis and has an elimination half-life of 3 to 7.3 hours. Once-daily or twice-daily administration is appropriate.461 Controlled trials have shown benefit of thalidomide compared with placebo in recurrent aphthous ulcers462 and in the recurrent oral ulceration in adult men with Behçet’s syndrome.463 There is one report of response to thalidomide in an infant with Behçet’s disease.464 In addition, several reviews465,466 have described multiple case series reporting improvement in patients with a variety of disorders, including cutaneous lupus467–469 and graft-versus-host disease.466 Single series or case reports have documented improvement in patients with palmoplantar pustulosis, sarcoidosis, rheumatoid arthritis, pyoderma gangrenosum, erythema multiforme, Weber-Christian disease, pemphigoid, Crohn’s disease (including two children),470,471 ulcerative colitis, rheumatoid arthritis,472 spondyloarthropathies,473 and adult-onset Still’s disease.474 Recently, Lehman and colleagues reported on two children with systemic-onset JRA resistant to various treatments (including etanercept) who responded well to thalidomide.475 In addition to embryopathy (which can occur with as small a dose as 100 mg given between 34 and 50 days of gestation), the major side effects of thalidomide include peripheral neuropathy and drowsiness. The neuropathy is predominantly sensory and manifests as painful paresthesias in a glove-and-stocking distribution.476 The neuropathy can progress despite discontinuation of thalidomide and may or may not be dose related; it has been reported in 1% to 70% of patients. Even after discontinuation of the drug, recovery may be delayed for several years. Baseline and routine follow-up electrophysiologic testing should be performed, and the dose should be reduced or discontinued on detection of abnormalities.477 A variety of other neurologic effects, including carpal tunnel syndrome, muscle weakness and cramps, and signs of pyramidal tract involvement, may occur. Endocrine effects include hypothyroidism, hypoglycemia, and stimulation of adrenocorticotropic hormone (ACTH) and prolactin production or secretion.478 The dose of thalidomide varies between 100 and 400 mg/day. Doses of 2.5 to 4 mg/kg/day have been suggested for children with SLE or systemic-onset JRA.475,479,480 Birth control must be practiced. Women who are prescribed thalidomide should sign a consent form indicating knowledge of potential birth defects and agreeing to adequate methods of birth control. Excellent control is maintained in a postmarketing surveillance program and a restricted distribution program, the System for Thalidomide Education and Prescribing Safety program (STEPS), monitored by Boston University, Celgene Corporation, and the U.S. Food and Drug Administration.481

Glucocorticoid Drugs Glucocorticoid drugs are the most potent anti-inflammatory agents in the treatment of rheumatic diseases.482 Reports of their use in children with rheumatic diseases, especially rheumatic fever, JRA, and SLE, began to appear

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in the 1950s and 1960s.483–486 Specific aspects of therapy are discussed in the chapters on individual diseases and in reviews.487–493 This chapter describes more general aspects, such as the pharmacology, physiology, and mechanism of action of glucocorticoids, as well as the indications and contraindications for systemic and local glucocorticoid therapy and their associated adverse effects.

CH2OH

CH2OH C

O OH

CH3

O

CH3

O

O PREDNISONE CH2OH

CH2OH

Pharmacology

Physiologic and Pharmacologic Effects Glucocorticoids are unique among the pharmacologic agents given to treat rheumatic diseases in that they are synthetic analogues of chemicals produced by the body and thus have a physiologic, as well as a pharmacologic,

C CH3

HO

C

O OH

CH3

HO CH3

CH3

CH3

O

O CH3

DEXAMETHASONE

METHYLPREDNISOLONE CH2OH C CH3

HO

O OH

CH3

O HYDROCORTISONE

■ Figure 5–16 Structure of the glucocorticoids.

role. Glucocorticoids enter cells passively and bind to two distinct cytosolic receptors, mineralocorticoid (type I) and glucocorticoid (type II) receptors (GRs). Type I receptors have highest affinity for aldosterone and are found on epithelial cells of the kidney, colon, and salivary glands, and on nonepithelial cells in the brain and heart. Activation of mineralocorticoid receptors induces activity of epithelial sodium channels, leading to sodium retention and hypertension. Type II receptors have highest affinity for dexamethasone and are present in virtually all cells, including those of the immune system. The receptors are present in the cytoplasm and consist of a

Equivalent Dose† (mg)

Relative Anti-inflammatory Potency

Relative Sodium-retaining Potency

20 6

1 4

1 1

5 5 4

4 4 5

0.8 0.8 0.5

0.75

25

0

Short-acting Hydrocortisone Deflazacort Intermediate-acting Prednisone Prednisolone Methylprednisolone Long-acting Dexamethasone

O OH

F

TABLE 5–14 Relative Doses and Equivalent Potencies of Glucocorticoids (Compared with Hydrocortisone) Glucocorticoid*

O OH

CH3

PREDNISOLONE

The glucocorticoid drugs are modeled on the principal naturally occurring glucocorticoid, hydrocortisone (cortisol). They are 21-carbon molecules that in active form have a hydroxyl group at C11. Synthetic preparations such as prednisone and cortisone must be metabolized to the active forms (prednisolone and hydrocortisone, respectively) (Fig. 5–16). Glucocorticoids that are used topically (e.g., dexamethasone) or given by intra-articular injection (e.g., triamcinolone hexacetonide) have a hydroxyl group at C11 and therefore are already in active form.494 The different relative potencies and durations of biologic action of the various synthetic analogues are outlined in Table 5–14. Orally administered glucocorticoids (prednisone, prednisolone) are rapidly absorbed. Prednisone is converted to prednisolone in the liver and reaches a peak plasma concentration within 2 hours. Hydrocortisone and prednisolone bind to the serum proteins transcortin (high affinity) and albumin (low affinity). Methylprednisolone and dexamethasone are bound primarily to albumin.494 Prednisolone has a large volume of distribution; about two thirds is taken up by muscle. After metabolism in the liver, excretion occurs principally by way of the bile.

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C CH3

HO

AND

*Biologic half-life: short-acting, 8–12 hr (deflazacort, ~1.5 hr); intermediate-acting, 12–36 hr; long-acting, 36–72 hr. † Oral or intravenous administration only. Adapted from Goodman LS, Gilman A (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8th ed. New York, Pergamon Press, 1990. Reproduced with permission of The McGraw-Hill Companies.

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hormone-binding portion, a DNA-binding portion, and an immunogenic region. Binding of the hormone to the receptor causes translocation of the complex to the nucleus, where the DNA-binding portion binds to glucocorticoid-responsive elements (GREs) of the DNA in the promoter or enhancer region of the responsive genes. This induces mRNA transcription of specific genes that encode for proteins of importance in the inflammatory and immune responses, such as phospholipase A2 inhibitory protein. The effect is reflected indirectly in decreased prostaglandin production.495,496 Binding to negative GREs may repress gene transcription. This mechanism of glucocorticoid effect, mediated via binding to a cytosolic receptor, reflects traditional understanding of the therapeutic effects of glucocorticoids and can be categorized as “genomic” action. GRs may also interact via protein–protein interaction with other transcription factors (e.g., NF-κB), preventing activation of transcription.497 Two forms of GR have been described, GRα and GRβ. GRβ does not bind glucocorticoids and may play a role in the glucocorticoid resistance of some diseases.498 The therapeutic effects of glucocorticoids occur in a modular fashion via both genomic and nongenomic mechanisms (Table 5–15).499 This modular hypothesis postulates the following steps. ■

■

Module 1: At very low dosages of glucocorticoids, genomic effects occur (module 1). These include the classic receptor-mediated actions that result in increased transcription of certain genes (e.g., those coding for lipocortin) and decreased transcription of others (e.g., those coding for various cytokines), resulting in net anti-inflammatory and immunosuppressive effects. These genomic effects start at least 30 minutes after glucocorticoid administration and result from binding to cytosolic receptors. Module 2: As the dosage is increased up to approximately 200 to 300 mg of prednisone equivalent per day, specific nongenomic effects occur due to a greater occupation of receptors. However, it is postulated that a further increase in dosage may affect pharmacodynamics (e.g., receptor off-loading and reoccupancy), receptor synthesis, and receptor expression and may bring additional therapeutic benefit via other mechanisms. In contrast with genomic actions, these receptor-mediated actions occur within minutes after glucocorticoid administration. The clinical correlates of these effects may include the negative feedback of ACTH production, behavioral changes, cardiovascular effects, and programmed cell death (apoptosis).

TABLE 5–15 Level of Therapeutic Effect (see text) Module 1 Module 2 Module 3

■

Module 3: The assumed additional therapeutic effects of higher dosages could be obtained predominantly via nonspecific nongenomic mechanisms, mediated by membrane-bound receptors, initiated by even more rapid effects (within seconds) through physicochemical interactions with cellular membranes.499 The antianaphylactic actions of glucocorticoids may be explained by this mechanism.

This hypothesis provides a modular system of increasing therapeutic effect with increasing dosage, occurring through recruitment of a number of nongenomic actions, with increasingly more rapid onset of effect than the classic genomic actions of glucocorticoids. The actions of glucocorticoids at physiologic levels are summarized in Table 5–16. Glucocorticoids are essential for normal vascular integrity and responsiveness; they suppress leukocyte migration and immune reactions and stabilize cell membranes.500–511 Glucocorticoids influence protein, carbohydrate, fat, and purine metabolism; electrolyte and water homeostasis; cardiovascular, nervous, and renal function; and bone and muscle integrity.

Carbohydrate, Protein, and Lipid Metabolism Glucocorticoids stimulate the synthesis of glucose, diminish its peripheral use, and promote its storage as glycogen. They increase secretion of insulin by pancreatic islet cells. In the periphery, they mobilize amino acids from tissues that are then diverted in the liver to the production of glucose and glycogen. This catabolic action results in lymphoid and muscular atrophy, osteoporosis, thinning of the skin, and negative nitrogen balance. Glucocorticoids stimulate fat cell differentiation and, in high doses, redistribution of fat in a typical cushingoid distribution. They increase the production of the peroxisome proliferator-activated receptor γ2 (PPAR-γ2), a nuclear hormone receptor important in adipogenesis. Various other effects on lipids have been reported, but most have not been conclusively demonstrated to result from the direct actions of glucocorticoids themselves. There is no consistent alteration in plasma lipids in either hypercorticism or hypocorticism.512

Electrolyte and Water Balance The glucocorticoid analogues used in the treatment of rheumatic diseases have been modified to decrease their

Dose-Effect Relationships of Glucocorticoids Prednisone Equivalent (mol/L) −12

>10 >10−9 >10−4

Mechanisms

Onset of Action

Genomic actions Additional nongenomic, receptor-mediated actions Additional nongenomic, physicochemical actions

After at least 30 min Seconds to 1–2 min Within seconds

From Buttgereit F, Wehling M, Burmester GR: A new hypothesis of modular glucocorticoid actions. Steroid treatment of rheumatic diseases revisited. Arthritis Rheum 41: 761–767, 1998. Copyright © 1998. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

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TABLE 5–16 Actions of Glucocorticoids at Physiologic Levels Negative feedback modulation of corticotropin-releasing factor and adrenocorticotropic hormone Maintenance of blood glucose and liver glycogen levels Maintenance of cardiovascular function, blood pressure, and muscle work capacity Excretion of a water load Permissive effects on pressor, lipolytic, and gluconeogenic activities of hormones Protection against moderate stress Adapted from Munck A, Guyre PM: Glucocorticoid physiology and homeostasis in relation to anti-inflammatory actions. In Scheimer RP, Claman HN, Oronsky A (eds): Anti-Inflammatory Steroid Action: Basic and Clinical Aspects. San Diego, Academic Press, 1989.

mineralocorticoid potency. In that manner, increased resorption of sodium ions from the distal renal tubules is moderated, as is increased urinary excretion of potassium and hydrogen ions. Patients on long-term therapy are nonetheless in positive sodium balance, have an increased extracellular fluid volume, and have a tendency toward hypokalemia and alkalosis. However, in practice, these changes are only moderate in severity, reflecting the relatively weak effect of glucocorticoids on electrolyte balance. Glucocorticoids also decrease the absorption of calcium from the intestine and increase its renal excretion, thus producing a negative calcium balance (discussed later).

Anti-Inflammatory and Immunosuppressive Actions Glucocorticoids have both anti-inflammatory and immunosuppressive effects.490–493,500–511 These effects are largely mediated by the inhibition of specific functions of leukocytes, such as the elaboration or the action of a variety of lymphokines.

Anti-inflammatory Actions Steroids inhibit both the early stages of inflammation (e.g., edema, fibrin deposition, capillary dilatation, migration of lymphocytes into inflamed areas, phagocytic activity) and the later manifestations (e.g., proliferation of capillaries and fibroblasts, deposition of collagen).512 Many of these effects are mediated by inhibition of the elaboration of a number of chemokines and cytokines, including the following: ■

■ ■ ■

Arachidonic acid and its metabolites (e.g., prostaglandins, leukotrienes): Glucocorticoids induce synthesis of lipocortins by macrophages and other cells.510,511,513 Lipocortins inhibit the binding of phospholipase A2 to its substrate and thus reduce the generation of arachidonic acid, the substrate for the COX-mediated synthesis of prostaglandins and leukotrienes Platelet-activating factor (PAF) This effect is also mediated by the induction of lipocortin.514 TNF IL-1: A number of inflammatory actions of IL-1 are inhibited, including stimulation of the production of prostaglandin E2 and collagenase, activation of T lymphocytes, stimulation of fibroblast prolifera-

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tion, and enhanced hepatic synthesis of acute phase proteins. In addition, glucocorticoids can inhibit the action of humoral regulators of inflammation such as PAF and macrophage migration inhibition factor (MIF).514 The reader who is interested in the subject of the anti-inflammatory effects of glucocorticoids is referred to the extensive review by Schleimer and colleagues.515

Immunosuppressive Actions The glucocorticoid effects on the immune system are mediated principally through T lymphocytes.503 Acute administration of hydrocortisone produces a 70% decline in circulating lymphocytes. T lymphocytes are affected more than B lymphocytes, and T helper cells more than T suppressor cells. The lymphocytopenia is probably a result of sequestration of cells in the bone marrow rather than cell lysis, although drug-induced apoptotic cell death may also be involved.516 The most pronounced lymphopenia occurs 4 to 8 hours after a single dose of glucocorticoid and disappears by 24 hours. There is also a 90% decline in circulating monocytes within the initial 6 hours. Proliferative T cell responses to antigens (streptodornasestreptokinase), mitogens (concanavalin A), and cell surface antigens (as in the mixed leukocyte reaction) are reduced by glucocorticoids. IL-2 production by T cells in vitro is also reduced.517 Glucocorticoids cause an increase in the numbers of blood neutrophils by increasing the release of cells from the marginated neutrophil pool, prolonging their stay in the circulation, and reducing chemotaxis of neutrophils to sites of inflammation.518 Another effect of the decreased action of phospholipase A2 is reduction of neutrophil chemotaxis, which decreases accumulation of these cells at inflammatory sites.507 However, no consistent effect of glucocorticoids on neutrophil phagocytosis or bacterial killing has been demonstrated.518 Intravenous glucocorticoid causes a fall in circulating IgG but little discernible effect on the serum titer of specific antibodies. However, the protein catabolic effects of long-term administration may have consequences on the humoral immune system. Endothelial secretion of C3 and factor B of the complement cascade is inhibited by glucocorticoid.519

Indications for Systemic Glucocorticoid Therapy When considering the use of glucocorticoids in children with rheumatic diseases, the risk/benefit ratio must be carefully weighed, because these agents are associated with substantial toxicity when used systemically in the long term (Table 5–17). Clinicians must review the specific indications for which glucocorticoids are to be used and the outcomes that will be monitored to measure response and consequently determine the duration of therapy. The overall aim is to limit the dose and duration of steroid therapy to the lowest possible levels while achieving disease control. Administration of a single dose in the morning and use of alternate-day regimens, which have been shown to minimize the suppression of linear growth in children, should be used whenever possible.520

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TABLE 5–17

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Adverse Effects of Glucocorticoid Drugs

Mood and behavioral disturbances Cushing’s syndrome Growth suppression Effects on bone Osteoporosis Avascular necrosis of bone Immunosuppression Lymphopenia and neutrophilia Central nervous system effects Psychosis Mood and behavioral disturbances Cardiovascular system effects Hypertension Dyslipoproteinemia Cataracts and glaucoma Metabolic effects Impaired carbohydrate tolerance Protein wasting Metabolic alkalosis Myopathy

The child who is being treated with these drugs should be under the care of a physician who is experienced in management of the disease and in minimizing the adverse effects of glucocorticoids.521–523

TABLE 5–18

Comparison of Idiopathic and Iatrogenic Cushing’s Syndromes Prominent in Idiopathic Cushing’s Syndrome Hypertension Menstrual irregularities Impotence Hirsutism Acne, striae Purpura, plethora

Equal Frequency Obesity Psychosis Edema

Prominent in Iatrogenic Cushing’s Syndrome Avascular necrosis Cataract, glaucoma Pseudotumor cerebri Pancreatitis Panniculitis

In Cushing’s syndrome, the distribution of fat is predominantly in the subcutaneous tissue of the abdomen and upper back (buffalo hump) and in the face (moon facies). Weight gain reflects both fluid retention and increased caloric intake: Children taking prednisone are often ravenously hungry. Attempts to minimize weight gain by limiting caloric and sodium intake may be useful but difficult. Skin changes, in addition to the characteristic purple striae on the lower abdomen, lower legs,

For example, in JRA the use of systemic glucocorticoids is mainly limited to treating the extra-articular features of systemic-onset disease. These include systemic “toxicity” and fevers unresponsive to NSAID therapy, severe anemia, myocarditis or pericarditis, and the macrophage activation syndrome.80,81 The presence of fever or arthritis alone in systemic-onset JRA is not sufficient indication for systemic glucocorticoid therapy. Lowdose, short-term systemic glucocorticoids may also be indicated in severe forms of polyarticular JRA with significant functional impairment and for chronic uveitis unresponsive to local therapy. High-dose systemic glucocorticoids are used in children with other inflammatory conditions such as JDM, vasculitis, and SLE.

Adverse Effects Two broad categories of adverse effects occur with the therapeutic use of systemic glucocorticoids: Those resulting from prolonged use of large doses and those resulting from withdrawal of therapy. The major manifestation of the latter is acute adrenal insufficiency with too-rapid withdrawal after prolonged therapy (see later discussion). The adverse effects of glucocorticoid excess are many (see Table 5–17). The mechanisms involved in the development of these adverse events have been recently reviewed.497

Cushing’s Syndrome Cushing’s syndrome, a term used originally to identify the effects of idiopathic hypercorticism, may also be induced by prolonged glucocorticoid administration (Table 5–18). It is characterized biochemically by high plasma glucocorticoid levels and suppression of the hypothalamic-pituitary-adrenal axis. The syndrome is characterized clinically by a number of features, including truncal obesity (Fig. 5–17), osteoporosis, thinning of the subcutaneous tissues, and hypertension.

■ Figure 5–17 Eleven-year-old girl with severe systemic-onset juvenile idiopathic arthritis requiring high-dose corticosteroid treatment. Cushingoid features demonstrated include moon facies, truncal obesity, and cutaneous striae.

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upper arms, and chest, include hirsutism and acne. Hypertension is usually mild but occasionally requires treatment or reduction of the glucocorticoid dose. Osteoporosis is one of the most troublesome consequences of long-term, high-dose glucocorticoid therapy and is further discussed later in this chapter.524 Few side effects occur at the start of therapy; the major manifestations of iatrogenic Cushing’s syndrome and other toxicities are related more directly to the total dose administered than to the length of time that the patient has been taking the drug. Cushingoid effects supervene when the long-term daily dose in a child (25 kg) exceeds approximately 5 mg of prednisone. Cushingoid appearance is an important source of distortion of body image and can affect self-esteem and psychological well-being, particularly in adolescents and young adults. However, with the exception of skin striae, all of the physical features contributing to the cushingoid appearance are reversible after cessation of glucocorticoid therapy.

Growth Suppression Growth suppression is one of the most worrisome long-term adverse effects. It occurs in young children who are receiving prolonged therapy525 in dosages equivalent to 3 mg/day of prednisone and increases with higher doses.526,527 However, there may be substantial interindividual variability in the severity of growth suppression and the minimal dose required to suppress growth.528 The mechanism of glucocorticoidassociated growth suppression in children with arthritis is controversial. Glucocorticoids have been shown to inhibit production of insulin-like growth factor I (somatomedin C).529,530 In addition, the general inhibitory effect of glucocorticoids on cell growth and cell division probably contributes to growth failure.526 Although early studies showed that growth hormone did not always improve growth failure in children with glucocorticoid-induced inhibition of growth,531 more recent reports have shown not only increased height velocity in many patients532 but also catch-up growth.533 Growth suppression may in fact be a consequence of the underlying disease process, as in JRA.534 Evidence suggests that when glucocorticoids are used, growth retardation is more severe in patients with JRA than in those with SLE receiving equivalent doses.535 Furthermore, growth suppression appears to be worse in patients with systemic-onset disease compared with those with polyarticular- or oligoarticular-onset disease.535 Although alternate-day regimens have been shown to minimize this adverse effect,536–538 the usefulness of such regimens for controlling the actual disease remains unclear. Effects on Bone: Osteoporosis and Avascular Necrosis Osteoporosis is another serious consequence of long-term glucocorticoid therapy in children with rheumatic disease. There are multiple other contributing factors, including inadequate dietary intake of calcium and vitamin D, the underlying disease activity (e.g., in children with polyarticularor systemic-onset JRA),539–541 reduced physical activity,542 reduced exposure to sunlight (e.g., in children with JDM or SLE), and low body weight.543

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Glucocorticoids are associated with both a reduction in bone formation and an increase in bone resorption, and it is the reduction in bone formation that appears to be the most important. Reduced bone formation is caused by a direct inhibitory effect on osteoblasts. Glucocorticoids also directly inhibit gut absorption of calcium and cause increased urinary calcium excretion, potentially resulting in secondary hyperparathyroidism and, hence, increased bone resorption544,545; however, this mechanism appears to play a minor role, at least in adults. The extent of bone loss appears to be related to both the dose and the duration of glucocorticoid therapy, although these factors do not necessarily have a consistent relationship with fracture risk. Significant trabecular bone loss occurs with doses of 7.5 mg/day or higher in most adults.546,547 Bone loss appears to occur rapidly within the first 6 to 12 months of therapy and then reaches a plateau.546 Alternate-day glucocorticoid therapy may not be protective.548 In adults, bone loss is predominantly trabecular (e.g., spine and ribs) rather than cortical, whereas in children the osteoporotic effect of glucocorticoids is more generalized. Not all patients exposed to long-term glucocorticoid therapy develop bone loss.549 However, there are no reliable biochemical markers that can be used to predict which glucocorticoid-treated children will undergo significant bone loss.550 Bone densitometry may be used to screen children who are at high risk for osteoporosis. Approaches to the prevention and treatment of glucocorticoid-associated osteoporosis are discussed later. Some of the mechanisms by which glucocorticoids result in bone loss have been explored and are depicted in Figure 5–18. They include effects on the production of local growth factors, reduction of matrix proteins and an increase in the production of enzymes that break down matrix, an increase in apoptosis of both osteoblasts and osteocytes, and an increase in osteoclastogenesis due to decreased production of osteoprotegerin and an increased production of RANK ligand.550a–550c High-dose glucocorticoids have also been associated with avascular necrosis of bone (AVN). Although the exact mechanism is not known,551 a variety of recent observations may help explain this devastating complication. Intramedullary vascular compromise may result from the increased osteocyte apoptosis induced by glucocorticoids. Absence of clearance of these apoptotic osteocytes may result in reduced blood flow and bony ischemia.552 Glucocorticoids induce adipocyte differentiation via the increased production of peroxisome proliferator-activated receptor γ2 (PPAR-γ2), which may result in increased fat in the marrow.552 Finally, glucocorticoids also increase the increased expression of endothelin-I, which may also lead to reduced intramedullary blood flow.553 Many sites can be involved, but the most common and clinically significant location for AVN is the femoral head. This complication is more frequently reported in SLE (in which the underlying disease process can be a contributing factor) and possibly also after highdose intravenous methylprednisolone therapy, although the data to support the latter association are not strong.554,555

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↓ bone formation

• FLUORIDE • ANABOLIC STEROIDS

↓ collagen ↑ collagenase ↑ apoptosis

↓ growth factor

CORTICOSTEROIDS

↓ FSH induced sex hormone production

↓ sex hormones

↓ LH response to LHRH GI calcium absorption • CALCIUM • VITAMIN D

Urinary calcium excretion

↓ OPG

OSTEOPOROSIS • ESTROGENS • TESTOSTERONE

↑ RANK Ligand

• THIAZIDE ↓ calcium

↑ PTH

↑ bone resorption

• CALCITONIN • BISPHOSPHONATES

■ Figure 5–18 Approaches to the prevention and treatment of steroid-induced osteoporosis. FSH, follicle-stimulating hormone; GI, gastrointestinal; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; OPG, osteoprotegerin; PTH, parathyroid hormone.

Infection and Immunity Glucocorticoids interfere with the ability to resist infection through two main mechanisms: (1) They act as immunosuppressives and unpredictably decrease the patient’s resistance to viral and bacterial infections. (2) They are also anti-inflammatory agents and hence may mask the signs and symptoms of infection. These may include, for example, important signs such as fever or abdominal pain in peritonitis. Susceptibility to infections in general is related to the dose and duration of glucocorticoid administration. However, the minimal amount of systemic steroids and the duration of administration sufficient to cause immunosuppression in an otherwise healthy child are not well defined.217 Additional factors that may affect the overall extent of immunosuppression in steroid-treated children with rheumatic diseases include the effects of the underlying disease and concurrent immunosuppressive therapies. The most profound effect of glucocorticoid administration is on cell-mediated immune reactions, including delayed hypersensitivity and allograft rejection. Patients receiving high doses of glucocorticoid for a prolonged period are prone to infections that are associated with defects of delayed hypersensitivity (e.g., tuberculosis). If possible, the Mantoux test (purified protein derivative [PPD], 5 tuberculin units) should be performed before glucocorticoids are started. If the result is positive at 72 hours, further investigations for tuberculosis should be carried out. The risk of complications of varicella infection must also be considered. The susceptible glucocorticoid-treated child who is exposed to chickenpox should receive zoster immune globulin within 96 hours (for maximum effectiveness, as soon as possible after exposure or ideally within 72 hours) or acyclovir during the infectious illness itself.217

There is little information to guide decisions about the glucocorticoid regimen in varicella-infected children who have been on chronic steroid therapy; it would seem reasonable to try to minimize doses while maintaining disease control during the course of such an infection. If bacterial infection develops in a child treated with glucocorticoids, the dose may be maintained or increased and the best available treatment for the infection vigorously administered. In those patients with Pneumocystis carinii pneumonia (PCP), early adjunctive treatment with glucocorticoids has been demonstrated to have a beneficial effect on the clinical course and outcome, at least in adult patients with acquired immunodeficiency syndrome (AIDS) and moderate to severe PCP.556 Although no controlled trials of glucocorticoids in young children have been performed, most experts would recommend glucocorticoids as part of therapy for children with moderate to severe PCP.217 The impact of glucocorticoids in immunocompromised hosts without AIDS appears to be similar to that in patients with AIDS.557

Hematologic System Glucocorticoids decrease the number of circulating lymphocytes, monocytes, basophils, and eosinophils but increase the number of circulating neutrophils.558 Excess glucocorticoid may also cause polycythemia. Central Nervous System The effect of glucocorticoids on the CNS results from changes in the concentration of plasma glucose, circulatory dynamics, and electrolyte balance. These effects are reflected by changes in mood, behavior, and electroencephalographic studies.559 Pseudotumor cerebri is rare but may occur after rapid reduction of glucocorticoid dose.560 Most glucocorticoid-induced psychoses have an acute onset, are related to high doses, and occur within 96 hours after initiation of medication.561,562 Psychosis is more common in idiopathic Cushing’s syndrome than in

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iatrogenic disease. Early, there may be euphoria and mania; later in Cushing’s syndrome, depression tends to predominate. Other types of mood and behavioral disturbances, such as anxiety and insomnia, may occur. A prospective cohort study of the adverse effects of high-dose intermittent intravenous glucocorticoids in 213 children with rheumatic diseases found behavioral changes in 21 (10%).563 These abnormalities included altered mood in 14, hyperactivity in 4, sleep disturbance in 3, and psychosis in 2 children. In some cases, CNS effects may be related to the underlying disease (e.g., SLE). Abnormalities of behavior usually disappear after glucocorticoids are withdrawn. However, there are anecdotal reports of depression lasting for several weeks in some children treated with short-term steroids in the form of intraarticular triamcinolone hexacetonide or high-dose intravenous pulse methylprednisolone.

Cardiovascular System The major effect of glucocorticoids on the cardiovascular system is mediated by their influence on the regulation of renal sodium excretion, sometimes leading to hypertension. However, this complication is uncommon in children with JRA who do not have underlying renal disease. The actual mechanism of glucocorticoid-induced hypertension is not fully explained. Although sodium retention plays a role, additional factors, such as increased plasma renin activity or antidiuretic hormone, may be involved.512 Glucocorticoids also exert an important effect on capillaries, arterioles, and myocardium.512 These influences are relevant in acute relative steroid deficiency when patients treated with long-term glucocorticoids are subject to physiologic stress (see “Preventing Acute Adrenal Insufficiency [Addisonian Crisis]”). Other important possible long-term effects of chronic glucocorticoid administration include hyperlipemia and accelerated coronary atherosclerosis.564 Patients with SLE, who often are treated with large doses of glucocorticoids for prolonged periods, are at increased risk for dyslipoproteinemia and coronary artery disease (CAD) after about 10 years of disease. Although the pathogenesis of CAD in these patients is multifactorial, some studies have suggested that a long duration of glucocorticoid therapy may be an important risk factor.565 A cross-sectional study of 40 children with SLE did not find steroids to be an independent risk factor for CAD.566 These children had a median age of 15.9 years and median disease duration of 1.4 years at the time of study. In contrast to adults, children with abnormalities in coronary perfusion tended to have shorter median duration of prednisone use as well as lower cumulative dose of steroids and fewer intravenous pulsed doses of steroids. Although the study was small and these were only observed trends and not statistically significant differences, they raise the possibility that CAD may be more a manifestation of the underlying disease process than of the glucocorticoid therapy used to treat it.

Cataracts and Glaucoma Subcapsular cataracts560,567,568 are more common with glucocorticoid therapy than in idiopathic Cushing’s syndrome. The risk of cataract development becomes significant when a dose of prednisone equal to or greater than 9 mg/m2/day has been maintained for longer than 1 year. Most children who have been treated

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with doses of glucocorticoid equivalent to 20 mg/day of prednisone for 4 years or longer develop cataracts.560 These cataracts often do not progress, are functionally benign, and rarely affect vision. Children on long-term glucocorticoid therapy should also be monitored for glaucoma, especially if they have a history of uveitis.

Muscle Disease The muscle wasting that results from highdose glucocorticoid administration is associated with atrophy of muscle fibers, especially type IIB fibers. Steroid myopathy can complicate the clinical assessment of a patient with SLE or JDM (see Chapters 16 and 18). Myopathy induced by glucocorticoids usually affects proximal muscles, is seldom painful, and is usually associated with normal serum levels of muscle enzymes and an electromyogram suggestive of myopathy. However, a muscle biopsy may be needed to differentiate between steroid myopathy and active myositis. Glucocorticoidinduced hypokalemia may also lead to muscular weakness and fatigue. Recovery from steroid myopathy may be slow and incomplete.569 Other Side Effects Glucose intolerance and glycosuria may occur after prolonged exposure to large doses of glucocorticoids, particularly if there is a genetic predisposition to diabetes.570 Such intolerance can usually be managed with diet or insulin; such side effects should not be important to the decision to continue glucocorticoid therapy or to initiate it in diabetic patients who need it. The role of glucocorticoids in peptic ulceration is controversial. Although some have suggested an increased risk, current evidence does not support a definitive association between peptic ulceration and glucocorticoid therapy independent of any other factors such as NSAID therapy or concomitant illness.571

Minimizing Toxicity The deleterious effects of glucocorticoids can be minimized by choosing a drug with a relatively short half-life (see Table 5–14).572 Prednisone is the drug most often given for oral therapy. Its enhanced glucocorticoid and minimal mineralocorticoid actions give it the lowest risk/benefit ratio of any of the analogues in general use.573 Adherence to the use of a single synthetic analogue simplifies communications with the patient, parents, and medical personnel and lessens the risk of an error in dose. The GR-DNA interaction induces genes that code for antiinflammatory proteins (transactivation). Genes that code for pro-inflammatory proteins are regulated by transcription factors such as NF-κB (transrepression). In this situation, the GR operates via protein interactions, inhibits the activity of the transcription factors, and thereby represses the expression of the pro-inflammatory proteins. Many glucocorticoid side effects appear to be mediated via binding to DNA elements, rather than protein elements. Therefore, if synthetic glucocorticoids could be designed to operate via the latter rather than the former pathway, the result would be maintenance of anti-inflammatory properties with reduction in toxicity. Work is in progress to develop such agents.497

Deflazacort, an oxazoline derivative of prednisone with anti-inflammatory and immunosuppressive activity,

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may have a bone-sparing effect compared with prednisone.574–576 However, there are at least two case reports of children who developed symptomatic vertebral collapse while receiving deflazacort for vasculitis and a lupus-like syndrome.577 Therefore, the long-term efficacy and safety of deflazacort in children with rheumatic diseases need further study before this drug can be recommended for general use. Both the anti-inflammatory effect and the toxicity of glucocorticoids increase with larger doses and more frequent administration (Table 5–19). Four-times-daily administration is more effective than twice-daily administration of the same total dose. Daily administration is more effective than administration of the same total dose every other day.536,576,578,579 Glucocorticoid administration should be as infrequent as is consistent with achieving disease control. Short-acting glucocorticoids given in the morning (on waking) have less capacity to suppress the pituitary than do those given later in the day (which suppress the normal surge of ACTH that occurs during sleep).512 Reduction in glucocorticoid dose must be gradual and should be individualized for the child and the disease. At high doses (e.g., 60 mg/day), reductions of 10 mg are usually well tolerated; at lower doses (e.g., 10 mg/day), reductions of only 1 or 2 mg may be necessary. The dose can be tapered on every second day so that an alternate-day regimen is established as early as possible. Glucocorticoid dose tapering is often fraught with difficulty because of the adaptation of the patient’s metabolism to chronic steroid excess.580,581 Steroid pseudorheumatism may result from a rapid dose decrease in some children.582 Signs and symptoms include increased stiffness and pain in the joints, malaise, fever, and irritability. Pseudotumor cerebri may occur under similar conditions.560 It is characterized by headache, vomiting, and papilledema. It must be differentiated from other causes of increased intracranial pressure. These withdrawal effects gradually resolve over 1 or 2 weeks and are minimized if each decrement in daily prednisone is 1 mg or less per week (at the lower dose levels). A number of approaches for the prevention and treatment of corticosteroid-associated osteoporosis have been studied in adults (see Fig. 5–18), and several guidelines have addressed these issues.583–585 Vitamin D and its analogues, calcitonin, and various bisphosphonates have been used. Calcitriol (vitamin D3) or cholecalciferol (vitamin D), with or without calcitonin, was shown to prevent bone loss from the lumbar spine better than calcium alone in several randomized controlled clinical trials of adult patients starting long-term glucocorticoid therapy.586,587 A

1998 meta-analysis also concluded that treatment with calcium and vitamin D in adult patients receiving glucocorticoids effectively retards lumbar and forearm bone loss.588 The reported adverse effects included mainly constipation (calcium) and hypercalcemia and hypercalciuria (calcitriol), although these may be less frequent with physiologic doses. However, the clinical significance of these findings needs interpretation in light of the fact that none of the studies was able to demonstrate any significant decrease in fracture incidence. This is probably a result of the lack of power for detection of infrequent events in these relatively small studies. Furthermore, because none of the controlled studies included children with rheumatic diseases, the generalizability of results to this group of patients also requires caution. However, several open studies suggest that some children with rheumatic disease receiving glucocorticoids may also benefit from calcium and vitamin D supplementation.589–592 The bisphosphonates have also been studied as a potential treatment for glucocorticoid-induced osteoporosis. Etidronate, pamidronate, alendronate, and risedronate have been shown in randomized controlled trials to increase lumbar spine bone mineral density in adult patients receiving long-term glucocorticoids for a variety of diseases.593–597 However, once again, these trials did not include children and did not demonstrate any significant reduction in fracture incidence, which is the most clinically relevant outcome. Bisphosphonates have been studied in children with osteogenesis imperfecta and appear to be of benefit in reducing bone resorption, increasing bone density, and reducing the chronic bone pain associated with this condition.598–600 In addition, they have been found to be useful and safe in open-label studies of children with idiopathic juvenile osteoporosis601 and osteoporosis associated with connective tissue diseases or induced by glucorticoids.602 In summary, although much is known about the mechanisms of glucocorticoid-induced osteoporosis, knowledge about how best to prevent and treat this complication, particularly in children, is somewhat limited. Standards of practice in this area are still evolving, but include, at least, treatment with calcium and vitamin D. Prospective trials evaluating prevention and treatment of glucocorticoid-induced osteoporosis in children are also needed.

Preventing Acute Adrenal Insufficiency (Addisonian Crisis) The short-term use of glucocorticoids for days or a few weeks does not lead to adrenal insufficiency on cessation of treatment. However, prolonged therapy may lead to

TABLE 5–19 Systemic Administration of Glucocorticoid Drugs Schedule

Advantages

Disadvantages

Divided daily doses Single daily dose Alternate-day dose IV pulse therapy

Better disease control Good disease control; fewer side effects Fewer side effects Less long-term toxicity

More side effects May not control severe disease Less disease control Acute toxicities

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suppression of pituitary-adrenal function that can be slow in returning to normal. This is potentially the most serious and life-threatening adverse effect associated with glucocorticoid therapy. The magnitude of the effect on adrenal function of relatively low amounts of glucocorticoid, especially if given over prolonged periods, is often underestimated (Table 5–20). However, the actual doses and duration of therapy that are associated with this suppression and the length of the recovery period after cessation of therapy are not well defined.603,604 Furthermore, some evidence suggests that a component of adrenal insufficiency may be a result of the underlying inflammatory process in some patients.605 If not recognized, suppression of the hypothalamic-pituitary-adrenal axis as a consequence of chronic glucocorticoid administration places the child at risk for vascular collapse, adrenal crisis, and death in situations that demand increased availability of cortisol.606 Under conditions of stress (serious infection, trauma, surgery), all children who may be at risk for hypothalamic-pituitary-adrenal axis suppression require additional glucocorticoids. Glucocorticoid supplementation should be prescribed before surgery in any patient who has received significant amounts of glucocorticoids at any time during the preceding 12 months (possibly as long as 36 months).606 For an elective procedure, a “steroid prep” consists of dexamethasone (0.05 to 0.15 mg/kg/24 hours) before the procedure in four divided intramuscular doses given 6 hours apart, and hydrocortisone (1.5 to 4.0 mg/kg/ 24 hours) as a continuous intravenous infusion beginning at the time of surgery and continuing for 24 hours postoperatively or until the child has recovered or is able to take prednisone again by mouth. This regimen is based on requirements for hydrocortisone during stress. Hydrocortisone (0.36 mg/kg/24 hours) is needed for physiologic maintenance. During maximal stress, 1.5 to 4.0 mg/kg/24 hours is required. Dexamethasone sodium phosphate (0.75 mg has a mineralocorticoid effect approximately equivalent to 20 mg hydrocortisone) is given preoperatively because of its long half-life; hydrocortisone is used during the procedure because of its immediate biologic availability. These recommended doses should be modified according to the magnitude of the stress and the severity and duration of suppression of the hypothalamic-pituitary-adrenal axis by exogenous steroid administration. The requirement of increased amounts of glucocorticoid during acute stress should be explained to the parents. In addition, each child should carry a card or wear a necklace or bracelet indicating that glucocorticoid medication is being taken. Such a warning can be of great

TABLE 5–20

Suppression of the Hypothalamic-PituitaryAdrenal Axis by Glucocorticoid Drugs In a 70-kg (1.73 m2) adult, prednisone in a daily dose of ≤5 mg given in the morning Does not suppress ≤5 mg given at night May suppress 7.5–15 mg for 1 mo Causes variable suppression >15 mg for 1 wk or longer Causes suppression

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value to emergency medical teams if the patient is involved in an accident.

High-Dose Intravenous Glucocorticoid Therapy Intravenous glucocorticoid “pulse” therapy is sometimes used to treat the more severe, acute, systemic connective tissue diseases such as SLE, JDM, and vasculitis.607–609 It has also been used to treat the refractory systemic features of systemic-onset JRA.610–613 The rationale of this approach is to achieve an immediate, profound antiinflammatory effect and to minimize toxicity related to long-term continuous therapy in moderate to high daily doses. The main benefit appears to be rapid clinical improvement that lasts for about 3 weeks after a single bolus. This may be useful in the context of concurrent treatment with a disease-modifying agent, which may take several weeks or months to begin to exert its effect. Although oral pulse regimens have been reported,614 most publications deal with studies in which intravenous pulse therapy has been used. Methylprednisolone has been the drug of choice, given in a dose of 10 to 30 mg/kg per pulse up to a maximum of 1 g, administered according to a variety of protocols (Table 5–21): a single administration repeated as clinical circumstances warrant, a pulse each day for 3 to 5 days, or alternate-day pulses for three doses. Intravenous glucocorticoid pulse therapy, although perhaps efficacious in selected circumstances (no controlled trials have been reported in children), may be associated with potentially serious complications (Table 5–22). The most frequently reported short-term adverse effect in children is abnormal behavior in up to 10% of patients.563 These behavioral changes included altered mood, hyperactivity, psychosis, disorientation, and sleep disturbances. Nonbehavioral adverse effects included headache, abdominal complaints, pruritus, vomiting, hives, hypertension,

TABLE 5–21

Suggested Protocol for Administration of Intravenous Methylprednisone Dose Methylprednisolone up to 30 mg/kg (maximum 1 g) Preparation Prepare drug with diluent provided with package Calculated dose is added to 100 mL 5% dextrose in water and infused over 1–3 hr Monitoring Temperature, pulse rate, respiratory rate, blood pressure before beginning infusion Pulse and blood pressure every 15 min for first hour, every 30 min thereafter Slow rate or discontinue infusion, and increase frequency of monitoring, if there are significant changes in blood pressure or pulse rate Side Effects Hypertension or hypotension, tachycardia, blurring of vision, flushing, sweating, metallic taste in mouth

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TABLE 5–22

Potential Acute Toxicities of Intravenous Glucocorticoid Pulse Therapy Cardiac arrhythmia secondary to potassium depletion Hypertension secondary to sodium retention Acute psychosis, convulsions Hyperglycemia with or without ketosis Anaphylaxis Infection Osteonecrosis

bone pain, dizziness, fatigue, lethargy, hypotension, tachycardia, and hyperglycemia.563 Potential longer-term effects, such as influences on bone metabolism and risk of AVN, have not been systematically studied. Although there have been a number of reports of AVN associated with intravenous-pulse methylprednisolone,615,616 a retrospective cohort study of patients with rheumatoid arthritis did not find an increased risk of AVN in those treated with pulse methylprednisolone.617

Intra-articular Steroids Injection of long-acting glucocorticoids directly into inflamed joints has emerged as a major advance in the management of various types of arthritis. Although intraarticular steroid (IAS) therapy has not been studied in the randomized controlled clinical trial setting, there is accumulating evidence for its efficacy and safety in children (i.e., a number of uncontrolled, prospective cohort studies).618–624 However, it is difficult to summarize the results of the available studies because of the variability in the populations studied and in the type, dose, and frequency of steroids used; the lack of control groups; and the variability in the assessment of outcomes, which often were not blinded and did not use standard outcome measures or lengths of follow-up. IAS therapy has been used most often in children with oligoarticular disease; indications for use have included lack of response to NSAIDs given in optimal dosage for 3 months or longer; significant NSAID toxicity; and the presence of joint deformity, growth disturbance, or muscle wasting. These drugs may also have a role as an alternative to NSAIDs in children with oligoarticular disease. In polyarticular disease, multiple IAS injections at one time can be used as a temporizing measure while awaiting response to second-line agents given systemically. IAS may also be useful as an alternative to increasing systemic therapy in children with polyarticular disease who have significant inflammation in only a few joints. Virtually all patients experience rapid resolution of symptoms and signs of joint inflammation within a few days after injection. About two thirds achieve remission for at least 12 months after a single injection.619,620 The duration of response seems to be longer in children with oligoarticular JRA than in those with polyarticular- or systemic-onset disease and in those with other forms of arthritis (e.g., spondyloarthropathies).625,626 Younger patients and those with shorter disease duration achieved longer remissions after IAS injection,618 as did patients with higher mean erythrocyte sedimentation rates in another study.627 Early use of intra-articular corticosteroid injections may result in less leg-length discrepancies in patients with asymmetric pauciarticular JRA.628 Neidel and associates629 reported a 2-year remission rate of 58% after a single injection of 1 mg/kg (maximum 40 mg) of triamcinolone hexacetonide into inflamed

hip joints; responses were better in children with pauciarticular or RF-negative polyarticular-onset disease (65%) compared to those with RF-positive polyarticular- or systemic-onset JRA.

Type of Steroid, Dosage, and Frequency of Injection A variety of preparations are available for intra-articular injection. The most frequently studied agents in children are the least soluble and hence longest-acting forms of injectable steroid: triamcinolone hexacetonide (THA)618,619,621and triamcinolone acetonide.620 These agents are completely absorbed from the site of injection over a period of 2 to 3 weeks. Because of its lower solubility, THA is absorbed more slowly than triamcinolone acetonide, thus maintaining synovial levels for a longer period and creating lower systemic glucocorticoid levels.630 THA is preferred by most pediatric rheumatologists. In a recent comparative study in patients with oligoarticular JIA, THA was found to be more effective than triamcinolone acetonide at equivalent doses.631 Intra-articular THA is superior to betamethasone632 and methylprednisolone.633 The dose of THA used in clinical studies has varied: Some data indicate that higher doses (about 1 mg/kg) may be associated with a better response.618 Although there are no hard and fast rules regarding the choice of steroid, the dosage and frequency of injection have been outlined. In general, children who weigh less than 20 kg receive 20 mg THA in large joints. Those weighing more than 20 kg receive 30 to 40 mg THA in the hips, knees, and shoulders and 10 to 20 mg in the ankles and elbows. In smaller joints such as the wrist, midtarsal, and subtalar joints, 10 mg THA is used. For injections into tendon sheaths and small joints of the hands and feet, 0.25 to 0.50 mL of a combination of methylprednisolone acetate mixed 1:1 with preservative-free 1% lidocaine (Xylocaine) is recommended. The shorter-acting steroid is associated with less risk of damage to tendon sheaths or of local soft tissue atrophy caused by leakage of steroid from the smallervolume joints. Repeated injections into the same joint are not performed more than three times per year, although there are few data on which to base this recommendation. There are also no controlled studies in children examining whether postinjection rest has a role. Although full immobilization of the injected joint is common practice in some clinics, the author’s recommendation is to limit ambulation for the first 24 hours and to avoid high-impact physical activity in the 24 to 72 hours after a joint injection. Adverse Effects Despite initial reservations about the safety of IAS therapy in children, clinical studies indicate an overall favorable adverse-effect profile. Iatrogenic septic arthritis is always a potential risk but has never been reported in children. It occurs very rarely in adults and can be avoided with aseptic precautions.633 Transient crystal synovitis occurs in a small proportion of patients.620 It is very similar to gouty arthritis and is selflimited, with resolution of symptoms within 3 to 5 days in most cases without any intervention.622 The most frequent adverse effects are atrophic skin changes at the site of injection, particularly of small joints such as wrists and ankles in young children, and asymptomatic calcifica-

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tions on radiographs in joints after multiple injections.625 The frequency of these skin changes ranges from 5.6% of knees injected, to 16% of ankles, 22% of wrists, and 50% of metatarsophalangeal joints.634 The skin changes are attributed to leakage of long-acting steroids into subcutaneous tissues and can be minimized by clearing the needle track with injection of saline or local anesthetic as the needle is withdrawn from the joint. Most skin changes eventually resolve.619,634 Radiographic reviews have demonstrated joint calcifications in 6% to 50% of injected joints.635,636 These are usually asymptomatic, but in one case surgical removal was required because of the size of the calcification.637 One of the main reservations about the use of IAS in young children was based on the theoretic potential for cartilage toxicity. Cartilage damage occurred after intra-articular injection of steroids in the rabbit model but was not reproduced in higher species.633 Clinical magnetic resonance imaging studies in children to assess cartilage integrity up to 13 months after steroid injection of single joints demonstrated no toxic effects on cartilage and no detrimental effects on statural growth.638,639 Some children with multiple steroid injections (more than five per joint) who are monitored for longer periods (6 to 18 years) may have nonspecific abnormalities of cartilage on magnetic resonance imaging.640 The clinical significance of these findings is not clear.

Although the majority of adverse effects associated with IAS injections are local, they are also associated with some systemic effects. Children develop transient suppression of endogenous cortisol production lasting 10 to 30 days after IAS injection.641,642 Younger children may undergo a more prolonged period of suppression. However, the clinical significance of this finding in terms of effects on linear growth or actual risk of adrenal crisis at times of stress is not known. Although these complications have not been reported after single injections, whether there is any risk after multiple injections, particularly in younger children, needs further study. The systemic absorption of steroid may also be associated with altered salicylate kinetics, resulting in a transient fall in serum salicylate levels. Diabetic children may require a temporary increase in insulin requirements.

Cytotoxic Agents Cytotoxic drugs prevent cell division or cause cell death. They act primarily on rapidly dividing cells such as those of the immune system, particularly T lymphocytes, and are therefore immunosuppressive. Cytotoxic drugs have both immediate anti-inflammatory actions and delayed immunosuppressive effects. Pharmacologic actions are usually considered to be either specific or not specific for the cell cycle phase. The cell cycle consists of the G1 presynthetic phase, the S phase (synthesis of DNA), the G2 resting (or postsynthetic) phase, and mitosis. 6-Mercaptopurine and azathioprine inhibit biosynthesis of purine and nucleotide interconversions and act during the G1 and S phases in proliferating cells. Mycophenolate mofetil (MMF) reduces the pool of guanine nucleotide, thus interfering with purine biosynthesis; it also acts in the G1 and S phases. Alkylating agents cross-link DNA and act during all phases of the cell cycle,

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whether or not a cell is replicating. These agents are maximally effective in inhibiting immunologic responses when their administration coincides with the period of proliferation of the specific immunologically competent cells. Although cytotoxic drugs have been used to treat children who are seriously ill with rheumatic diseases after other modes of therapy have proved ineffective, there have been no adequately controlled trials in such patients. In most instances, the effects of these drugs are delayed; therefore, they have proved more valuable in moderate- to long-term therapy than in an acute crisis. The potential toxicity of these drugs is substantial. Although extensive experience has been accumulating with the use of these agents, each child’s illness must be considered thoroughly before drugs from this class are recommended. These agents are not approved for unrestricted use in children with rheumatic diseases and should be used only by physicians who are familiar with their administration, toxicity, and expected benefits. Occasionally, a cytotoxic agent is used for its steroid-sparing effect.

Azathioprine Azathioprine (Fig. 5–19), a purine analogue, is inactive until it is metabolized to 6-mercaptopurine (6-MP) by the liver and erythrocytes.643 Hypoxanthine phosphoribosyl transferase metabolizes 6-MP to 6-thioinosinic acid, which suppresses the synthesis of adenine and guanine, thereby interfering with DNA synthesis. Furthermore, 6-inosinic acid inhibits phosphoribosyl pyrophosphate conversion in purine nucleotide synthesis, conversion of inosinic acid to xanthylic acid by purine nucleoside phosphorylase, and incorporation of nucleotide triphosphates into DNA. Azathioprine suppresses cell-mediated immune functions and inhibits monocyte functions.644–647 These immunosuppressive effects are related primarily to inhibition of T cell growth during the S phase of cell division. A measurable decrease in antibody synthesis occurs with long-term administration; occasionally, a decrease in serum antibody concentration occurs. Approximately 50% of the drug is absorbed after oral administration, of which one third is protein bound.643 The plasma half-life is approximately 75 minutes. The kidneys are the major route of excretion. Azathioprine crosses the placenta. However, because the fetal liver lacks the ability to convert azathioprine to its active metabolites, the fetus is generally protected from adverse effects, although rare cases of fetal bone marrow suppression have been reported.648 It is best to avoid using azathioprine during pregnancy, although this is not always possible. Azathioprine does appear in breast milk, and nursing is not recommended.649

N

S N

N N

O2N

CH3

N

N H

■ Figure 5–19 Structure of azathioprine.

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Toxicity to the GI tract (oral ulcers, nausea, vomiting, diarrhea, epigastric pain) is common.650 Toxicity to the liver (mild elevation of serum concentrations of liver enzymes, cholestatic jaundice), lung (interstitial pneumonitis), pancreas (pancreatitis), or skin (maculopapular rash) is uncommonly associated with azathioprine therapy. Dose-related toxicity to the bone marrow results in leukopenia and, less commonly, thrombocytopenia and anemia. An idiosyncratic arrest of granulocyte maturation that occurs shortly after initiation of therapy has been described and results from reduced activity of the enzyme thiopurine methyltransferase (TPMT).651,652 TPMT is responsible for inactivating 6-MP. There is genetic polymorphism for TMPT, and at least eight alleles have been identified. The majority of the population has high enzymatic activity; approximately 0.03% of the population is deficient.653 These latter patients may rapidly develop severe leukopenia on exposure to azathioprine. Lower levels of enzymatic activity have been observed in AfricanAmericans compared with Caucasian-Americans.654 Testing of TMPT levels is now available and should be considered for patients who develop severe leukopenia while taking azathioprine. The bone marrow effects of azathioprine may be increased by concomitant use of trimethoprim.655 Although the risk of malignancy theoretically increases in patients treated with azathioprine, the long-term data are not conclusive. Data are insufficient with respect to childhood rheumatic diseases, but in adults with rheumatoid arthritis treated with azathioprine, the risk of malignancy did not appear to be greater than that in similar patients who did not receive azathioprine.656–658 The use of azathioprine has been reported anecdotally in many pediatric rheumatic diseases and in series of patients with JRA or SLE.659,660 Starting doses should be 1 to 1.5 mg/kg/day, increasing as needed and as tolerated to 2 to 2.5 mg/kg/day (Table 5–23).

Mycophenolate Mofetil MMF, an agent initially used with great success in patients with solid organ transplants, has been found to be effective

TABLE 5–23

Guidelines for Use of Azathioprine

Dose 0.5–2.5 mg/kg/day in a single dose (taken with food) for 1 yr or longer

in a variety of autoimmune diseases (Fig. 5–20). Mycophenolic acid (MPA), a fermentation product of Penicillium stoloniferum, is the active immunosuppressant species, and MMF was developed to increase the oral bioavailability of MPA. Its major effect is on T and B lymphocytes, for which it is relatively selective. Action of MPA is mediated through noncompetitive binding to inosine monophosphate dehydrogenase, an enzyme critical for de novo synthesis of guanine nucleotide, a pathway on which T and B lymphocytes are primarily dependent. In vitro MPA inhibits T- and B-cell mitogen proliferation,661–663 antigen-specific antibody response of memory B cells,664,665 suppression of the humoral immune response,666 and attachment of monocytes to endothelial cells.667 MPA enhances vascular cell adhesion molecules induced by TNF-α and E-selectin surface expression on endothelial cells.668 It does not inhibit IL-2 production, IL2 receptor expression, phagocytic activity, or secretion of type 1 helper T cell (Th1) cytokines. Some of the improvement seen in renal disease in MRL/lpr mice may be associated with inhibition of renal nitric oxide production.669,670 Because its effect appears to be at a late stage of T cell activation, MMF can be used safely with cyclosporine and tacrolimus. MMF is rapidly absorbed after oral administration and is hydrolyzed in the liver to the biologically active MPA. MPA is 8% albumin bound, and the activity of the drug results from the unbound MPA. Peak plasma levels occur 1 to 3 hours after a single dose, with a second peak at 6 to 12 hours as a result of enterohepatic circulation (Table 5–24). The oral bioavailability is approximately 94%. The elimination half-life is approximately 17 hours after oral administration.671 Because of its extensive binding to albumin, MMF may interact with other albumin-bound drugs. Antacids containing aluminum and magnesium decrease absorption and should not be administered simultaneously. There may be competition for renal tubular secretion with acyclovir. The effective adult dose in solid organ transplantation is 2 g/day in two divided doses. The dose used to prevent solid organ transplant rejection in children has been 46 mg/kg/day.671 Cyclosporine and, to a lesser extent, tacrolimus alter the kinetics of MMF so that higher doses are required in the transplantation setting.672 In children with autoimmune diseases, mean doses reported have included 900 mg/m2/day,673 and 22 mg/kg/day.674 Individual pharmacokinetic profiling is available and can

Clinical Monitoring Clinical evaluation at 1–2 mo and then every 3 months (or more often if disease uncontrolled)

O

OH

CH3 O

Laboratory Monitoring CBC with WBCC, differential, and platelet count weekly until stable dose is achieved, then monthly Hepatic enzymes, BUN, serum creatinine initially and then monthly Discontinue if WBCC <3500/mm3, platelet count <100,000/mm3, or elevated liver enzymes BUN, blood urea nitrogen; CBC, complete blood count; WBCC, white blood cell count.

N O

O OCH3 CH3 Mycophenolic acid portion Morpholino portion

■ Figure 5–20 Structure of mycophenolate mofetil.

O

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TABLE 5–24

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Guidelines for Use of Mycophenolate Mofetil

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Guidelines for Use of Daily Cyclophosphamide

Dose

Dose

Starting dose usually 250 mg bid, work up to 1 g bid as a maximum dose (see text for dosing guidelines) At predicted optimal dose, consider measuring trough levels and area under the curve and adjusting dose accordingly

0.5–2.0 mg/kg/day in a single oral dose 0.5–2.0 mg/kg/day as an IV pulse (with ample IV fluids for 24 hr) Encourage fluid intake to minimize risk to bladder Encourage frequent emptying of bladder

Clinical Monitoring

Clinical Monitoring

Clinical evaluation every 1–2 mo and then every 3 months (or more often if disease uncontrolled)

Clinical evaluation every month Laboratory Monitoring

Laboratory Monitoring CBC with WBCC, differential, and platelet count 4–6 wk Discontinue if WBCC <3500/mm3, platelet count <100,000/mm3, falling hemoglobin not related to disease activity CBC, complete blood count; WBCC, white blood cell count.

CBC with WBCC, differential, and platelet count and urinalysis every week until stable dose is achieved, then every month Hepatic enzymes, BUN, serum creatinine initially and then every month Discontinue drug if WBCC <1500/mm3 (1.5 × 109/L), platelet count <100,000/mm3 (100 × 109/L), hematuria BUN, blood urea nitrogen; CBC, complete blood count; WBCC, white blood cell count.

be especially helpful in determining the lowest effective dose in patients experiencing side effects.675,676 Adverse effects of MMF include toxicity on the GI tract, hematologic effects (leukopenia, anemia, thrombocytopenia, pancytopenia), and opportunistic infections. The GI side effects are usually improved by giving the dose three or four times a day instead of twice a day, or by reducing it. Hematologic toxicity usually responds to therapy cessation within 1 week. The incidence of lymphoma has been reported at 0.6%, similar to that for azathioprine.677 Although early reports of MMF use in patients with rheumatoid arthritis showed promise,678 the availability of newer agents seems to have had an effect on further study in this area. However, MMF is being used increasingly in patients with SLE,674,679–684 systemic vasculitis,673,677,685 (although flares may be common686), or inflammatory eye disease.687,688 MMF crosses the placenta and is teratogenic in rats and rabbits, and one case with severe fetal malformations has been reported.689 If immunosuppression is required, a switch to azathioprine is recommended. No human data are available regarding breast feeding at this time

Cyclophosphamide Cyclophosphamide, an alkylating agent, is a nitrogen mustard derivative (Fig. 5–21). It is well absorbed after oral administration and may also be given intravenously (Table 5–25). It is inactive until metabolized, principally in the liver, by the cytochrome P-450 mixed-function oxidase system to inactive intermediates and the active metabolite phosphoramide mustard. Phosphoramide mustard covalently binds to guanine in DNA, destroying the purine ring and thereby preventing cell replication.690,691 Cyclophosphamide potentially acts on all cells, O

CH2CH2CI P

NH

O

N

H2O

including those that are mitotically inactive (G0 interphase) at the time of administration (e.g., memory T cells).692,693 Excretion of the drug is primarily by the kidney, and the dose must be reduced in patients with renal impairment (Table 5–26). Intravenous doses should be lowered by 20% to 30% in patients with severe renal insufficiency.694 Because cyclophosphamide is dialyzable, it is important to delay hemodialysis until at least 12 hours after intravenous administration of the drug.694 Acrolein, the other principal metabolite, is thought to be therapeutically inactive but is responsible for bladder toxicity. The half-life of cyclophosphamide is approximately 7 hours. Cyclophosphamide exerts anti-inflammatory actions by its effects on mononuclear cells and cellular immunity. Alkylating agents cause B- and T-cell lymphopenia. B cells appear to be more sensitive than T cells to the effects of cyclophosphamide.695 It has been suggested that the route of administration influences the nature of the effects of this drug; daily oral low-dose therapy may more profoundly affect cell-mediated immunity, whereas intermittent high-dose intravenous therapy predominantly affects B cell immunity.696,697 In humans, IgG and IgM synthesis is depressed, and there is a measurable decrease of serum antibody concentration after chronic administration.692,693

TABLE 5–26

Recommended Reductions of Cyclophosphamide Dose in Patients with Impaired Renal Function Serum Creatinine Concentration (mmol/L) <250 250–500 >500

Oral Cyclophosphamide Dose (mg/kg/day) 2 1.75 1.5

CH2CH2CI

■ Figure 5–21 Structure of cyclophosphamide.

Adapted from Luqmani RA, Palmer RG, Bacon PA: Azathioprine, cyclophosphamide, and chlorambucil. Clin Rheumatol 4: 595, 1990.

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The alkylating agents have prominent toxic effects.698–706 Short-term side effects are common; although troublesome to the child, they are seldom serious. These include anorexia, nausea and vomiting, and alopecia. Alopecia appears to be related to dose and duration of treatment and is usually reversible. Pulmonary fibrosis has been reported in a small number of patients receiving daily cyclophosphamide therapy.706a,b Leukopenia and thrombocytopenia are the most common adverse reactions, although with careful monitoring they are seldom of clinical significance. The cyclophosphamide dose should be adjusted to maintain the total granulocyte count at 1500/mm3 (1.5 × 109/L) or higher. The nadir of granulocytopenia with intravenous therapy occurs between the first and the second weeks of therapy, and the dose should be adjusted accordingly based on the complete blood count and differential white blood cell count obtained on days 7, 10, and 14 after intravenous cyclophosphamide administration. Lymphocyte counts lower than 500/mm3 (0.5 × 109/L) are also an indication to lower the dose. Glucocorticoids probably aid in protecting bone marrow from the neutropenia-inducing effects of cyclophosphamide. Cyclophosphamide is administered in one of two ways: either orally each day or by intravenous bolus every 2 to 4 weeks (Table 5–27). Intravenous pulse administration is less toxic and at least as efficacious for lupus nephritis707; in some systemic vasculitides, it is not clear whether the intravenous route is as effective as oral administration.697 Bladder toxicity (cystitis, fibrosis, transitional cell carcinoma) is a major risk of cyclophosphamide therapy and

TABLE 5–27

Suggested Protocol for the Administration of Intravenous Cyclophosphamide Dose 0.5–1.0 g/m2 cyclophosphamide Preparation Start IV with 5% dextrose in water Administer 2 L/m2 of IV fluid as 5% dextrose in water or 2/3 5% dextrose in water and 1/3 normal saline over next 24 hr; start hydration 4 hr before administration of cyclophosphamide MESNA (30% of cyclophosphamide dose) IV in 240 ml of 0.2 normal saline at 10 mL/hr over 24 hr, starting immediately after cyclophosphamide Ondansetron (0.15 mg/kg per dose) IV or PO 30 min before cyclophosphamide and every 8 hr until infusion is complete Dilute cyclophosphamide to 10 mg/mL in 5% dextrose in water and infuse prescribed dose over at least 1 hr (to minimize nausea and vomiting) Monitoring Pulse, blood pressure, and respiratory rate every 30 min during infusion, then every 4 hr for next 24 hr Urinalysis before and after infusion Monitor urinary output: Empty bladder every 2–4 hr. If urinary output falls to less than 50% of IV input over any 4-hr period, give furosemide 1 mg/kg IV. Repeat at 2–4 mg/kg in 2 hr, if necessary. MESNA, 2-mercaptoethanesulfonic acid.

results from prolonged contact of acrolein with the bladder mucosa.701–703 In rats, the toxicity appears to be mediated through nitric oxide produced by inducible nitric oxide synthase.708 To prevent cystitis, adequate hydration and frequent voiding must be emphasized for children receiving daily cyclophosphamide. Persistent nonglomerular hematuria is an indication for cystoscopy; if cystitis is observed, the dose should be reduced or the drug stopped. Intravenous pulse therapy reduces the risk of toxicity, including hemorrhagic cystitis, and confines those risks to a short period each month instead of every day. Prophylactic 2-mercaptoethanesulfonic acid (MESNA) should be considered a part of any intravenous cyclophosphamide protocol to minimize contact of acrolein with the bladder mucosa. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported in patients receiving large doses of cyclophosphamide and is exacerbated by the large fluid load that must be administered.709 It does not matter which hydration solution is used.710 With the large doses of cyclophosphamide administered by intravenous bolus, children must be encouraged to empty their bladders every 2 hours and must be awakened during the night to do so; if this is not possible, furosemide should be given and catheterization considered to prevent significant contact of the bladder mucosa with acrolein. Nausea and vomiting can be a significant problem; prophylactic use of a potent antiemetic (e.g., ondansetron) is encouraged as part of intravenous protocols. An important consideration with the use of alkylating agents is their effect on fertility for both males and females.711 The stage of sexual maturity is critical in terms of inducing gonadal dysfunction; the further beyond puberty, the greater the chance of infertility with an equivalent dose of cyclophosphamide.712 In female patients with lupus nephritis, amenorrhea and oligomenorrhea occur more frequently with higher total dose and with increased age at administration.713–716 Use of intravenous bolus administration at currently recommended doses results in a much lower total cumulative dose than does daily oral administration and therefore should be the preferred route, presuming equivalent effectiveness. Ovarian destruction attributable to cyclophosphamide was reported in one child.698 Luteinizing hormone-releasing hormone (LHRH) may protect the ovary against cyclophosphamide-induced damage and may be effective in patients treated with cyclophosphamide, as was demonstrated in a study of women with lymphoma who received gonadotropin-releasing hormone agonist.717 Protocols using the gonadotropin-releasing hormone agonist analogue preserved ovarian function in young women treated with cyclophosphamide,718 as well as in adolescents with cancer.719 Oocyte or ovarian tissue cryopreservation holds potential promise for the future. In male patients, sperm cryopreservation is suggested before cyclophosphamide treatment is instituted. Additional approaches include the use of testosterone.720 Cyclophosphamide is associated with an increased risk of malignancy in adults with rheumatoid arthritis, a risk that is dose related and increases with duration of follow-up. One case-control study demonstrated a fourfold

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elevation of myeloproliferative disorders,705 and there are increased risks of bladder and skin cancer.721 The incidence of bladder cancer in adults with Wegener’s granulomatosis treated with cyclophosphamide is 5% at 10 years and 16% at 15 years; the incidence is related to both total dose and duration of treatment. Nonglomerular hematuria identified a subgroup of patients at high risk for bladder cancer.722 Short courses of very high doses of cyclophosphamide have been used either as primary therapy in myeloablative doses for SLE and aplastic anemia723 or as part of a transplantation protocol for patients with autoimmune disease. Monthly intravenous cyclophosphamide is used commonly in patients with severe lupus nephritis (World Health Organization [WHO] class IV) and other lifethreatening complications of lupus. However, because of the well-known toxicity of cyclophosphamide and the effectiveness of agents such as MMF and azathioprine in maintaining remission, it has been recommended that the duration of intravenous treatment be shortened to as little as 3 months in some patients with lupus nephritis.724 In addition, cyclophosphamide is well accepted in the treatment of severe necrotizing and granulomatous vasculitis. Cyclophosphamide crosses the placenta and is teratogenic; it is contraindicated both during pregnancy and during breast feeding.649

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COOH

CH2CH2CI N

CH2CH2CH2

CH2CH2CI

■ Figure 5–22 Structure of chlorambucil.

for very narrow indications. It is the drug of choice for amyloidosis complicating inflammatory disease and occasionally for severe uveitis.725 However, the very high risk of malignancy, ranging up to 7.5%,726 precludes its use in all but the most severe cases. In addition to the risk of malignancy, male infertility is very common once total doses of 25 mg/kg are reached.727 Thrombocytopenia and infection are also common.725,728

Cyclosporine Cyclosporine (Fig. 5–23), a cyclic peptide of fungal origin, has been shown to have profound effects on the immune system.729 The observation that cyclosporine could virtually eliminate mitogen-induced proliferation by T cells but had little effect on other cell types730 indicated the potential of this drug in the treatment of immunologically mediated disease. It has had a major impact on the prevention of solid organ transplant rejection. Cyclosporine is inactive until complexed with its intracellular receptor, cyclophilin. In the process of T- or B-cell activation, cell receptor signaling leads to a release of intracellular calcium, which binds to calmodulin, activating the protein serine/threonine phosphatase calcineurin.731 Once activated, calcineurin stimulates the translocation of nuclear factor of activated T cells (NF-AT), a transcription factor that is an important stimulus for IL-2 gene transcription732 and cell-mediated immune responses.730,733–735 The cyclosporinecyclophilin complex binds to calcineurin, thus inhibiting

Chlorambucil Chlorambucil (Fig. 5–22), like cyclophosphamide, is an alkylating agent that preferentially reduces B cell numbers, with less effect on memory T cells and natural killer cells, and acts by cross-linking macromolecules, thereby interfering with several cellular functions. It is usually prescribed for oral administration at a dose of 0.1 to 0.2 mg/kg/day but can be given intravenously as well. Because of serious toxicity, use of chlorambucil is reserved

■ Figure 5–23 Structure of cyclosporin.

CH3

H C C

H CH3

CH3 CH

CH2

CH3

H CH3 H

CH3 CH CH3

CH2 CH3

N

C (10) CO C

(9)

N

(8)

OC

C

CH3

CH3

CO

N

CH

C (11)

H C

CH2

HO H

C

CH3

CH3 N

H

C

H CO

C (1)

N H

O

CH3 CH2 CH3 H CH2 C C N (2) (3) CO O N

N H

CH3

H

CO

(7)

H

C

N H

CH3

(6) C

C

N

O (5)

H

C

N

C

H O

CH2

CH CH3

CH3

CO

H C

H

CH3

CH CH3

CH3

(4)

CH2 CH3

CH CH3

CH3

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the early phase of T cell activation and IL-2 production. Cyclosporine inhibits the production of IL-3, IL-4, IFNγ,736,737 and IL-15,738,739 and it enhances the production of transforming growth factor β1 protein.740 It is also antiangiogenic, as demonstrated by the inhibition of vascular endothelial growth factor (VEGF) expression in several systems.741,742 Cyclosporine may also result in immune suppression by inhibiting degradation of I-κB.743 In addition, it may modulate anti-inflammatory effects by inhibiting monocyte production of tissue factor, a potential stimulus of the coagulation cascade via inhibition of NF-κB.744 It may also result in apoptosis of T and B cells.745 Whether cyclosporine affects antigen presentation is uncertain. Some studies have shown that the drug has no effect on macrophage function in antigen presentation,746 whereas others have suggested that the drug interferes with antigen presentation by dendritic cells747 and Langerhans’ cells.748 Cyclosporine is incompletely and variably absorbed from the GI tract, bound principally to serum albumin and erythrocytes, metabolized by the liver, and excreted in the bile. It has a half-life of approximately 18 hours. A microemulsion formulation of cyclosporine has been developed to improve absorption and bioavailability749; this preparation has more consistent interpatient and intrapatient pharmacokinetics. Cyclosporine crosses the placenta and is present in breast milk. It is important to note the several significant drug interactions associated with cyclosporine480 and the considerable toxicity associated with the use of this drug, including impaired renal function,750,751 hypertension, hepatic toxicity,752 tremor, mucous membrane lesions, and nausea and vomiting. Hypertrichosis, paresthesias, and gingival hyperplasia have been observed. Renal toxicity may result in hypertension from interstitial fibrosis or tubular atrophy, even in adults treated with relatively low dosages (3 to 5 mg/kg/day orally). Concomitant use of NSAIDs may exacerbate this toxic effect of the drug. Cyclosporine is effective in the treatment of rheumatoid arthritis, both alone753 and in combination with MTX.754,755 Several open trials have shown improvement in children with JRA, 756–758 JDM, 759 and uveitis. 760,761 The addition of cyclosporine to MTX was associated with significant clinical improvement in 8 of 17 patients with JIA.762 However, side effects are common and often necessitate reduction or discontinuation of treatment, particularly as a result of reduced renal function or hypertension.758 Cyclosporine has been reported to have dramatic beneficial effects in patients with the macrophage activation syndrome.80,81 Patients with membranous lupus nephritis may benefit from cyclosporine treatment,763 as has been documented in pediatric patients with WHO class III or IV lupus nephritis and heavy proteinuria.764 It may be especially helpful as a steroid-sparing agent.765 Despite concern, a case-control series766 did not show any increased risk of malignancy over a 5-year follow-up period in adult patients treated with cyclosporine compared with controls. Current guidelines for cyclosporine use are outlined in Table 5–28. Factors that most commonly limit clinical use of cyclosporine are hypertension and a rise in serum creatinine of greater than 30% from baseline. Unfortunately, long-term renal damage can occur despite normal serum creatinine levels during the course of therapy.749 In the rheumatic diseases, the goal has been to achieve a whole blood trough level between 125

TABLE 5–28

Guidelines for Use of Cyclosporine

Dose 3–5 mg/kg/day orally Clinical Monitoring Blood pressure every week for first month, then monthly Laboratory Monitoring Renal function studies (BUN, creatinine, urinalysis) at start of therapy and every month Hepatic enzymes, CBC with WBCC differential, and platelet count every month Maintain 12 hr whole-blood trough drug levels between 125 and 175 ng/mL (RIA method) Reduce dose if serum creatinine increases by ≥30% BUN, blood urea nitrogen; CBC, complete blood count; WBCC, white blood cell count. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; MCV, mean cell volume; WBCC, white blood cell count.

and 175 μg/mL. It is important to note that grapefruit juice increases cyclosporine and cyclosporine metabolite levels significantly.767

Antibiotics The concept that rheumatoid arthritis was caused by microbial pathogens led to early use of antimicrobial therapy. In fact, it was for that reason that gold was first introduced as a treatment for rheumatoid arthritis. Sulfasalazine was synthesized to take advantage of its antimicrobial properties. Recently, antibiotics have again been considered in the treatment of inflammatory rheumatic disease. Penicillin plays a key prophylactic role in preventing the recurrence of acute rheumatic fever and perhaps in preventing of poststreptococcal arthritis.768 Cutaneous polyarteritis, which may be a streptococcus-related disease, is also often treated with prophylactic penicillin.769 In Wegener’s granulomatosis, treatment with trimethoprim-sulfamethoxazole may prevent disease relapses.770 Studies in rheumatoid arthritis have suggested a role for synthetic tetracycline antibiotics.771 In early disease, minocycline was more effective than placebo772 or hydroxychloroquine.773 The mechanism of action may depend more on the biochemical than on the antimicrobial effect of these agents. Antibiotics do not seem to be effective in enteric reactive arthritis, but they may have a role in urogenital reactive arthritis.774 Although a small pilot study suggested that minocycline might be effective in systemic sclerosis,775 a more recent study refuted those findings.776

Biologic Therapies Intravenous Immunoglobulin Intravenous immunoglobulin (IVIG) is prepared from pooled human plasma. Its effectiveness in the treatment of Kawasaki disease777 has encouraged its use in a num-

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ber of other childhood rheumatic diseases. It is also reported to be of benefit in some cases of JDM778 and systemic-onset JRA,779 although placebo-controlled randomized trials did not show benefit in either systemic- or polyarticular-onset JRA.780,781 There are also many anecdotal reports of improvements in patients with SLE, systemic vasculitides, and autoimmune neuropathies.782 Although IVIG has a good record of safety, anaphylactoid reaction is a risk. Other potential side effects include myalgia, fever, and headache during the infusion and aseptic meningitis 24 to 48 hours afterward.783 Current preparation protocols purify the product so that it is free from contamination with human immunodeficiency virus (HIV), hepatitis C virus, and other known viruses, but there is a theoretic risk of transmission of CreutzfeldtJacob disease as well as other, as-yet unidentified pathogens. Guidelines for IVIG administration are listed in Table 5–29. The mechanisms whereby IVIG exerts its therapeutic effect are not clear and may differ in different situations. Several recent reviews have thoroughly addressed these issues.782,784,785 Potential mechanisms include (1) Fc receptor blockade (in idiopathic thrombocytopenic purpura); (2) inhibition of complement activation and function of the membrane attack complex (in dermatomyositis); (3) inhibition of cytokine production and function (in Kawasaki disease); (4) increased catabolism of IgG mediated by FcRn (IgG transport receptor) blockade (which may be responsible for the rapid reduction in autoantibody levels in autoimmune disease); and (5) generation of anti-idiotype antibodies, reducing the production of pathogenic autoantibodies (in a variety of autoimmune diseases). Its action may be mediated by specific antibodies that neutralize an as-yet unknown causative agent such as a virus. IVIG contains anti-idiotype antibodies that may bind to the idiotype of an antibody involved in the pathogenesis of the disease.786 Such anti-idiotype antibodies have been shown to suppress autoimmune disease in animal models.787

TABLE 5–29

Guidelines for Use of Intravenous Immunoglobulin (IVIG) Dose Up to 2 g/kg Preparation Start IV with normal saline Administration Give IVIG at rate of 0.5 mL/hr for 30 min, then 1.0 mL/kg/hr for 30 min, then 2.0 mL/kg/hr for the remainder Monitor Blood pressure and pulse rate every 15 min for first hour, every 30 min for second hour, every 60 min thereafter Observe Sudden fall in blood pressure (anaphylaxis) Headache, vomiting 18–36 hr after infusion (aseptic meningitis)

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Antibodies to inflammatory mediators, including cytokines, may also have important therapeutic roles. The rapid defervescence that occurs after IVIG administration in Kawasaki disease suggests that interleukins, particularly IL-1 and IL-6, are removed from the circulation or neutralized, or that their production is stopped by some constituent of the IVIG. It is known that normal serum contains antibodies to IL-1α,788 IL-6,789 TNF-α,790 IFN-α2b, and IFN-γ.791 Normalization of T cell number and function has also occurred after administration of IVIG.792 IVIG can neutralize superantigens, which may be involved in Kawasaki disease.793 Another mechanism of action whereby IVIG might exert its beneficial anti-inflammatory effects is a reduction in the expression of adhesion molecules. In JDM, IVIG can decrease the activity of the membrane attack complex.794

Specific Biologic Agents Elucidation of some of the basic mechanisms involved in rheumatoid arthritis has resulted in an understanding of many of the cellular and molecular mechanisms that participate in inflammatory states. Specific biologic agents have been developed that can target one or several steps involved in the immune response. Strategies for intervention (adapted from Wallis and associates795) can be grouped as follows: ■ ■ ■ ■ ■

Tolerance induction Inhibition of MHC/antigen/T cell receptor (TCR) interaction Inhibition of cellular function and cell–cell interaction Interference with cytokines Apoptosis

Although the initial excitement regarding biologic therapy was tempered by either lack of efficacy or severe toxicity, more recent developments justify a great deal of optimism for the development of new, more focused and targeted therapies over the next few years.

Induction of Tolerance Autoreactive T cells that escape thymic deletion during ontogeny can be deleted by at least two peripheral mechanisms of tolerance.796 If the T cells interact with antigen but are not activated, T cell dormancy, or anergy, develops. If type 2 helper (Th2) T cells have the same TCR as the autoreactive clone, cytokines with an antiinflammatory profile will be released and can suppress an antigen-specific Th1 response. This is the principle behind attempts to achieve oral tolerance to an antigen. Reactive Th2 cells can leave the gut and migrate to sites in which the antigen may be localized and are stimulated to release anti-inflammatory cytokines, thereby mediating local immune suppression. Trials of oral administration of type II collagen have been attempted because of the high incidence of autoimmunity to type II collagen in adult rheumatoid arthritis (and in approximately 25% of children with JRA), as well as the success of this approach in a variety of animal models of arthritis in which type II collagen autoimmunity occurred.797 Studies in humans

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have shown varying results, but results seem to be better when lower doses of collagen are administered.798 In an open trial involving 10 patients with JRA who were treated with type II chick collagen, 8 responded; no adverse effects were observed.799 With the advances that have occurred with other therapies, there have been no further studies in this area.

LJP-394 LJP-394 (abetimus sodium) is a molecule consisting of double-stranded DNA (ds-DNA) epitopes that cross-link anti–ds-DNA antibodies in solution or on cell surfaces. In rodents, LJP appears to induce B-cell tolerance by cross-linking anti–ds-DNA surface immunoglobulin receptors on B cells, leading to B-cell anergy or apoptosis. It has been shown to reduce the titers of anti–ds-DNA antibodies in patients with SLE.800 A randomized, double-blind, placebo-controlled trial was performed to examine whether LJP prevents or delays renal flares in patients with SLE and previous renal disease.801 Although the number of renal flares and the time of flares did not differ between the two groups, the time to institute “aggressive treatment” with corticosteroid or cyclophosphamide (or both) was longer, and the number of aggressive treatment courses were fewer in the LJP group. There was a significant reduction in the titer of anti–ds-DNA antibodies and a concomitant, although not significant, rise in the serum complement levels. Patients with high-affinity anti–ds-DNA antibodies had the greatest reduction in antibody titer. The treatment was well tolerated. Although it was not statistically significant, there was a trend toward more thromboembolic events in the LJP-treated group. Clinically important differences in the health-related quality of life were seen in the treatment group.802

Inhibition of MHC /Antigen/T Cell Receptor Interaction The immune response is driven by the processing and presenting of an antigenic peptide by an antigen-presenting cell to a specific TCR in the context of a specific MHC molecule. Any component of this trimolecular complex could theoretically be targeted for biologic modulation. If the initiating antigen were known, an immunization program could be developed to prevent disease, and this is the principle behind oral tolerance (see earlier discussion). TCR vaccines may be one way to prevent or reduce activity of synovial inflammation, as shown in animal models. This strategy would work only if specific variable region (Vβ subtypes could be shown to predominate in synovitis and did not change over time. Early studies in patients with rheumatoid arthritis who were vaccinated with several Vβ subtypes show promise and are continuing.803 Data in children with JRA and spondyloarthropathies suggest that this approach may have some merit.804 Another possible route of attack is to block the MHC site by anti-MHC antibodies.

Inhibition of Cellular Function and Cell–Cell Interaction T cells appear to play a central role in initiating the rheumatoid process in adult disease and in JRA, but their role in continuing to drive the inflammatory process is less clear. Results of early studies using monoclonal T cell–depleting antibodies were disappointing. Initial

clinical improvements, if they occurred at all, were short lived or were associated with profound lymphopenia, precluding further treatment.805,806 These included studies with anti-CD7 monoclonal antibodies (mAbs), CD-5 PLUS (immunotoxin composed of murine anti-CD5 mAbs conjugated to the toxin ricin),807 CAMPATH (humanized αCDw52 mAb),808,809 and cM-T412, an anti-CD4 mAb.810,811 Possible explanations for the lack of efficacy in these studies are that T cells are not necessarily critical for the perpetuation of synovitis; that the specific T cells targeted by monoclonal antibodies are not the ones involved in synovitis; that targets are too nonspecific; and that, although peripheral T cells may be affected, synovial T cells are not.812 One placebo-controlled trial in adult rheumatoid arthritis treated with nondepleting anti-CD4 mAbs showed some efficacy, but unacceptable CD4 lymphopenia and rash precluded further study.813 Generation of the immune response involves not only antigen processing and TCR/MHC interactions but also interactions between molecules expressed on the surface of T cells and on antigen-presenting cells, as well as various adhesion molecules and their companion receptors. Although preclinical studies in animals are encouraging, no studies have been reported to date in humans.814,815

CTLA-4Ig In order to activate resting T cells, two molecular signals are required: (1) the interaction of the TCR with processed peptide, presented in the appropriate MHC setting; and (2) interaction of CD28 on T cells with CD80/86 on the surface of the antigen-presenting cell. There is another high-affinity receptor, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), which can also bind to CD80/86, with a higher avidity than CD28, thereby preventing the second signal required for T cell activation. CTLA-4 immunoglobulin (CTLA-4Ig) is a soluble immunoglobulin receptor fusion protein that consists of the extracellular domain of human CTLA-4 and a fragment of the Fc domain of human IgG.816 By binding to CD28, it can prevent T cell activation. Early preclinical studies showed benefit in rodents with inflammatory synovitis, and initial studies in adults with rheumatoid arthritis showed modest improvement, both when compared with placebo alone817 and also when used together with MTX compared with MTX alone in patients who had an inadequate response to MTX.818 Anti-CD40 Ligand The interaction between CD40 (found mainly on T cells) and CD40 ligand (also known as CD154), is essential in the production of pathogenic autoantibodies and tissue injury in lupus nephritis. Antibodies to CD40 ligand have been shown to improve renal disease, even if well established, in animals with lupus nephritis. Several small studies using anti-CD40 ligand in patients with lupus nephritis have been reported. Various doses of IDEC-131 (a humanized mAb against CD154) were compared with placebo in 85 patients with mild to moderate lupus. Although the treatment was safe and well-tolerated, patients did not improve relative to placebo.819 However, subsequent studies with this agent were halted after the report of a thrombotic event in a patient with Crohn’s disease. In an open-label study

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involving 28 patients with diffuse proliferative lupus nephritis, treatment with a different anti-CD154 antibody, BG9588, resulted in a significant reduction on anti–ds-DNA antibodies, a significant increase in serum C3, and improvements in proteinuria and hematuria.820 However, adverse events, including myocardial infarctions in two young patients, precluded completion of the treatment trial. Therefore, although the concept makes biologic sense, the current preparations cannot be used and require further experimentation.821 Interactions between activated endothelium and leukocytes via adhesion molecules allow leukocytes to leave the peripheral circulation to enter sites of inflammation (e.g., the synovium). The results of early studies using a murine IgG2 anti-intercellular adhesion molecule mAb to inhibit this interaction in rheumatoid arthritis were encouraging,822 but retreatment frequently resulted in allergic side effects,823 which suggested that repeated treatment would not be a useful strategy.

Rituximab Rituximab is a chimeric monoclonal mouse– human antibody that is reactive with the B cell CD20 receptor, which is present on pre-B and mature B cells but not on stem cells or plasma cells.824 It has been effective in the treatment of relapsed Hodgkin’s B cell lymphoma. The role of CD20 is not clear, but rituximab exerts its effect by removing B cells from the circulation, both by antibody-dependent and complement-dependent cellular cytotoxicity and by the induction of apoptosis of B cells. Although the antibody-producing plasma cells are not removed from the circulation, B cells that may act as antigen-presenting cells produce cytokines, and infiltrate tissues are removed for a prolonged period. Memory B cells, which are also responsible for antibody production, may be removed as well. Rituximab is theoretically beneficial in diseases in which B cell autoantibodies may be pathogenetically important. This was observed first in patients with idiopathic thrombocytopenic purpura825 and more recently in small case series or case reports of a variety of autoimmune diseases. At an intravenous dose of 375 mg/m2 administered weekly for four infusions, B cells are reduced dramatically for a period of 6 to 9 months. Although disease manifestations may return later, coincident with the reappearance of B cells, baseline medications may be tapered during this period. Side effects are rare and include flushing and itching, usually with the first dose. These manifestations are probably allergic in nature and may be alleviated with pretreatment with an antihistamine and corticosteroids.

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Reduced levels of immunoglobulins for prolonged periods appeared to be more common and significant in children then in adults and may require immunoglobulin replacement therapy. Patients must be observed closely for development of viral infections, because post-rituximab infections have been reported with parvovirus, varicella-zoster virus, cytomegalovirus, and enterovirus. Binstadt and colleagues826 reported on a series of four children with undiagnosed autoimmune illnesses who received rituximab treatment after failure of multiple other agents. Impressive improvement in the neurologic manifestations of these patients was observed. Nadir of IgG levels were seen at 4 to 6 months and three of the four patients required immunoglobulin replacement therapy, at least in the short term. Leandro and associates827 reported on six patients with SLE treated with a combination of two rituximab infusions of 500 mg, two infusions of cyclophosphamide at 750 mg, and high-dose oral corticosteroids, with a very good response at 6 months in five of the six. Interestingly, although hypocomplementemia in these patients returned to normal, the response of anti-DNA antibodies was quite variable. The exact role of rituximab in the treatment of autoimmune diseases is still evolving.828,829

Interference with Cytokines The biologic effects of T cell–derived and monocytederived cytokines can explain much of the clinical syndrome of synovitis as well as the systemic manifestations associated with JRA.830–832 Cytokines are critical in perpetuating and damping the immune response, and, as such, they are important targets for therapeutic manipulation. A great deal of evidence supports the role of TNF-α in the initiation and perpetuation of the rheumatoid process. Children with JRA have high levels of TNF-α in the synovial fluid and peripheral circulation.833,834 Studies in adults have shown that high levels of TNF-α in synovial fluid are associated with bone erosions. Animal studies, and early studies in adults, showed convincingly that blocking TNF improved symptoms of inflammatory arthritis. Subsequent studies showed that these agents may be dramatically beneficial, not only in reducing disease activity, but also in improving function and retarding, and perhaps reversing, structural damage. Anti-TNF agents currently in use or under study in children are etanercept, infliximab, and adalimumab.

Etanercept Etanercept is a fully human, dimeric protein containing the extracellular domain of the human p75 TNF receptor fused to the Fc region of human IgG1 (Fig. 5–24). It is produced with the use of recombinant DNA

s

s

s

■ Figure 5–24 Structure of etanercept. s s

CH3

s

s

s

s s

CH2

Fc region of human IgG1

Extracellular domain of human p75 TNF receptor

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technology. By binding to TNF-α in the circulation, etanercept prevents the interaction of TNF-α with its cell surface receptor, thereby preventing cell activation and perpetuation of the inflammatory cascade. It can also modulate biologic responses that are mediated by TNF, such as expression of adhesion molecules, serum concentration of MMPs and cytokines.835 Although soluble forms of the TNF-α receptor occur naturally, they are generally inadequate to block TNF activity in systemic inflammatory disorders. The dimeric form of the TNF-α receptor is much more efficient at binding TNF, because it binds at a much greater affinity (50 to 1000 times higher) than that of the naturally occurring form. Its halflife, administered subcutaneously, is approximately 4 days. In adults with rheumatoid arthritis, steady-state concentrations are achieved in about 2 weeks.835 Etanercept has been used extensively in children with JRA since the initial report of its effectiveness in 2000.836 It is currently indicated for children who have had an inadequate response or who have not tolerated MTX and still have polyarticular disease. The initial study by Lovell and colleagues,836 as well as a large case series report by Quartier and coworkers,837 suggested that approximately 70% of children will have an initial response to etanercept. The response is usually dramatic, occurs by the third or fourth injection, and is associated with a dramatic reduction in active joint count and markers of inflammation. Although long-term data are lacking, a French study reported that only 39% of patients had a sustained improvement of 30% or more by 12 months.837 The North American follow-up study, in which 43 patients completed 2 years of treatment, showed that 81% of patients improved by at least 30%, 79% by at least 50%, and 67% by at least 70%.838 However, most of these patients were from an early responder group, and these data are less generalizable to a standard JRA population. Unfortunately, the results in children with systemic-onset JRA do not seem to be nearly as promising.839,840 Studies in adults have shown that the combination of etanercept and MTX is better than either drug alone, in terms of disease activity, functional disability as measured by the Health Assessment Questionnaire, and retardation of radiographic progression.841,842 The combination of etanercept and MTX has been used extensively in pediatric clinical practice.843,844 Although no data are available, the standard practice in treating children with JRA currently is to add etanercept to MTX for patients who have had only a partial response. Etanercept is administered subcutaneously, twice per week at a dose of 0.4 mg/kg, to a maximum of 25 mg. Higher doses do not seem to be more effective845 (Table 5–30). Administration of the dose on a once-weekly basis has been effective in adults846 and is currently being evaluated in children. It would still need to be administered in two injection sites. Given the success in treating early adult rheumatoid arthritis, research is currently underway to assess the optimum timing during the course of the patient’s arthritis. The ability to improve radiographic changes in adults suggests that etanercept may repair structural damage, in additional to improving disease activity. Therefore, it has been suggested that etanercept be administered very early in the course of disease.

TABLE 5–30

Guidelines for Use of Etanercept in the Treatment of Juvenile Idiopathic Arthritis Dose 0.4 mg/kg twice per week subcutaneously Clinical Monitoring Improvement should be seen by the third to fourth dose Monitor every 1–2 mo initially, then every 3–6 mo, depending on course Hold if suspected bacterial infection, varicella Laboratory Monitoring CBC with WBCC, differential and platelet count; AST, ALT, albumin every 4–8 weeks.

Magnetic resonance imaging studies in adults have shown that bone erosion can occur as early as 4 months after disease onset. Studies are underway in children to determine whether early administration of etanercept may lead to remission. To date, etanercept has been very well tolerated. The placebo-controlled study showed an increase in symptoms of upper respiratory tract infection as well as injection site reactions, although these were generally mild836 and may be treated with topical corticosteroids. However, postmarketing studies have reported a variety of unusual side effects; most importantly, systemic infection must be closely watched for. This includes bacterial infection, viral infection such as varicella with or without superimposed bacterial infection, and granulomatous infection. Although these are more common in elderly patients, physicians must be attuned to their development in any age group. Early postmarketing studies suggested that demyelinating syndromes, including multiple sclerosis, might be more common in patients treated with etanercept. Another TNF antagonist, lenercept, used to treat patients with multiple sclerosis; patients taking active drugs had exacerbations.847 Patients with JRA have developed demyelinating syndromes, as have adults with rheumatoid arthritis.848 Patients with previous demyelinating syndromes should not be treated with TNF antagonists, and those with a strong family history should be observed carefully for the development of symptoms that may be suggestive of demyelination. A variety of other side effects have been noted. Although rare enough to be the subject of case reports, there does seem to be an association between treatment with etanercept and the development of vasculitic skin rash849 or drug-induced lupus.850 The associations with pancytopenia and aplastic anemia are less clear.851 One case of diabetes mellitus after etanercept treatment has been reported in a child with JRA.852 Changes in mood and weight gain have also been noted.837 Other disorders in which etanercept has been studied with early promise include psoriatic arthritis,853 ankylosing spondylitis,854 uveitis,855 and Wegener’s granulomatosis.856

Infliximab Infliximab is a chimeric IgG1 anti–TNF-α antibody consisting of a mouse antibody and the constant region of the human antibody.857 It was the first anti-TNF

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agent that was shown to be effective in patients with rheumatoid arthritis,858,859 and is also effective in patients with Crohn’s disease. As opposed to etanercept, it binds not only to soluble TNF-α but also to membrane-bound TNF-α, leading both antibody-dependent and complement-dependent cytotoxicity. It therefore seems to be more efficacious in granulomatous inflammatory disorders (e.g., sarcoidosis) but also seems to be somewhat more risky in the development of granulomatous opportunistic infections (see later discussion). Administration of infliximab is through the intravenous route (Table 5–31). Dose and frequency vary somewhat with the clinical response. Initial doses usually start at 3 mg/kg and are given at time 0, at 2 weeks, at 6 weeks, and then every 8 weeks depending on clinical response. Doses often require escalation, and doses up to 20 mg/kg have been used occasionally in children.860 Alternatively, the length of time between infusions can be shortened. Because of the development of anti-infliximab antibodies, administration with MTX is recommended, because these antibodies seem to correlate with infusion reactions and accelerated clearance of infliximab.857 It is not certain, however, that they actually reduce the effectiveness. Similar to etanercept, combination treatment with MTX seems to improve the response to infliximab.861 Interestingly, infliximab may improve the radiologic status without necessarily improving the clinical status of disease.862 Early studies in children with JRA showed improvement, although no placebo trials have been done.844 Improvement occurs soon after the first infusion. Gerloni et al reported the results of 24 patients with JIA (5 systemic, 5 rheumatoid factor negative polyarthritis, 1 rheumatoid factor positive polyarthritis, 10 extended oligoarthritis and 3 psoriatic arthritis patients) who were treated with infliximab. All but 5 were “young adults” at the time of treatment, and still had active disease despite treatment with weekly methotrexate at a dose of at least 10 mg/m2. All started infliximab at a dose of 3 mg/kg at times 0, 2 and 6 weeks and then were scheduled to receive infliximab again every 8 weeks, but 20% of patients who received more than 3 infusions required that the interval between infusions be shortened. Fourteen patients required an increase in their maintenance dose. Only 9 patients completed one year of therapy. Five patients dropped out during the first year (infusion reactions in 4, failure of therapy in 1). All clinical parameters improved quickly and the improvements were sustained over time. However, there was no overall significant TABLE 5–31

Guidelines for Use of Infliximab in the Treatment of Juvenile Idiopathic Arthritis Dose 3 mg/kg IV on weeks 0, 2, and 6, then every 4–8 wk thereafter, depending on course; dose may be increased up to 10 mg/kg Clinical Monitoring Improvement should be seen soon after the first dose Monitor at each visit Hold if suspected bacterial infection, varicella Laboratory Monitoring CBC with WBCC, differential and platelet count; AST, ALT, albumin every 4–8 weeks.

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improvement in the HAQ score, perhaps because these patients were so severely affected prior to starting infliximab treatment. Adverse events occurred in 50% of patients, including 15 infusion reactions in 7 patients (requiring discontinuation of treatment in 4 patients). Antibodies to ds-DNA developed in 2 patients by the second month of treatment, were not associated with any signs or symptoms of systemic lupus erythematosus, and disappeared despite continuing infliximab. No serious infections occurred.

Infection remains the major concern with the use of infliximab. Many more cases of tuberculosis have been reported in patients treated with infliximab than in those treated with etanercept, probably because of the destabilization of previously formed granulomata.863 Other infections that have occurred with greater than expected frequency include histoplasmosis, coccidioidomycosis, and listeriosis.857 In addition to the side effects noted with etanercept, infusion reactions ranging from mild allergic reactions to anaphylactic reactions may occur, more commonly on the second or third infusions. Therefore, infliximab must be administered under close observation. In addition to treatment of JRA, infliximab may be beneficial in other autoimmune diseases, including vasculitis,864 Kawasaki disease,865 sarcoidosis,866 uveitis,867 and Behçet’s disease.868

Adalimumab Adalimumab is a recombinant human IgG1 mAb that acts in a similar fashion to infliximab by binding to TNF both within the circulation and on the cell surface.869 Therefore, it may result in cell lysis in the presence of complement. It is administered subcutaneously with a half-life of approximately 2 weeks. Recommended dosing in adults is 40 mg every second week. As with other anti-TNF agents, the results are seen quickly but the dose may need to be given once a week for sustained improvement. Injection site reactions can be problematic. In trials in adults with rheumatoid arthritis, adalimumab was shown to be more effective than MTX, in terms of disease activity, function- and healthrelated quality of life, and ability to limit structural damage.869 Adalimumab can be added safely to MTX with increased efficacy.870 Lovell et al reported the preliminary results from a 16 week open label lead into a multicenter phase III randomized double blind placebo controlled trial of adalimumab given at a dose of 24 mg/m2 every other week to patients with polyarticular JIA with a minimum of 5 swollen and 3 tender joints despite treatment with methotrexate.870a Of the 171 patients enrolled, 155 completed the 16 week open trial; 52% remained on MTX. By week 16, 95% of the patients on MTX and 88% on monotherapy reached at least a 30% improvement by ACR criteria, which occurred in the majority of children by 2 weeks. Infection was the most common adverse event, primarily upper respiratory tract infections, although three serious events (genital herpes, pneumonia, acute gastritis) occurred. Post-marketing studies have shown significant cytopenias such as thrombocytopenia, leukopenia, and pancytopenia.

Common Issues with Anti-TNF Agents With increasing use of anti-TNF agents, a number of common concerns have arisen, one of which is the increased risk of infection, particularly tuberculosis. In general, before starting treatment with any of these agents, the following approach is

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recommended. Patients should be screened for the presence of latent tuberculosis with a tuberculosis skin test. A chest radiograph is probably unnecessary unless the PPD result is positive. If the skin test is positive, thorough investigation of the patient and family for active tuberculosis must be done, and the patient must be treated accordingly. If the investigations prove negative, the patient should be given isoniazid (INH) for 9 months. Treatment with anti-TNF agents may be initiated 1 month after starting INH.871 Anti-TNF treatment should not be used in patients with active infection and should be discontinued in the case of a serious infection. Mild upper respiratory tract infections are not a reason to stop anti-TNF agents. Concern remains regarding the development of malignancy, particularly lymphoma. However, any association is difficult to sort out because of the known increased incidence of malignancy in patients with rheumatoid arthritis.851 Nevertheless, patients must be observed closely for the occurrence of malignancies. Finally, trials have been performed to block TNF in patients with congestive heart failure (CHF); neither infliximab nor etanercept was effective, and they may have even worsened the CHF.872 A recent report concluded that these agents might exacerbate, or even induce, CHF in patients with no previous risk factors.873 It does not seem that any specific laboratory monitoring is required routinely for any of these agents. Although the induction of antinuclear antibodies is common (up to approximately 15% of patients), screening for them is necessary only if suspicion of a developing autoimmune disease (e.g., drug-induced lupus) is raised.

Anakinra IL-1 plays a prominent role in rheumatoid arthritis by stimulating synoviocytes and chondrocytes to produce small inflammatory mediators (e.g., prostaglandins) and MMPs that lead to cartilage destruction and bone erosions. IL-1 also increases the expression of receptor-associated NF-κB ligand (RANK ligand), leading to osteoclast differentiation and activation and bone destruction. It exerts its effect by binding to IL-1 receptor and through cell signaling and production of these various molecules and cytokines. Interleukin-1 receptor antagonist (IL-1Ra), or anakinra, is a naturally occurring, acute phase anti-inflammatory protein, part of the IL-1 supergene family.874 IL-1Ra is the most important physiologic regulator of IL-1–induced activity. By binding to the IL-1 receptor on cell surfaces, it prevents the interaction of the receptor with IL-1 and subsequent cell signaling. An imbalance between IL-1 and IL-1Ra can lead to uncontrolled inflammation. Anakinra is a human recombinant form of IL-1Ra that is produced by recombinant technology in Escherichia coli. Its half-life is 4 to 6 hours when dosed at 1 to 2 mg/kg in adults with rheumatoid arthritis.874 It is administered subcutaneously by daily injection. Preliminary studies in animals showed improvement, which led to studies in adults with rheumatoid arthritis. Several studies showed improvement in American College of Rheumatology (ACR)-20, -50, and -70 scores versus placebo at 12 and 24 weeks.874 Although the improve-

ments have not been as dramatic as these reported with anti-TNF agents, they do offer another option for treatment. In a study by Cohen and associates875 of combination therapy with MTX, there was an increasing response to anakinra, and the response occurred early, by 2 to 4 weeks. Furthermore, the response appeared to be sustained (at least four of six patients improved) in a dosedependent fashion, and improvement appeared to continue beyond 24 weeks. Importantly, anakinra also appears to halt876 and perhaps even repair bone destruction as viewed radiologically.877 Adverse events have, in general, not been serious. The most common are injection site reactions, which tend to occur within the first 4 weeks and are rare later. They consist of rash, erythema, and pruritus and may be relieved with ice packs and application of topical corticosteroid. Rarely are they severe enough to stop treatment. Although serious infections (pneumonia, cellulitis) were more common compared with placebo, no deaths from infection have been reported, and, in contrast to anti-TNF agents, opportunistic infections have not occurred in the studies to date. It appears safe to use MTX with anakinra,875 but etanercept does not seem to add benefit to anakinra in patients with rheumatoid arthritis.878 A small series demonstrated that, in general, patients who had failed to respond to anti-TNF agents also did poorly with anakinra.879 Its role in children with JIA is unclear and is currently under study; preliminary data have indicated some promising benefit.880 Seven patients with MTX and etanercept-resistant systemiconset JRA treated with anakinra were reported from 5 separate centres.880a Most patients improved within 2 weeks and showed a sustained response, which included a reduction in the number of active joints, an improvement in the laboratory values and a reduction in the requirement for prednisone. Similarly, 4 children with MTX and etanercept-resistant systemic-onset JRA were reported from a single centre.880b All four showed improvement of at least 30% after one and two months of anakinra. Side effects were mild and did not require discontinuation from therapy.

Anti-IL6 Receptor Antibody IL-6 appears to be an important potential target, particularly in the treatment of systemic-onset JIA. There is ample evidence that IL-6 is central to the many clinical and laboratory manifestations of this disease. An imbalance between IL-6 and its soluble receptor can lead to increased IL-6 binding on cell surfaces with its receptor, binding gp130, on the cell membrane, leading to intracellular signaling and resulting cytokine production and release.881 Elegant studies have produced evidence that levels of IL-6 correlate with spikes of fever, thrombocytosis, and joint involvement,882 and, in mice transgenic for IL-6, growth retardation is observed.883 Therefore, neutralization of IL-6 would be expected to be very beneficial. Anti-IL6 receptor antibody, MRA, is a genetically engineered, humanized, mAb that is produced by grafting the complementarity-determining region of mouse anti-human IL-6 receptor to human IgG1.881

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MRA competes with both the soluble and the membrane-bound IL-6 receptor to prevent cell signaling. Studies in animals showed that MRA reduces joint inflammation in collagen arthritis.884 Preliminary data show evidence for MRA in adult-onset Still’s disease,885 in Castleman’s disease,886 and in adult rheumatoid arthritis.887 The suggested dose is 5 mg/kg/week intravenously, tailored as necessary. In a very preliminary study recently presented, 11 children with systemic-onset JIA were treated with MRA in a dose-escalation trial, depending on the initial response to a dose of 2 mg/kg of MRA, to a maximum dose of 8 mg/kg. Three patients received 2 mg/kg, five received 4 mg/kg, and three received 8 mg/kg, with a 70% JIA core set response in 33.3%, 60%, and 100%, respectively. No children withdrew due to adverse events or disease flare.888 The long-term effects of anti-IL6 receptor monoclonal antibody (aIL-6R Mab) were reported in 4 children who received treatment once every two weeks for 2.5 to 3 years. Growth improved and corticosteroids were withdrawn in three and reduced in the fourth, and the aIL-6R Mab was able to be discontinued in two children after three years. Two patients had paronychiae and one developed a subcutaneous abscess.888a An international multi-centre trial is currently being planned.

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TABLE 5–32

Combination Therapies Reported to be Effective in the Treatment of Rheumatoid Arthritis and Juvenile Idiopathic Arthritis Sulfasalazine, methotrexate, and hydroxychloroquine272 Methotrexate and cyclosporin754,891 Chloroquine and methotrexate892 Prednisolone, methotrexate, and sulfasalazine893,894 Leflunomide and infliximab895 Biologic therapy combined with methotrexate841,842,861,870,875 IV methylprednisolone, IV cyclophosphamide, and methotrexate610,613

Apoptosis (programmed cell death) is a process whereby normal tissue growth is maintained and controlled by the expression of oncogenes. Inflammatory cytokines in rheumatoid arthritis synovial fluid upregulate the expression of apoptosis factors, but apoptosis per se appears to be defective,889 possibly because of a defect in the interaction between the oncogene Fas and its ligand. Strategies to correct defective apoptosis include monoclonal anti-Fas antibodies and administration of Fas ligand; this approach may be amenable to gene therapy (see later discussion).

fasalazine alone (COBRA Trial).893,894 There is a suggestion that the combination of leflunomide and infliximab may also be effective. 895 In addition, the improvement noted with biologic therapy can be enhanced by combining it with MTX,841,842,861,870,875 and the combination of etanercept and MTX may also retard structural damage, opening the door to potential long-term remission (TEMPO Trial).841 However, one combination of the biologic agents anakinra and etanercept was no more effective than either agent alone and was more toxic.878 In JRA, combination therapy has included intravenous methylprednisolone, intravenous cyclophosphamide, and MTX.610,613 In addition, MTX is usually used together with either etanercept or infliximab with no increase in toxicity.837,839,843,844 Combination therapy would seem particularly appropriate in cases of severe systemic-onset JRA. Important questions remaining to be answered include which patients are most at risk for long-term damage and therefore most likely to benefit from combination therapy; whether therapy should be started in combination or medication should be added only after a partial inadequate response; and whether full or reduced doses of each agent should be used.

Combination Therapies

Gene Therapy

In the past, there was a reluctance to use combinations of DMARDs for arthritis because of concerns about increased toxicity of agents with similar toxicity profiles. However, a number of factors support the use of combination therapies. In adult rheumatoid arthritis, single agents seem to lose efficacy over time890; furthermore, these agents rarely induce sustained long-term remissions. An increased appreciation of the long-term morbidity of both rheumatoid arthritis and JRA supports a more aggressive approach to medical management (Table 5–32).147 A better understanding of the mechanisms of action of these agents, as well as recent welldesigned studies of combination therapy in adults that demonstrated efficacy without a significant increase in toxicity, support the use of this approach. In adult rheumatoid arthritis, studies have demonstrated the efficacy of triple therapy with sulfasalazine, MTX, and hydroxychloroquine versus any two of these drugs alone272; MTX and cyclosporine versus MTX or placebo754,891; chloroquine and MTX versus MTX892; and prednisolone, MTX, and sulfasalazine versus sul-

The successes seen with biologic therapy have supported a potential role for gene therapy in patients with arthritis. The costs and inconvenience of ongoing therapy, and the potential ability of gene therapy to deliver sustained concentrations of therapeutic molecules directly to sites of inflammation make this an attractive option. Ideally, children with the worst prognoses would be targeted for study. However, this would most likely require systemic rather than local therapy, and systemic gene therapy has been more difficult to control. It might be ideal for oligoarticular JRA once its safety is established.896 There are a variety of mechanisms in the inflammatory process that can be targeted by gene therapy (summarized in recent reviews897,898). Proof-of-principle studies in animals have led to trials in adults with rheumatoid arthritis,899 in the form of autologous synovial cell implants containing IL-1Ra in a retroviral vector. Results of long-term outcome and safety data are awaited. There is potential for gene therapy to control gene expression (e.g., IL-10 to change a Th1 to a Th2 response; Fas ligand to correct defective apoptosis; blockade of NF-κB);

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their impact on systemic manifestations awaits clinical trials, which are underway.

High-Dose Immunotherapy with Transplantation Cures of adjuvant arthritis in animal models by either syngeneic900 or autologous bone marrow transplantation,901 together with “experiments in nature” in which patients with rheumatoid arthritis who underwent bone marrow transplantation for other disorders were noted to experience an improvement in their rheumatoid arthritis, have paved the way for new approaches to the treatment of autoimmune disease (i.e., autologous transplantation). The principles behind this treatment are that high-dose myeloablative therapy will destroy the autoreactive clones that initiate the autoimmune process, and the marrow can be repopulated with a “naive” population of stem cells. As the immune system redevelops after transplantation, immune cells may become “tolerized” to the putative antigens that are involved in the autoimmune process. In fact, allogeneic matched bone marrow transplantation for patients with RF-positive rheumatoid arthritis and associated aplastic anemia has led to remission of the arthritis. However, the length of the remission varied, from as short as 1 year to as long as 13 years.902,903 Allogeneic bone marrow transplantation carries a significant risk of both mortality (15% to 35%) and development of graft-versus-host disease (GVHD). The use of an autologous transplant, from either marrow or peripheral blood stem cells (autologous stem cell transplantation, or ASCT), reduces the mortality from the procedure to 1% to 5% and is not associated with GVHD. Therefore, highdose immunotherapy with ASCT has become a method that has been used in treating several autoimmune diseases. Initial studies in patients with autoimmune diseases and associated malignancies who underwent ASCT showed recurrence of disease within 5 weeks to 1 year.904 In these initial studies, the “retransplanted” stem cells were not manipulated in either a positive way (selection for CD34-positive stem cells) or a negative way (removal of T cells with potential autoreactivity). Relapses may also occur because (1) the putative autoantigens responsible for the disease were not eliminated, (2) the HLA status of the host did not change and therefore a predisposition to select arthritogenic peptides and a limited number of T cell developmental pathways persists, and (3) autoreactive T cells were not completely eliminated before transplantation. Preliminary studies of ASCT have been described in children with JRA and scleroderma, with excellent outcomes in most but not all studies.905,906 An initial mortality rate of 14% raised significant concerns despite remarkable improvement in some patients.907 Wulffraatt and associates908 reported their experience with 31 patients (25 systemic-onset, 6 polyarticular-onset) with polyarticular-course JIA treated with ASCT from eight different European pediatric transplantation centers. Bone marrow cells were transfused in 23 cases and peripheral stem cells, after harvesting with cyclophosphamide (2 g/m2) and granulocyte colony-stimulating factor, in 8. T cells were selected for CD34

stem cells by either negative or positive selection techniques. Conditioning included 5 days of antithymocyte antiglobulin (ATG) on days −9 through −6 and cyclophosphamide (50 mg/kg) on days −5 through −2; low-dose total body irradiation (TBI) was given to 21 patients on day −1. Frozen stem cells were thawed and infused on day 0. The neutrophil and platelet counts returned to normal by day 35. In vitro mitogenic T cell responses normalized within 6 to 18 months, and T cell counts were normal by 5 to 9 months. Seventeen patients had a drugfree period of 8 to 60 months. Mild relapses, which were easy to control, occurred in 7 patients. Four patients had no response to ASCT at all, and 3 patients died—2 with macrophage activation syndrome (1 induced by EBV) and 1 with disseminated toxoplasmosis. Catch-up growth was seen in younger children but not in older children or in those with long disease duration. All patients developed chills, fever, and malaise during the infusion of ATG. In addition to the two patients who died from infection-related causes, infectious complications were common (varicella-zoster in seven patients, atypical mycobacteria and Legionella pneumonia in one each). ASCT has been shown to alter laboratory abnormalities that reflect the immunologic process, including perforin expression,909 expression of myeloid-related proteins (MRP8/MRP14),910 and synovial cellularity and cytokine expression.911

Encouraging reports from the use of ASCT in patients with SLE912,913 and systemic sclerosis914 have led to the development of new studies, whose results are awaited. Although ASCT has not been curative in patients with rheumatoid arthritis, the disease seems easier to control with DMARDs after the procedure.915 Many questions remain regarding this treatment and the crucial variables in the protocols. The intensive immunotherapy required (high-dose cyclophosphamide ± irradiation ± antithymocyte globulin) may itself result in disease remission, as described in several cases of aplastic anemia and SLE.916,917 It is not clear whether irradiation is necessary, particularly because it may significantly increase the risk of malignancy; it did not seem to improve the outcome in the 31 patients described by Wulffraatt and associates.908 It is likely that manipulation of the “graft” is required before reinfusion. The number of stem cells required must be defined. Other preconditioning regimens may be more effective.918 If ASCT is ultimately proven to be effective, patient selection will be critical to its success. Patients should be chosen whose disease can be predicted to have a severe outcome but who are not yet at the stage of severe, irreversible damage. The development of prognostic markers is critical for proper selection of candidates. The ethical issues of attempting a procedure with a mortality rate of at least 5% in children with chronic diseases but much lower predicted mortality rates are monumental.919 The long-term risk of immunosuppression is significant, and safer ways to provide immunosuppression need to be developed. ACKNOWLEDGMENT The author wishes to express his gratitude to Madlen Gazarian for her participation in the development of this chapter in the previous edition.

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C H A P T E R 872. Khanna D, McMahon M, Furst DE: Anti-tumor necrosis factor alpha therapy and heart failure: what have we learned and where do we go from here? Arthritis Rheum 50: 1040–1050, 2004. 873. Kwon HJ, Cote TR, Cuffe MS, et al: Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 138: 807–811, 2003. 874. Cohen SB: The use of anakinra, an interleukin-1 receptor antagonist, in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 30: 365–380, 2004. 875. Cohen SB, Moreland LW, Cush JJ, et al: A multicentre, double-blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis 63: 1062–1068, 2004. 876. Bresnihan B, Cobby M: Clinical and radiological effects of anakinra in patients with rheumatoid arthritis. Rheumatology (Oxf) 42 (Suppl 2): 22–28, 2003. 877. Rau R, Sander O, Wassenberg S: Erosion healing in rheumatoid arthritis after anakinra treatment. Ann Rheum Dis 62: 671–673, 2003. 878. Genovese MC, Cohen S, Moreland L, et al; 20000223 Study Group. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50: 1412–1419, 2004. 879. Buch MH, Bingham SJ, Seto Y, et al: Lack of response to anakinra in rheumatoid arthritis following failure of tumor necrosis factor alpha blockade. Arthritis Rheum 50: 725–728, 2004. 880. Reiff A, Porras O, Rudge S, et al: Preliminary data from a study of Kineret (anakinra) in children with juvenile rheumatoid arthritis. Arthritis Rheum 46: S215, 2002. 880a. Irigoyen PI, Olson J, Hom C, Ilowite NT: Treatment of systemic onset juvenile rheumatoid arthritis with anakinra. Arthritis Rheum; 40: S437–438, 2004. 880b. Henrickson M: Efficacy of anakinra in refractory systemic arthritis. Arthritis Rheum; 40: S438, 2004. 881. Choy E: Clinical experience with inhibition of interleukin-6. Rheum Dis Clin North Am 30: 405–415, 2004. 882. De Benedetti F, Martini A: Is systemic juvenile rheumatoid arthritis an interleukin 6 mediated disease? J Rheumatol 25: 203–207, 1998. 883. De Benedetti F, Alonzi T, Moretta A, et al: Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I: a model for stunted growth in children with chronic inflammation. J Clin Invest 99: 643–650, 1997. 884. Takagi N, Mihara M, Moriya Y, et al: Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum 41: 2117–2121, 1998. 885. Iwamoto M, Nara H, Hirata D, et al: Humanized monoclonal anti-interleukin-6 receptor antibody for treatment of intractable adult-onset Still’s disease. Arthritis Rheum 46: 3388–3389, 2002. 886. Nishimoto N, Sasai M, Shima Y, et al: Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95: 56–61, 2000. 887. Choy EH, Isenberg DA, Garrood T, et al: Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46: 3143–3150, 2002. 888. Yokota S, Miyamae T, Imagawa T, et al: Phase II trial on anti-IL6-receptor antibody for children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 48: S429, 2003. 888a. Yokota S, Imagawa T, Miyamae T, Mori M, Nishimoto N, Kishimoto T: Longterm therapeutic experience of humanized anti-IL-6 receptor monoclonal antibody (aIL-6R Mab) in systemic-onset juvenile idiopathic arthritis (SoJIA). Arthritis Rheum; 40: S438, 2004. 889. Nakajima T, Aono H, Hasunuma T, et al: Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis Rheum 38: 485–491, 1995. 890. Felson DT, Anderson JJ, Meenan RJ: The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two metaanalyses. Arthritis Rheum 33: 1449–1461, 1990. 891. Stein CM, Pincus T, Yocum D, et al: Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: an open-label extension study. The Methotrexate-Cyclosporine Combination Study Group. Arthritis Rheum 40: 1843–1851, 1997. 892. Ferraz MB, Pinheiro T, Helfenstein M, et al: Combination therapy with methotrexate and chloroquine in rheumatoid arthritis: a multicenter randomized placebo-controlled trial. Scand J Rheumatol 23: 231–236, 1994. 893. Boers M, Kostense PJ, Verhoeven AC, van der Linden S; COBRA Trial Group: Combinatietherapie Bij Reumatoide Artritis. Inflammation and damage in an individual joint predict further damage in that joint in

5 PHARMACOLOGY 894. 895. 896. 897. 898. 899. 900. 901.

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patients with early rheumatoid arthritis. Arthritis Rheum 44: 2242–2246, 2001. Landewe RB, Boers M, Verhoeven AC, et al: COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 46: 347–356, 2002. Hansen KE, Cush J, Singhal A, et al: The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis. Arthritis Rheum 51: 228–232, 2004. Londino AV, Rothman D, Robbins PD, Evans CH: Gene therapy for juvenile rheumatoid arthritis? J Rheumatol 27 (Suppl 58): 53–55, 2000. Evans CH, Ghivizzani SC, Kang R, et al: Gene therapy for rheumatic diseases. Arthritis Rheum 42: 1–16, 1999. Muller-Ladner U, Pap T, Gay RE, Gay S: Gene transfer as a future therapy for rheumatoid arthritis. Expert Opin Biol Ther 3: 587–589, 2003. Robbins PD, Evans CH, Chernajovsky Y: Gene therapy for arthritis. Gene Ther 10: 902–911, 2003. van Bekkum DW, Bohre EP, Houben PF, Knaan-Shanzer S: Regression of adjuvant-induced arthritis in rats following bone marrow transplantation. Proc Natl Acad Sci U S A 86: 10090–10094, 1989. Knaan-Shanzer S, Houben PF, Kinwel-Bohre EP, van Bekkum DW: Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation. Bone Marrow Transplant 8: 333–338, 1991. McKendry RJ, Huebsch L, Leclair B: Progression of rheumatoid arthritis following bone marrow transplantation: a case report with a 13-year followup. Arthritis Rheum 39: 1246–1253, 1996. Snowden JA, Kearney P, Kearney A, et al: Long-term outcome of autoimmune disease following allogeneic bone marrow transplantation. Arthritis Rheum 41: 453–459, 1998. Euler HH, Marmont AM, Bacigalupo A, et al: Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation. Blood 88: 3621–3625, 1996. Wulffraat N, van Royen A, Bierings M, et al: Autologous haemopoietic stem-cell transplantation in four patients with refractory juvenile chronic arthritis. Lancet 353: 550–553, 1999. Martini A, Maccario R, Ravelli A, et al: Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis. Arthritis Rheum 42: 807–811, 1999. Barron KS, Wallace C, Woolfrey CEA, et al: Autologous stem cell transplantation for pediatric rheumatic diseases. Rheumatol 28: 2337–2358, 2001. Wulffraat NM, Brinkman D, Ferster A, et al: Long-term follow-up of autologous stem cell transplantation for refractory juvenile idiopathic arthritis. Bone Marrow Transplant 32 (Suppl 1): S61–S64, 2003. Wulffraat NM, Rijkers GT, Elst E, et al: Reduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem-cell transplantation. Rheumatology (Oxf) 42: 375–379, 2003. Wulffraat NM, Haas PJ, Frosch M, et al: Myeloid related protein 8 and 14 secretion reflects phagocyte activation and correlates with disease activity in juvenile idiopathic arthritis treated with autologous stem cell transplantation. Ann Rheum Dis 62: 236–241, 2003. Brinkman DM, ten Cate R, Vossen JM, et al: Decrease in synovial cellularity and cytokine expression after autologous stem cell transplantation in patients with juvenile idiopathic arthritis. Arthritis Rheum 46: 1121–1123, 2002. Traynor AE, Barr WG, Rosa RM, et al: Hematopoietic stem cell transplantation for severe and refractory lupus: analysis after five years and fifteen patients. Arthritis Rheum 46: 2917–2923, 2002. Jayne D, Tyndall A: Autologous stem cell transplantation for systemic lupus erythematosus. Lupus 13: 359–365, 2004. Tyndall A, Matucci-Cerinic M: Haematopoietic stem cell transplantation for the treatment of systemic sclerosis and other autoimmune disorders. Expert Opin Biol Ther 3: 1041–1049, 2003. Snowden JA, Passweg J, Moore JJ, et al: Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: a report from the EBMT and ABMTR. J Rheumatol 31: 482–488, 2004. Brodsky RA, Sensenbrenner LL, Jones RJ: Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation. Blood 87: 491–494, 1996. Petri M, Jones RJ, Brodsky RA: High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus. Arthritis Rheum 48: 166–173, 2003. Kishimoto T, Hamazaki T, Yasui M, et al: Autologous hematopoietic stem cell transplantation for 3 patients with severe juvenile rheumatoid arthritis. Int J Hematol 78: 453–456, 2003. Laxer RM, Harrison C: Bioethical issues in autologous stem cell transplantation in children and adults with arthritis. J Rheumatol 28: 2147–2150, 2001.

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DESIGN, MEASUREMENT, AND ANALYSIS OF CLINICAL INVESTIGATIONS Edward H. Giannini

~'rf

EVIDENCE-BASED MEDICINE AND CLINICAL INVESTIGATION Today, more than ever, the clinician is encouraged to practice "evidence-based medicine." That is, the practitioner must be able to access, summarize, and apply information from the literature to day-to-day clinical problems. 1,2 But how strong should the evidence be before a clinician modifies his or her practice because of new data in a clinical research report? The same question can be asked of any clinical or biomedical research report, whether or not it applies to clinical practice. The strength of evidence depends on many factors, including the rigor of the study design, the selection of patients and appropriate controls, and the meticulousness and appropriateness with which the data were gathered, analyzed, interpreted, and reported. In addition, the similarity between the patients described in a study and the patients seen by a particular clinician is of utmost importance in determining the relevance of a study. The reader must be able to judge the quality of the work in order to determine its overall validity and the acceptability of the conclusions. The mere fact that the work has been published (even in a reputable journal) may not be enough of a yardstick whereby one decides that the work is of superior quality. Since the last edition of this text, the Cochrane Collaboration has done much to add to the practice of evidence-based medicine, including pediatrics. 3- 7 Founded in 1993 and named after the British epidemiologist, Archie Cochrane, its chief goal is to provide systematic reviews of health care interventions and thus to promote the search for evidence in the form of clinical trials and other types of studies of interventions. At present, the Cochrane Database of Systematic Reviews, its main product, contains approximately 1700 complete reviews, with another 1300 underway. Outstanding "Users' Guides to the Medical Literature" have now been published, and the reader is encouraged to supplement the discussion in this chapter with the appropriate guide for a specific topic.H--4O

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Any student of clinical research must now be aware of the sizable obstacles currently facing the clinical research enterprise. 41 ,42 There now appears to be a general consensus among medical scientists, public health policy makers, and the United States Congress that the remarkable advances in biotechnology that have been realized during the past 20 years have not translated, at an acceptable rate, into improved health status for the nation and the world in general. The situation is thought to be worsening as acquisition of basic science knowledge continues to accelerate. Clinical research is viewed as a continuum-beginning from basic biomedical research, progressing to clinical science and knowledge, eventuating in improved health of the public. Two "major transitional blocks" are identified that impede efforts to apply science to better human health in an expeditious fashion. The first "translational block" occurs between basic biomedical research and clinical science and knowledge, the second between clinical science and knowledge and improved health. Contributing factors to the first block include lack of willing study participants, regulatory burden, fragmented infrastmcture, incompatible databases, and a lack of qualified investigators. Contributing to the second block are career disincentives, practice limitations, high research costs, and lack of funding. These obstacles should remain foremost in the reader's mind, with the realization that the design and analysis of studies must necessarily be grounded in what is reasonable from a logistical, practical, ethical, and economic point of view. This chapter proVides readers with enough clinical, epidemiological, and biostatistical skills to critically assess the literature and to independently determine the "strength of the evidence" (Le., to become more proficient at the practice of evidence-based medicine). It also promotes basic skills that facilitate the design, undertaking, and reporting of clinical research. Although this chapter emphasizes clinical research, many of the concepts discussed here are easily translated to the realm of basic science. Whetllcr working in the laboratory or in the clinic, an investigator must understand the basic concepts of, for example, frequency distributions and statistical inferences.

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DEFINmON OF CLINICAL RESEARCH Academicians have argued for years about exactly what is incorporated in the concept of clinical research. The Nathan Report (http://www. nih .gov/news/crp/97report/ index.htm) defines clinical research as epidemiologic and behavioral studies, outcomes research and health services research, and patient-oriented research. Research conducted with human subjects (or on material of human origin, such as tissues, specimens, or cognitive phenomena), for which an investigator (or colleague) directly interacts with human subjects, also qualifies as clinical research. This area of research includes mechanisms of human disease, therapeutic interventions, clinical trials, and development of new technologies. Excluded from this definition are in vitro studies that use human tissues but do not deal directly with patients. This definition, however, does not exclude laborato!), or translational research ("bench-to-bedside"), provided that the identity of the patients from whom the cells or tissues under study are derived is known.

GENERAL TERMINOLOGY AND BASIC CONcEPTS ASSOCIATED WITH CLINICAL STUDIES To be conversant in clinical study designs and methodology, one needs a working knowledge of the vocabula!)' and basic concepts relevant to the various approaches. Readers must attempt to generalize the usage of common terms from one type of study to the next. For example, "exposure" may mean that the subject was exposed to cigarette smoke in a retrospective casecomparison study, exposed to a drug in a clinical trial, or exposed to human leukocyte antigen (HLA)-B27 in a genetic study. All clinical investigations may be divided broadly into observational or experimental studies. In observational studies, there is no artificial manipulation of any factor that is to be assessed in the study, nor is there active manipulation of the patient. In observational studies, the subjects have received the "etiologic" agent by mechanisms other than active assignment or randomization. Examples of such mechanisms are self-imposed exposure (personal habits or nutritional patterns), prescription by a physician, atmospheric pollutants, and occupational toxins. Observational studies may be either retrospective or prospective. Retrospective implies that the data already exist and are retrieved using a systematic approach, but missing data are not retrievable. In prospective observational studies, a cohort is observed prospectively through time, and data are gathered on an ongoing basis. In this 'case, missing data may possibly be retrieved for purposes of the study. Experimental studies are those in which the experimenter artificially manipulates some study factor-subjects, therapeutic regimen, or some other parameter. In experimental studies, the subjects are observed prospectively, some artificial manipulation is conducted, and the results of this manipulation are then observed. Meta-analysis is an approach whereby the quantitative evidence from two or more studies bearing on the same

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question is statistically combined. 43 Usually, the summa!)' statistics rather than the raw data from the various studies are combined. Meta-analysis may be considered a form of retrospective experimental study in that the data already exist and were gathered during prospective experimental studies. The Cochrane Collaboration relies heavily on meta-analytic techniques.

Hypothesis-Generating Versus Hypothesis-Testing Studies The design of a clinical investigation depends on whether the study intends to generate hypotheses to be tested in future studies or to test specific hypotheses for which the investigator has some existing evidence to support the belief that they are true or not true. Hypothesis-generating studies are considered exploratory; studies that are designed as tests of hypotheses may be called pivotal or confirmatory studies. A single study may have both confirmato!)' and explorato!)' aspects. Each type of study has distinct advantages and disadvantages. The design chosen is always deeply influenced by reality-what is economically, logistically, ethically, and scientifically possible. A common exercise used by methodologists is to design the best theoretical experiment to answer the question being posed, without regard to time, money, ethics, patient availability, or anything else that could cause a lessening in the quality of the study. (A related approach is known as the "infinite data set. "44) Then, realizing that there is no such thing as the perfect clinical study, the designer eliminates the most unrealistic "requirement." (For example, it is not likely that one can enroll 300 patients with scleroderma who will agree to the pOSSibility of being randomized to placebo for a year.) The study is compromised further and further by reality until one arrives at what can be done in consideration of all the issues. If the result is unacceptable scientifically, perhaps the question cannot (and should not) be answered. The decision to pursue or not to pursue the "compromised" study, based in reality, is one of the most difficult in the entire research process. It is worth remembering that one's rights as a clinical investigator are the exact opposite of one's constitutional rights as a citizen: the investigator (or the study) may be considered guilty (of anything and eveI)'thing) until proven innocent.

Main ObJectives, Process ObJectives, Hypotheses, and Long-Term Goals The first challenge, after identifying a clinical question to be addressed, is to clearly establish the main (or primary) objectives and the secondary objectives. Objectives are statements as to what the investigators plan to learn or accomplish by conducting the study. Process objectives follow the main objectives; they are the procedures that must be completed in order to meet the main objectives. Hypotheses are then developed. Hypotheses are formal statements that declare what the investigator will test and then either reject or fail to reject. As discussed earlier, explorato!)' (hypothesis-generating) studies may not state

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hypotheses a priori. Such studies frequently allow the data to drive the hypotheses to be tested in the dataexploration phase. Finally, longer-term goals are stated. Often, they are to be met only after the main objectives of the current projects are complete. They frequently give a hint as to what future direction the research may take. Clinical research proposals often misstate hypotheses or mix main objectives (specific aims) with process objectives or longer-term goals. The following example may assist the reader in formulating each of these elements of a research proposal. Suppose the question is, "Does the selective cyclooxygenase-2 inhibitor, celecoxib, produce fewer gastrointestinal (GI) adverse effects in children with juvenile rheumatoid arthritis (TRA) than does naproxen when each drug is given in anti-inflammatory doses for a period of up to 3 months?" The objectives are typically written nonjudgmentally and are more informal in their language than the hypotheses. A primary objective for this project could be, "To determine the incidence of GI adverse drug events among patients with ]RA treated for up to 3 months with celecoxib compared with naproxen." Equally acceptable (but less distinguished from the statement of hypothesis) is, "To test the hypothesis that celecoxib produces fewer GI adverse drug effects than does naproxen in children with ]RA." A secondary objective could be, "To determine the incidence of GI events requiring pharmacologic intervention in the two groups and compare the differences." The main objective would not be, for example, "To enroll 250 patients with ]RA in a clinical trial in which half are randomly assigned to celecoxib and half to naproxen." That is a process objective-one of the necessary steps that will be carried out to meet the main objective. Even large studies typically have only one or two main objectives and accompanying hypotheses. The usual null hypothesis (abbreviated Ho) is that the treatments are not different with regard to the primary outcome. Ho can be stated as, "There is no difference in the incidence of GI adverse drug effects among patients treated with naproxen compared with those treated with celecoxib." The alternative hypothesis (abbreviated H) is, "There is a difference in the incidence of GI adverse drug effects,." As stated, the Ha does not specify whether there are more or fewer GI effects with celecoxib. This is a two-tailed hypothesis. A one-tailed hypothesis could be stated as follows: "Patients with ]RA treated with celecoxib will have a lower incidence of GI adverse drug effects than those treated with naproxen." However, this hypothesis sounds as if the investigator is not interested in testing to see whether celecoxib produces more GI effects, just less. For this reason, the usual approach is to use two-tailed hypotheses, at least in early studies when the direction of the difference (if any) is not known. The choice of a one-tailed as opposed to a two-tailed hypothesis influences the statistical interpretation of the data, as discussed later. A secondary null hypothesis in this example might be, "There is no difference in the incidence of GI adverse drug events that require pharmacologic intervention among patients with ]RA treated with celecoxib compared with those treated with naproxen."

A N A LY SIS

0 FeLl N I CAL

I N YES T I GAT ION S

Finally, the longer-term goal for this example is not, "To complete the study in a 5-year time frame," but rather, "To provide safer and more effective anti-inflammatory medications to children with ]RA."

EPIDEMIOLOGIC AND BEHAVIORAL STUDIES Clinical epidemiology is a medical science that studies the distribution and determinants of disease frequency in human populations in order to understand why some people contract a disease and others do not. Epidemiology, combined with biostatistics, makes up the basic tools of the clinical investigator. Epidemiologic methods can be used to answer questions in the following categories.

Descriptive Epidemiology Studies in descriptive epidemiology typically concern themselves with patterns of disease occurrence with respect to person, place, or time. Descriptive epidemiologic studies serve as hypothesis-generating studies for studies of causation, much the same way as small exploratory clinical trials serve as preliminary studies for therapeutic confirmatory trials. The person variable is concerned with who experiences the disease. A basic tenet is that the disease does not occur at random but is more likely to develop in some people than in others. Personal factors of potential importance include age, sex, race, ethnicity, socioeconomic status, existing morbidity, health habits, and genetics. The place factor is concerned with where the disease develops. Variation in place of occurrence can be evaluated at the local, regional, or international level. The time variable is concerned with variation in the occurrence of disease in time and its seasonality or periodicity. A hypothetical example of a descriptive epidemiologic study is the investigation of a group of workers in a factory who have what is suspected of being environmentally acquired lupus. The epidemiologist would investigate the detailed characteristics of the workers to determine whether there are patterns among those who do and do not have lupus. Do all types of workers (management through hourly manufacturing employees) demonstrate the same rate of disease development? Are persons living close to the factory or its effluent also affected? Systematic investigation of the patterns of disease allows a more precise hypothesis of causation, particularly if some exposure or dose level is found to be more strongly associated with the illness.

Frequency of Disease Occurrence The frequency of disease occurrence is an important aspect of understanding a disease process. It can be measured in a number of ways. Prevalence is the number of existing cases in a defined population. Mathematically, prevalence is equal to the number of existing cases divided by the number of persons in the population. It is expressed in different ways: as a proportion (0 to 1), as a percentage (0 to 100), or by actual

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numbers using a convenient denominator (e.g., cases per 1000 children). Point prevalence is the number of new and old cases in a defined population at a given "instant" in time. For example, hospital epidemiologists are frequently asked to estimate the point prevalence of nosocomial infections among current inpatients. The epidemiologist then counts all the confirmed and suspected cases of hospitalacquired infections within the hospital on a given day and divides this total by the census for that day to obtain the point prevalence. Period prevalence is the number of new and old cases that exist in a defined population during a given time period (e.g., 1 year). Incidence is the rate at which newly diagnosed cases develop over time in a population. Mathematically, incidence is equal to the number of new cases (numerator) divided by the number of persons at risk in the population multiplied by the time (duration) of observation (denominator). This rate is expressed in units of cases/person-time. Incidence is related to the concept of risk, defined as the proportion of unaffected individuals who will, on average, contract the disease over a specific period of time. Risk is equal to the number of new cases divided by the number of persons at risk. Risk has no units and can have values between 0 (no new occurrences) and 1(the entire population becomes affected during the risk period). Epidemiologic theory states that incidence is best estimated from prospective studies; prevalence may be calculated by prospective or retrospective approaches.

Etiology of Disease In his presidential address to the Royal Society of Medicine in January of 1965, Sir Austin Bradford Hill gave his now famous oration entitled, "The Environment and Disease: Association or Causation. "45 In it, he described what have become known as Koch's postulates Jor epidemiologists. These postulates describe what evidence must be present to establish a factor as being causally linked to a disease and include the following: • Strength of the association: How strong is the association between the factor and the outcome? For example, how significant is the probability (P) value of the association between dietary intake of calcium and bone mineral density among children with JRA? • Consistency of the association: Does the association between factor and disease persist from one study to the next, even if variations in study design and samples of patients vary substantially? • Specificity ojthe association: Is the association limited, for example, to specific alleles and types of disease, with little association between the alleles and other diseases? (As the study of causation, including genetic risk, has advanced, the issue of specificity is considered less important than it once was.) • Temporal correctness: Did the exposure to the factor occur before the disease? • Biologic gradient: Is there a dose-response relationship between the factor and the disease? For example,

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does increasing the dose or time of exposure to cyclophosphamide result in a consequent increase in frequency of malignancy? • Biologic plausibility: Does the association make sense with what is currently understood about the disease and its pathogenesis? • Experiment: Does the association hold up under experimental conditions? For example, if one reduces the dose or time of exposure to cyclophosphamide, is there a corresponding decrease in the frequency of malignancy? No single study can prove indisputably that any potential etiologic factor causes a disease, complication, or adverse event. It is the accumulating body of knowledge concerning factor and disease, or (to generalize the terms) treatment and outcome, that finally allows the medical community to state that evidence is sufficient to prove a causal link between the two. An important concept in the study of disease etiology is that of relative risk. The relative risk (risk ratio) can be defined as the risk of developing a disease among the members of one group (e.g., boys) compared with another group (e.g., girls). Relative risk can range from zero to infinity and has no units. A relative risk of 1 means that there is no difference in risk between the groups. A relative risk greater than 1 means increased risk, and a relative risk less than 1 indicates decreased risk (protection). In pediatric rheumatology, the concept of risk is used frequently to specify increased or decreased risk of disease associated with certain genetic markers. Table 6-1 presents terms that are relevant to risk and shows how each may be calculated using a 2 x 2 contingency table. Disease state (present or absent) is considered the dependent variable (DV) and is usually placed in the columns (x-axis). The risk factor (positive or negative) is considered the independent variable and is usually placed in the rows (y-axis). Notice that the relative risk is calculated differently from the odds ratio, although in medicine the two are frequently used synonymously. More correctly, however, relative risk is calculated from incidence studies, whereas odds ratios are calculated from retrospective studies.

Epidemiologic Study Designs Aimed at the Establishment of Associations and Cause-Effect Relationships The Case-Controlled Retrospective Study One of the most common types of study designs used to establish an association or cause and effect is the observational case-controlled, retrospective study. (The term case-comparison is now frequently used because the studies are not controlled in the usual sense.) In this situation, patients who have the disease are compared with those who do not, and data documenting prior exposure to some agent are ascertained retrospectively. The most frequent statistic to come from this type of study is the odds ratio (see Table 6-1). The odds ratio is a fairly good estimate of the relative risk, provided the disease is rare.

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Terms Assodated With Risk Factors dnd Disease

Risk Fador

Disease Present a c

Positive Negative

Disease Absent b d

The 2 x 2 table may be used to calculate associations between the risk factor and the disease:

Term

CalculaUon

Meaning

Incidence Absolute risk Attributable risk

(a + c) / (a + b + c + dl

-

Relative risk

(a / [a + bJ) -;- (c / [c + dJ)

Odds ratio

(a x d) / (b x c)

Case exposure rate

a / (a + c)

Control exposure rate

b / (b + d)

Number of new cases among those at risk Synonymous with incidence Incidence among those with the risk factor minus incidence among those without the risk factor (sometimes expressed as a percentage of the incidence rate among those with the risk factor) Incidence among those exposed divided hy incidence among those not exposed An approximation to the relative risk used in retrospective studies Among those with the disease, the proportion who had the risk factor Among those without the disease, the proportion who had the risk factor

[a / (a + b)] - [c / (c + dl]

Patients included in the study are often identified from a search of medical records or a disease registry. However, there are no standard guidelines for selection of control subjects. Control subjects may be hospitalized patients with conditions other than the disease of interest, residential neighbors, a probability sample of the general population, or a combination of these. The casecontrol classroom peers design is an appealing methodology for the selection of appropriate controls now finding uses in pediatric rheumatology.46 Originally (and still) used in studies of pediatric cancer patients, the technique identifies one classroom peer of the same sex and closest in age to the subject, and then compares the two on whatever variables are relevant to the specific study.47 Advantages of case-controlled studies include efficiency, low cost, quick results, and low risk to study subjects. The disadvantages of the case-controlled study are several, however. The temporal relationship of exposure and disease may be obscured. Historical information may be incomplete or inaccurate; a detailed study of mechanisms of disease is often not possible; and if the study is not well done, results may be biased.

The Prospective Cohort Study The observational approach that most closely resembles an experiment is the prospective cohort study. In this case, a population is defined from which the sample is drawn. Exposure to some factor is then established, and subjects are categorized as having been either "exposed" or "not exposed" to a factor thought to contribute risk of some outcome. Each of the two cohorts is monitored prospectively to observe whether the outcome develops. Relative risk is the statistic most commonly used in describing this study. The identification of exposed persons presents several problems. The first is to correctly

identify the exposed persons and measure the degree of exposure. This may be done by selecting subjects with some type of unusual occupational or environmental exposure. Another method is selecting those who are available and suitable for the needed investigation or selecting those who offer some special resource that facilitates the study, such as members of a health plan, or a combination of all these factors. The advantages of a prospective observational cohort study are that a clear temporal relationship between exposure and disease is established, and the study may yield information about the length of induction (incubation) of the disease. Relative risk can be estimated directly. The design facilitates the study of rare exposures and allows calculation of rates of disease occurrence. The disadvantages of cohort studies include the potential for loss to follow-up or alteration of behavior because of the long follow-up time that may be necessary. Cohort studies are not particularly good for rare diseases when the outcome is onset of the disease. Detailed studies of the mechanisms of the disease typically are not possible in cohort studies. A rheumatologic example of a cohort study designed to detect disease causation is the study by Inman and associates,48 who prospectively observed a cohort of persons "exposed" to Salmonella typhimurium infection to determine whether reactive arthritis developed. Prospective cohorts also find use in pediatric rheumatology when the aim is identify risk factors for development of certain complications or outcomes in a group of children who, typically, have the same disease but vary in "predictor" or "risk" variables. 49--'52

Diagnosis of Disease and Classification Criteria The diagnosis of disease, as it applies to epidemiology, refers to the performance of screening and diagnostic

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tests used in populations rather than the process of differential diagnosis of individual patients. Classification criteria typically employ a set of "core variables" fashioned into an algorithm. Numerous classification criteria relevant to pediatric rheumatic disease have been developed and/or validated since the previous edition of this text. They include criteria for flare of JRA, criteria for improvement in juvenile idiopathic myopathies and lupus, and preliminary criteria for clinical remission in JRA.S3-'i6

information about several parameters: it demonstrates the tradeoff between sensitivity and specificity for different criteria or cut points; the nearer the curve follows the left border and the top border of the ROC space, the more accurate the test; the closer the curve comes to the 45degree diagonal of the ROC space, the less accurate the test is; and the area under the curve is a measure of the accuracy of the test or criteria.

Validity of a Diagnostic or Screening Test or Criteria

Prognosis refers to the possible outcomes of a disease and the frequency with which they can be expected to occur. Prognostic factors need not cause the outcome but must merely be associated with an outcome strongly enough to predict it. Prognosis is somewhat narrower in focus and more short-term in aspect than those consequences of disease and treatment that are considered in the field of outcomes research (discussed later). For example, the six most frequently measured outcomes in outcomes research are known as the 6 Ds: death, disease, disability, discomfort, dissatisfaction, and dollars. Many studies of prognosis are cohort studies that prospectively monitor large numbers of patients to determine eventual clinical events and then look for certain prognostic factors for the events. At present and in the past, the estimation of prognosis has largely concentrated on clinical variables. Studies of prognosis in JRA, for example, have included the sex of the patient, the age at onset, and a variety of clinical and laboratory variables to estimate outcome. 49 .S7-63 Genetics, genomics, and microarrays to study RNA expression (and the accompanying new technologies of informatics and computational medicine) are being investigated more intensely to delineate their ability to predict outcome. 64-71 Pharmacogenetics has entered the scene as a way to determine the probability of response or adverse reaction to certain drugs. 72 It is likely

The validity of a diagnostic or screening test or set of criteria involves a variety of parameters, as shown in Table 6-2. The table typically is constructed with the presence or absence of disease as the column labels (Le., x-axis) and the test results as the row values (Le., DV shown on y-axis). Those patients in row 1, column 1 are called true positives; those in row 1, column 2 are false positives; those in row 2, column 1 are false negatives; and those in row 2, column 2 are true negatives. Sensitivity, specificity, positive and negative predictive values, false-positive and false-negative rates, and reliability are terms used to describe the validity of a screening test. A widely used tool that allows one to compare visually the performance of a set of different criteria or different cut points for a diagnostic or screening test is known as the receiver operating characteristic (ROC) curve (Fig. 6-1). First used in industrial engineering, an ROC curve is a plot of the true-positive rate against the false-positive rate-that is, sensitivity on the y-axis and 1 minus specificity on the x-axis. An excellent example of the use of this technique is demonstrated in Brunner's paper describing the relative performances of various criteria for disease flare in JRA.S3 An ROC curve provides

,~.

fABLE 6-2

Prognosis of Disease

Estimating the Validity of a Diagnosti( Test

Test Resun

Disease Present

Disease Absent

Positive Negative

True positive (TP) False negative (FN)

False positive (FP) True negative (TN)

The 2 x 2 table may be used calculate measures of the test's validity:

Term

Calculation

Meaning

Sensitivity

TP / (TP + FN)

Specificity

TN / (TN + FP)

Positive predictive value

TP / (TP + FP)

False-positive rate

FP / (TP + FP)

Negative predictive value

TN / (TN + FN)

False-negative rate

FN / (TN + FN)

Reliability (also called reproducibility)

-

Proportion (or percentage) of persons with the disease who test positive Proportion (or percentage) of persons without the disease who test negative Proportion (or percentage) of persons who test positive who have the disease Proportion (or percentage) of persons who test positive who do not have the disease Proportion (or percentage) of persons who test negative who do not have the disease Proportion (or percentage) of persons who test negative who have the disease The ability of a test to yield the same result on retesting

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1.0 - , - - - - - - - - - - - - - - - - - - - : / 1

.

0.9 +---;:D;-e.f.-:;1-'-..,.-------:::::-c:.---,-~:-,- - - 1 / /

• Worsening of 2 CRV without improvement of more than 1 of the remaining CRV by 30% or more • Worsening of 2 CRV

/

... Worsening of 3 CRV without improvement of more than 1 of the remaining CRV by 30% or more o Worsening of 3 CRV

* Worsening of 4 CRV without improvement of more than 1 CRV by 30% or more

o Worsening of 4 CRV 0.5 + - - I - - - , - ' ' - - - - - - - - - - - - - - - - j

~

Changes in CHAO, ESR and AJC only

0.4 +------.---...,--------r---r----,-------j 0.000 0.100 0.200 0.300 0.400 0.500 0.600 1 - Specificity (false positive rate)

• Figure 6-1 The receiver operating characteristic (ROO curve, a plot of the true-positive rate against false-positive rate (i.e., sensitivity on the y-axis and 1 minus specificity on the x-axis). ROes allow one to observe the tradeoff between sensitivity and specificity at various cut points of a diagnostic test. Values (or criteria for classification of patients) that fall on the upper left side of the curve are more useful (see text for further explanation). In the example shown, various criteria for describing flare in JRA are plotted. (Modified from Brunner HI, Lovell DJ, Rnck BK, Giannini EH: Preliminary definition of disease flare in juvenile rheumatoid arthritis. J Rheumatol29: 1058-1064,2002.)

that, in the future, determination of outcome will be based in large part on screening for various genetic markers that can predict whether individuals will respond to a particular therapy, whether they will experience an adverse drug effect, and whether their quality of life will be improved after a particular treatment.

Treatment of Disease For special emphasis, this chapter considers clinical trials separately from epidemiologic studies (see "Clinical Trials: Useful Guidelines").

Behavioral Studies The National Institutes of Health (NIH) considers behavioral studies as a category of clinical research. This class of studies is not considered here.

OUTCOMES AND HEALTH SERVICES RESEARCH The terms clinical effectiveness and health services research are closely related to outcomes research and are considered synonymous here. Outcomes research may be defined as the study of effectiveness, cost-effectiveness, and quality of health care. The interest in outcomes research has been generated by a more cost-conscious health care system. 73 For example, only 10% to 20% of medical procedures have been evaluated through ran-

domized controlled trials. Both established and new technologies can be ineffective. Certainly, the outcomes researcher must rely on much evidence-based medicine present in the literature as well as new studies. Outcomes researchers often use randomized controlled trial designs, prospective cohorts, retrospective cohorts, and case-control studies (described later). Chart reviews are frequently used, as are administrative data including local hospital discharge data, insurance claims, and national health survey information. In addition, meta-analysis, decision analysis, and cost-effectiveness analysis are typical study designs employed by the outcomes researcher. There are few reports of "true" outcomes research related to pediatric rheumatology. Excellent gUides are available for evaluating outcomes research. 15 .2(l-24

Decision Analysis Decision analysis may employ all of the techniques mentioned in the previous section and therefore is discussed in greater detail here. Decision analysis is an analytic formulation of a decision in which uncertainty exists. It incorporates probability of events as well as values for the consequences of action. It is decision oriented (not truth oriented), it is prescriptive (not descriptive), and it enhances, but does not replace, clinical judgment. The premises of decision analysis are that decisions must be made, the consequences of actions are uncertain, the consequences of action include both favorable and unfavorable effects, and health care resources are constrained. Decision analysis should enhance the ability to

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make rational decisions that lead to optimal therapeutic outcomes. Often, the principles of decision-making are obscured by substitution of established protocols. "Decision trees" should not be confused with flow charts presented in clinical practice guidelines for the management of particular diseases such as JRA.74 Decision trees tend to be more complicated, more branched, and more speculative than flow charts. Elements of a decision analysis are as follows. Choices are outlined, and the method to assess the overall value of the outcome of each choice is determined. The underlying assumptions are that there is uncertainty about the future and that various possible outcomes are valued differently. A decision tree is then constructed. Decision analysis itself includes outlining the problem, laying out the options and possible outcomes in explicit detail, assessing the probabilities and values of each outcome, and selecting the "best choice." In summary, the elements of decision analysis are choices, outcomes, and utilities. The areas of outcomes research and decision analysis are in their infancy in pediatric rheumatology. Each should offer a fruitful field for investigators for many years to come, because many different "standards of care" exist for most diagnoses that are included under the topic of pediatric rheumatology. Two excellent guides for judging the quality of decision analysis studies are those by Richardson and Detsky.1B.19

PATIENT-ORIENTED RESEARCH The NIH definition of clinical research groups four categories of investigation under the major heading of patient-oriented research: mechanisms of human disease, therapeutic interventions, clinical trials, and development of new technologies. This chapter emphasizes clinical trial classification and methods. However, many of the concepts and much of the terminology presented herein can be generalized to the conduct of clinical studies in any of these four areas of clinical research.

Olnlcal Trials: Useful Guidelines For simplicity, the generic term drng is used in the follOWing discussions. It should be considered synonymous with any medicinal product, vaccine, or biologic agent. The principles discussed can also apply to interventional procedures such as surgery and radiotherapy. Clinical epidemiologists are frequently concerned with evaluating the effectiveness and safety of new therapies. Numerous useful guidance documents (as distinguished from guidelines) are now in the literature and should be consulted for a more detailed explanation of the principles outlined here. Of particular relevance to the pediatric rheumatologist is the U. S. Food and Drug Administration (FDA) document entitled, "Guidance for Industry: Clinical Development Programs for Drugs, Devices and Biological Products for the Treatment of Rheumatoid Arthritis" (available at http://wwwfda.gov/ cber/gdlnslrheumcln.pdj). This document summarizes the pOSition of the FDA as to what clinical development programs should consist of, and it provides a framework

149

for conducting studies used to obtain regulatory agency approval of therapies for rheumatoid arthritis (RA) or JRA. An extremely useful set of guidance documents also available on the FDA's Web site is the "International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use." These documents contain valuable guidance for industry and the clinical investigator as well as definitions of terms related to overall clinical development programs, considerations for individual trials, statistical methods and reporting, and a variety of other topics. The ICH guidance documents seek to establish harmonization of clinical trials in various regions throughout the world, and their acceptance is very broad. It is strongly recommended that the designer or reader of clinical trials be familiar with their content. A list of available ICH guidelines may be found at http://wwwfda.gov/ cber/guidelines.htm or http://www.ich.org. Before general and specific considerations for individual trials can be discussed, an understanding of the various systems of classification of clinical trials is essential.

Classification of Olnlcal Trials by Initiator Clinical trials may be initiated either by industry or by an individual investigator. Those that are part of a clinical development program and conducted under a sponsor's (pharmaceutical company's) investigational new drng (IND) submission are usually initiated by industry. Trials undertaken under a sponsor's IND are used frequently by the sponsor in its submission to obtain approval for a new drug, known in the United States and elsewhere as a new drng application (NDA). If the NDA is approved by the regulatory agency, the drug may be marketed and labeled for the specific indication (Le., disease or conditions) stated in the NDA. Investigator-initiated protocols are typically, but not always, conducted after the drug has been approved for market. The main objective of investigator-initiated protocols may be new dosage regimens or use in diseases other than that for which the drug has obtained an indication. Many such trials are exploratory rather than confirmatory. Funding for investigator-initiated protocols in pediatric rheumatology has come from the NIH, the FDA, manufacturers, foundations, and the European Union.

Classification of Clinical Trials by Phase Clinical drug development programs are often described as consisting of four temporal phases, numbered I through IV. This system of classification, despite its shortcomings, is perhaps the one most commonly used today by the pharmaceutical industry and by regulatory agencies75 (Fig. 6-2).

Phase I Phase I studies are human pharmacology trials whose overall aim is to establish preliminary safety and tolerability of the dose range expected to be needed for later clinical studies and to determine adverse drug effects that can be expected. Studies in this phase include both

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Therapeutic Use

•• • • c • ••

Therapeutic Confirmatory

n

Therapeutic Exploratory

•••

Human Pharmacology

0

> • ••

0

u u

0

0

u

III

PHASES OF DEVELOPMENT

0

C0 IV

Time • Most typical kind of study in this phase

o Possible information generated • Figure 6-2 Study types and the phases of development in which they are performed. Filled circles indicate the most typical kind of study in the phase shown; open circles indicate possible information generated.This graph shows that study types are not synonymous with phases of development. (From E8: General Considerations for Clinical Trials Federal Register. Vol. 62, No. 242. Wednesday, December 17, 1997/Notices p.66116.)

single- and multiple-dose administration schedules and have one or more of the following aspects,

Pharmacokinetics Pharmacokinetics (PK) studies typically determine the drug'S absorption, distribution, metabolism, and excretion pathways. PK may progress throughout a clinical development program and be assessed in separate studies or as part of larger trials to determine efficacy and safety. These studies are necessary to assess the clearance of the drug and to anticipate possible accumulation of the drug or its metabolites and the potential for drug-drug interactions, Assessing PK in subpopulations, such as those with impaired renal function or hepatic failure, is another important aspect of this phase of studies. PK data are usually expressed using the following terms 76 :

• Area under the time-concentration curve (AUC, or AUC O_24 if done over a 24-hour period) is a measure of the total amount of drug absorbed; it is frequently estimated after the drug has reached steady-state levels. • Peak concentration (Crna) is the maximum concentration reached at a particular dosage. • Time to peak concentration (Trnax) is used together with Crnax to measure the rate of absorption. • Cumulative percentage of drug recovered (Ac%) usually relates to urine data and is the cumulative amount of drug recovered over a specific time period (e.g., 24 hours) divided by the initial dose. • Elimination (or terminal) half-life (til) is a measure of how long it takes to clear a drug from the system; it can be estimated by dividing 0.693 by the absolute value of the slope of the terminal linear phase of the concentration profile plotted on a semilog scale. Special considerations for PK studies in children are available on the FDA Web site at http://wwwfda.gov/ cber/gdlns/pedphrm.pdj

Estimation of Initial Safety and Tolerability Drug safety refers to the frequency of adverse drug effects (Le., physical or laboratory toxicity that could possibly be

related to the drug) that are treatment emergent-that is, they emerge during treatment and were not present before treatment, or they become worse during treatment compared with the pretreatment state, An adverse drug effect is distinguished from an adverse event (or experience), which refers to any untoward experience that occurs while a patient is receiving the medication, whether or not it is attributable to the drug. The seriousness of an adverse event dictates how qUickly it must be reported to regulatory agencies and to others who may have ongoing experimental protocols. A serious adverse event (SAE) is defined as one that results in death, is lifethreatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. Investigators conducting pharmaceutical industry-sponsored studies should be aware that companies may have their own, more strict definition of SAEs. The term severity is distinguished from serious in that severity refers to the intensity of a specific event, whereas serious refers to the outcome or consequences of the event. Drug tolerability refers to how well subjects are able to tolerate overt adverse drug effects.

Assessment of Pharmacodynamics Pharmacodynamics (PD) studies assess the uptake, movement, binding, and interactions of pharmacologically active molecules at their specific sites of action. These studies also typically observe the relation of drug blood levels to clinical response or to adverse drug events, They may provide early estimates of drug activity and potential efficacy, and they help to establish the dosage and dose regimen used in later phases of drug development.

Early Assessment of Drug Activity Although early assessment of drug activity is not part of human pharmacology, phase I studies may also determine preliminary efficacy in terms of secondary variables that may be confirmed in later studies.

Phase II Phase II studies are the earliest attempt to establish efficacy in the intended patient population. Many are called therapeutic exploratory studies and will form the basis for later trials. The hypotheses may be less well defined than in later studies, and they may be data driven. The designs are flexible so that changes can be made as the data accumulate. These studies may use a variety of different types of study design, including comparisons with baseline status or concurrent controls. In these studies, the eligibility criteria are typically very narrow, leading to a homogeneous population that is carefully monitored for safety, Further studies may establish the drug's safety and efficacy in a broader population once it is determined that a drug does indeed have activity. These studies may also aim to determine more exactly the doses and regimens for later studies. Phase II studies may use dose-escalation designs to estimate dose response, which may be confirmed in later

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studies. In phase II, doses of the drug are typically, but not always, less than the highest doses used in phase I. Another important goal of phase II studies is to determine potential study end points, therapeutic regimens (including the use of concurrent medications), and subsets of the disease population (mild versus severe).

Phase III The primary objective of phase III studies is to confirm a therapeutic benefit. Therefore, the most typical kind of study is the therapeutic confirmatory study, which provides firm evidence of an agent's efficacy and safety. This type of trial always has a predefined hypothesis that is tested. These studies also estimate (with substantial precision) the size of the treatment effect attributable to the drug. Also incorporated in phase III development are further exploration of the dose-response relationship, study of the drug in a wider population and in different stages of the disease, and the effects of adding other drugs to the investigatory agent. These studies continue to add information to the accumulating safety database.

Phase IV Phase IV studies, sometimes called postmarketing surveillance studies, begin after the drug reaches the market. These studies extend the prior demonstration of the drug's safety, efficacy, and dose. The most frequent phase IV study is one of therapeutic use, which goes beyond the prior demonstration of the drug'S safety and efficacy. These studies demonstrate how the drug performs when used in the everyday setting of the clinic, by patients who may have comorbid conditions, and by patients who may be taking a host of concurrent medications.

Investigations in Special Populations Investigations in children typically take place after considerable data have been gathered in an adult population

!:

III

TABLl 6-3

with a similar disease. If clinical development includes children, it is usually appropriate to start with older children before extending the studies to younger children. The exception to the "adults first" rule is when a medication is developed to treat a condition that occurs only in childhood. The Pediatric Research Equity Act of 2003 (available at http://wwwfda.gov/opacom/lawslprea.html), referred to formerly as the Pediatric Rule, requires manufacturers to assess the safety and effectiveness of a drug or biologic product in children if the disease for which the drug was developed in adults also occurs in the pediatric population.

Classification of Olnlcal Trials by Objective The ICH believes that the classification system based on phases of development is inadequate for classifying clinical trials because one type of trial may occur in several different phases, as was shown in Figure 6-2. Table 6-3 presents an alternative classification system based on the objective of the study, using terminology described earlier.

CONSIDERATIONS FOR INDIVIDUAL CLINICAL TRIALS For special issues relevant to trials in children, the reader is referred to the document entitled, "Guidance for Industry: Ell Clinical Investigation of Medicinal Products in the Pediatric Population," which is available at http://wwwfda.govlcber/gdlnslichclinped.pdf

Objectives Clearly stated primary and secondary objectives and hypotheses form the backbone around which every clinical trial is developed. These should all be clearly stated in the protocol and study report. Table 6-3 provides a framework for developing appropriate objectives for the various types of study planned. In general, trials tend to

An Approach to Classifying Clinical Studies According to Objective

Type of Study

Objective of Study

Examples

Human pharmacology

Assess tolerance Define/describe PK and PO Explore drug metabolism and drug interactions Estimate activity Explore use for the targeted indication Estimate dosage for subsequent studies Provide basis for confirmatory study design, end points, methods Demonstrate/confirm efficacy Establish safety profile Provide an adequate basis for assessing the risk/benefit relationship to support licensing Establish dose-response relationship Refine understanding of risk/benefit relationship in general or special population Identify less common adverse reactions Refine dosing recommendation

Dose tolerance studies Single- and multiple-dose studies of PK and/or PD Drug-interaction studies

Therapeutic exploratory

Therapeutic confirmatory

Therapeutic use

PO, pharmacodynamics; PK. pharmacokinetics.

151

Earliest trials of relatively short duration in welldefined, narrow patient populations, using surrogate or pharmacology end points or clinical measures Dose-response exploration studies Randomized, parallel dose-response studies Clinical safety studies Studies of mortaliry/morbidity outcomes Large simple trials Comparative studies Comparative effectiveness studies Studies of mortality/morbidity outcomes Studies of additional end points Large simple trials

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have one to three main objectives and numerous process objectives. One should be wary of trials with more than a few objectives, although exploratory trials may have objectives that are less clearly delineated than those of later trials.

Population The specific population to be studied is delineated by the inclusion/exclusion criteria. The development of these criteria is one of the more formidable tasks in the entire process. Developers of trials must attempt to reach a compromise between limiting the heterogeneity of the sample and not making the criteria so strict that recruitment of eligible subjects becomes untenable or threatens to restrict the generalizability of results. The heterogeneity of the patient population that will be allowed to enroll in the trial is influenced by the phase of development. Early, exploratory studies are often concerned with whether a drug has any effect whatsoever. In these trials, one may use a very narrow subgroup of the total patient population for which the agent may eventually be labeled. Later-phase, confirmatory trials typically relax the eligibility criteria to allow for a broader, more heterogeneous sample of the target population. Still, if the criteria for enrollment are too broad, interpretation of treatment effects becomes difficult.

Design The study's phase, objectives, ethics, and feasibility influence the specific design of a trial. New designs have appeared in recent years that reduce the time during which children receive placebo or a known inferior medication. 77 ,78 More than one type of design may be used to answer the same question. If the same results and conclusions are reached regardless of the design and analysis used, the results are said to demonstrate robustness. Although a study may be designed as being "pivotal," it is rare that any single trial establishes incontrovertible evidence of an agent's clinical worth.

Comparative and Noncomparatlve Studies Trials may be classified as either comparative or noncomparative studies. A comparative study implies that some type of comparison is made between the drug under investigation at a particular dosage level and either a placebo, another dosage level of the investigational drug, or an active comparator (an existing drug known to be effective for the specific condition). Noncomparative trials involve no such comparisons with the investigational agent. Studies that compare the agent with placebo or an active comparator are called controlled studies. For a discussion and guidance on the proper selection of a control group, the reader is referred to http://wwwfda.govlcber/gdlnslclincontr0501.htm. Studies that involve dose escalation or that compare the PK and PD for differing dosage levels of the same drug are not considered controlled in the usual sense.

Open Studies The early human pharmacology studies in the first phase of development and the postmarketing surveillance (phase IV) studies are usually open label, meaning that everyone involved with the study, including the patient and the physician, knows what the patient is receiving. Studies that occur in phases II and III may have an openlabel extension phase, during which patients who took part in the comparative phase receive the investigational drug openly for an extended period. The chief purpose is to gather longer-term safety and efficacy data. Investigator-initiated protocols may also be open if the intent is simply to gather additional information about an agent in another disease or at a dosage level other than that indicated in the label. As one would expect, the possibility of bias in interpretation of safety and efficacy information with open studies is much greater than with blinded studies. Open studies may be randomized to ensure that subject populations are similar in test and control groups.

Blinded Comparative Studies Beginning either in late phase I or early phase II, blinded, controlled (comparative) studies are performed. Blinding refers to the masking of those involved in the assessment of the patient and, in some situations, of the data analyst. The purpose of blinding is to prevent identification of the treatment until any opportunity for bias has passed. These biases include (but are not limited to) decisions about whether to enroll a patient, allocation of patients, clinical assessment of end points, and approaches to data analysis and interpretation. Designs in which both the assessor and the patient are blinded are called double-blind designs. Designs in which only the patient or only the assessor is blinded to the treatment are called single-blind designs. Studies should attempt to maintain blinding until the final patient has completed the study, although this has proved difficult in certain pediatric studies of severe diseases. Clinical studies in humans typically have a Steering Committee to provide oversight of the trial and a Data Safety and Monitoring Board (DSMB) to provide ongoing monitoring. To perform their charges, committee members may observe results of the trial categorized into groups of patients-that is, the committee members are aware of which group a patient is in but unaware of which intervention that group is receiving. The committee members are said to be group unblinded, whereas the investigators remain totally blinded.

Blind Assessor Certain studies present challenges to the maintenance of blinding because blinding is either unethical or impractical. For example, surgical versus nonsurgical interventions prevent the patient and the surgeon from being blinded because they know whether surgery was performed. In this situation, a blind assessor may be used to evaluate the patient's condition. The blind assessor may

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be a physician, nurse, or other health professional who evaluates the patient's response to treatment but is unaware of the treatment being given.

,

II

TABLE 6-4 Example of a Randomization Schedule (Nonstratified, Blocks of 8)"

Patient Number

Double-Dummy Design to Maintain Blinding

Randomization Block 1

Another situation in which blinding of the patient is difficult is when the dosage administration regimen is different for two drugs being compared. An example in rheumatology is the comparison of methotrexate (administered once weekly) versus hydroxychloroquine (administered once daily). In this case, the double-dummy design can be a useful way to maintain the blind. In the example mentioned, patients who are to receive methotrexate take active methotrexate once per week and dummy hydroxychloroquine each day, whereas patients who are to receive hydroxychloroquine receive active hydroxychloroquine each day and dummy methotrexate once per week. Double-dummy designs are limited by ethical issues involving, for example, repeated infusions or other aggressive means of delivering the "dummy" agent.

Treatment A Treatment B

Randomization The purpose of randomization is to introduce a deliberate element of chance into patient assignment to the treatment groups. Randomization reduces (but does not eliminate) the chance of an unequal distribution of known or unknown prognostic factors among the treatment groups. It also reduces possible bias in the selection and allocation of subjects. Many randomization schemes are currently employed. The simplest form of randomization is unrestricted. Patients are assigned to one of two or more treatment groups by a sequential list of treatments. The list of treatments is known as the randomization schedule. Blocked randomization is commonly used to ensure that equal numbers of patients are placed in each treatment group (Table 6-4). Note in the table that the assignment to groups is not sequential, but when the block is full an equal number of patients will have been enrolled into each group. If the blocks are too small, there is a risk of unblinding. As an extreme example, suppose blocks were only two cells large for a study that planned to compare two drugs. If a clinical investigator knew the block size, enrolled only two patients, and became aware of what one of the patients was receiving through an adverse drug effect, then he or she would automatically know what the other patient was receiving. On the other hand, if the blocks are too large they may not be completely filled, thus increasing the likelihood of unequal assignment to the groups. In recent pediatric rheumatology studies involving two groups, block sizes of six to eight have been used. Clinical investigators are never made aware of block size during the trial. Blocks may also be stratified by some prognostic factor to ensure equal distribution of the factor among the treatment groups. In multicentered trials, randomization may be stratified by center, such that each center has its own set of blocks. This tends to produce equal numbers

1 3

2 4

6 5

8

12

13

14

9

10

11

15 16

7

Randomization Block 2 Treatment A Treatment B

'The first patient entering the study receives treatment A, the second receives treatment A, the third receives treatment B, and so on. The sequence of assignments is random. When the block is full, equal numbers of patients have been enrolled into each treatment group. After block 1 is full. the assignment moves to block 2.

of patients in each group at individual centers. In pediatric rheumatology, stratification by center is frequently not possible because only small numbers of patients are enrolled at each center. If a multicentered trial uses only one randomization schedule for all centers, whether it is unrestricted or stratified, the study is said to be randomized across all centers. Typically, a central coordinating center takes responsibility for giving all centers randomization numbers. The use of more than two stratification factors is rare. Such designs are logistically difficult and do little to achieve a balance of prognostic factors. Typically, a DMSB checks whether randomization is achieving balance of important prognostic factors while the trial is continuing. If imbalance of one (or at the most two) prognostic factors is found, the randomization scheme may be altered to achieve more balanced groups. This is known as dynamic or adaptive randomization.

Design Configurations of Comparative Studies Design configurations refer to treatment group assignments after initial randomization (Le., whether or not patients remain in the same treatment group throughout the study). All of these configurations may be open, blinded, or both. If patients remain in the same group to which they are initially assigned, the study is known as a parallel group design. In crossover designs, patients switch from one treatment to the next, often in a randomized manner, and each acts as his or her own control for purposes of analysis. The crossover design in the trial must be distinguished from the frequently used open-label extension phase (discussed earlier), in which all patients receive the active drug. Factorial designs allow for study of the interaction of two treatments that are likely to be used in combination. The simplest factorial design is a 2 x 2 design in which patients are assigned to receive drug A only, drug B only, both drug A and drug B, or neither drug A nor drug B. Factorial designs are also used to study dose response when two agents are used together. Group sequential designs are particu-

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lady well suited to interim analyses. This design implies that the various treatment groups are evaluated for safety and efficacy at periodic intervals during the trial to determine whether the trial should continue or be stopped because of safety or efficacy concerns. Other comparative designs, whose basic approaches are evident from their names, include dose-escalation and fixed-dose dose-response trials. A design recently used to study etanercept in the treatment of polyarticular JRA77 is the blinded withdrawal design. In this approach, all patients receive active medication long enough to establish whether patients respond (according to a standard definition). Patients who are not classified as "responders" after the prescribed time period are discontinued from the study and classified as therapeutic failures. Patients who respond are randomly assigned either (1) to be withdrawn blindly from active medication and given placebo or (2) to continue to receive active medication but in a blind manner. A common phenomenon in blinded-withdrawal studies is a mild flare of disease among patients who continue to receive (blinded) active medication after randomization. This is called the reverse placebo effect, because it is the reverse of the beneficial effect that often is observed in patients who are blindly randomized to placebo. The primary outcome after randomization can be time to flare or percentage who flare (according to a standard definition). A design that has gained widespread acceptance in oncology and is now being used in pediatric rheumatology is the open-randomized, actively controlled trial. Patients are randomly assigned to one of two or more treatment arms, all of which are active. The trial is open and, in general, no additional trial procedures or visits other than routine care are required. These trials have numerous advantages but also substantial disadvantages. 79 This design has gained in popularity as a method to study treatments of rare conditions in which pivotal, confirmatory trials are not possible and for which there is little economic incentive for pharmaceutical companies to develop the product or for studies of combination therapy.Ho.H! These trials tend to be more "user friendly" than studies that are part of a clinical development program. Perhaps their biggest advantage is that they are inexpensive to conduct, because third-party payers may be billed for the procedures. They are not used to seek a new label or indication for an agent, and they are considered exploratory.

N of 1 Design The N of 1 approach repeatedly and randomly crosses over individual patients from one therapy to the next. For example, the randomization scheme may be A, B, B, A, A, B. Data from numerous N of 1 trials in individuals may be combined to increase the sample size, but this is fraught with difficulties and sources of potential bias. These studies are considered exploratory and are hampered in rheumatology and other diseases by the carryover effects of the treatment, natural fluctuations of the disease state unrelated to therapy, and logistic problems. For a discussion of the usefulness

OF CLINICAL INVESTIGATIONS

of these designs in rheumatology, see the review by Giannini. H2

Intent of Comparative Studies The type of comparison that one intends to carry out must be decided on before the protocol can be synthesized. Major types of comparisons include trials to show superiority, trials to show equivalence, trials to show noninferiority, and trials to show dose-response relationship. All comparative trials must possess assay sensitivi~y, defined as the ability of a study to distinguish between active and inactive treatrnents. H3 Trials to show superiority are perhaps the most frequent type of comparative studies. They are designed to show superiority of the investigative agent compared with either placebo or an active comparator or to demonstrate a dose-response relationship. In pediatric rheumatology, placebo-controlled studies have become more difficult because some existing agents are clearly better than placebo. In such situations, the use of a placebo design is considered unethical and an active comparator is substituted. Trials to show eqUivalence do not aim to show superiority but rather equivalence (either biologic or clinical). They intend to show that the difference in response to two or more treatment approaches is clinically unimportant. For equivalence trials, the usual statistical approach is to use two-sided confidence intervals (CIs) (explained later). Equivalence is inferred if the entire CI of the true treatment difference falls within the equivalence margins. Stated another way, a statistical test of inference that results in a nonsignificant P value (i.e., no difference between the test drug and the active comparator) is not enough to conclude that the two agents are equivalent. Trials to show noninferiority are similar to equivalence trials, but the question is asked in only one direction (i.e., whether the investigative agent is no worse than the standard therapy). In this case, a one-tailed CI is used to infer noninferiority. Again, a simple one-sided test of the null hypothesis (Ho) that finds "no difference" between the treatments is insufficient to make conclusions about noninferiority. The latter two trial types can be difficult to design, and sample size requirements are often much higher than for superiority trials. This is particularly true in active control equivalence or noninferiority trials that do not use placebo or that do not use multiple doses of the new drug.H3 The lack of internal validity makes external validation necessary. Active comparators should be chosen that have been shown through convincing, confirmatory trials to be efficacious in the particular condition. Further, the same response variables should be used in the equivalence or noninferiority trials that were used in the confirmatory trials of the active comparator, and equivalence margins should be clinically sound. Trials to show dose-response relationships occur throughout the development phase of a drug and may have numerous objectives, including confirmation of efficacy, establishment of the dose-response curve, estimation

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of the most appropriate starting dose, strategies for dose adjustment, and estimation of the maximum dose.

Ethical Requirement for Clinical Equipoise in Comparative Studies Clinical equipoise refers to the equality regarding probability of benefit that must exist between two or more groups being compared in a study. This probability of benefit is derived from existing, scientifically valid evidenceof the effectiveness of the agents being tested, and not from anecdotal or "gut" feelings. In other words, an investigator may ethically enroll patients into a comparative trial if there is a lack of convincing evidence of superiority of one of the agents, or if there is reasonable doubt in the medical community about the clinical utility of the agents. The requirement of clinical equipoise is often mistakenly interpreted as making any placebo-controlled study unethical. Ongoing debate in the literature of the ethics of placebo-controlled trials, particularly in children, is much too extensive to discuss in detail here. 83-t85 Excellent arguments for when placebo trials are appropriate have been presented by Freedman. 86--88 According to these authors, five conditions in which a placebo control may be used are as follows: There is no standard treatment. Standard treatment is no better than placebo. Standard treatment is placebo. The net therapeutic advantage of standard treatment has been called in question by new evidence. • Effective treatment exists but is not available due to cost or short supply.

• • • •

The final arbiter is always the Human Subjects or Ethics Committee.

Conducting the Clinical Trial With the advent and widespread use of independent forprofit clinical research organizations (CROs) and site management organizations (SMOs), the quality of clinical trial conduct has risen substantially. Academic research organizations (AROs) appeared in the 1990s. Although not typically involved in the day-to-day operations of the trial, AROs provide the basic scientific and theoretical background for the trial. These functions may include biologic justification for the selection of the particular therapy, identification of biologic and clinical response variables, development of the protocol, interpretation of the results, and final report preparation. Pediatric rheumatology clinical trials, with few exceptions, are multicentered approaches. This term implies that multiple clinical investigative sites are used to enroll enough patients to meet statistical power requirements. A coordinating center (CC) is responsible for coordinating almost all trial activities. The role of the CC is determined in part by whether a CRO is used and whether the trial is part of a clinical development program or an investigator-initiated protocol. Site monitoring may be a function of the CC or the CRO. During visits to clinical sites, site monitors-known throughout industry as clinical research associates (CRAs)-verify the data on the

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case report forms against source documentation (j.e., original reports from the laboratory and clinical records). Data collection (or capture) is moving to "paperless coordinating centers." Before the widespread use of electronic communication, almost all data were collected during the site-monitoring visit, or forms were mailed to the CC or directly to the sponsor. Now, use of e-mail and electronic entry of data via scanning of forms is increasing. The electronic age has drastically reduced the number of patients entered into trials who do not meet the eligibility criteria and the amount of inappropriate, incorrect, or missing data. Data collation refers to the distillation of data from the case report forms to summary tables and spreadsheets. This step is necessary before data analysis can be performed and facilitates the review of both safety and efficacy data by the DMSB. The DMSB is charged with, among other items, determining whether the trial should continue unchanged, be modified, or be stopped early because of safety or efficacy concerns.

Data Analysis Plan The role of the statistician begins with planning of the study and not after the data are already in hand. Plans for exploratory studies may not be as formal as those for confirmatory trials, because the former permit the use of data-driven hypotheses to be tested. That is, data exploration is encouraged in exploratory, hypothesis-generating, nonpivotal trials. A single study may have both confirmatory and exploratory aspects. At a minimum, the statistical considerations document includes the following items: 1. Whether descriptive statistics, statistical inference, or both will playa role in the analysis 2. Identification of the primary and secondary response (outcome) variables 3. Calculation of sample size, including assumptions that will be used to justify the sample size, which in turn include the a and ~ error levels, the difference that one wishes to detect as statistically significant, and how the variance estimate will be obtained 4. How the various analysis sets of patients to be used in the analysis will be formed, including the plan for handling dropouts, noncompliant patients, and other sets of patients who do not complete the protocol as written 5. Which statistical tests of inference will be used and the justification for their use 6. Plans for adjustment of P values based on the number of secondary hypotheses to be tested 7. Statement of which aspects of the analysis plan are expected to generate confirmatory data and which are exploratory, including plans for any subgroup analyses 8. Plans for handling covariates 9. The data management and statistical analysis software that will be used

Most of these items are discussed later (see "Understanding and Describing Data" and "Statistical Tests of Inference Commonly Used in Clinical Investigations"); others are selfexplanatory. Items 2 and 4 require further attention here.

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Primary and Secondary Response Variables Response variables are defined as those outcomes that will be used as the main evidence of the treatment effect of the investigational drug. Students of clinical research should keep in mind that the field of response variables is not static, and advances in their measurement, description, and methods of analysis will continue to change and improve, as they have done since the previous version of this text.89 Treatment effect is defined as an effect that is expected to result from a therapy. In comparative trials, the treatment effect of interest is a comparison of two or more agents. Treatment effect is distinguished from effect size, which is a measure of the responsiveness (sensitivity to change) of the outcome variable and is defined mathematically as the mean change of the variable among the patient groups divided by the standard deviation (SO) of the baseline score. A related term is the standardized response mean, which is the mean change in a variable's score from baseline to the follow-up visit, divided by the SD of this change. 90 In studies designed primarily to observe safety and tolerability of an agent, the "response" variable relates to adverse events or treatment-emergent adverse drug effects rather than to efficacy. Thus, the choice of primary response variables largely depends on the objectives of the trial and should reflect clinically relevant effects. Secondary response variables are usually (but not always) associated with the exploratory nature of the study. Surrogate endpoints are outcomes that are intended to relate to a clinically important end point but do not in themselves measure a clinical benefit. The use of biologic surrogate end points in rheumatology as primary outcomes is somewhat suspect. For example, a decrease in some targeted T cell type may not produce clinical benefit even though the desired biologic effect was achieved. A frequently encountered problem in rheumatology is that of multiplicity (Le., the use of multiple primary end points with repeated statistical testing). To avoid this problem, the use of composite variables has become popular. This strategy involves the integration or combining of multiple relevant variables into a single variable, using a predefined algorithm. Three examples of composite variables are the American College of Rheumatology 20 (ACR-20)91 and the Disease Activity Score (DAS)92 for use in trials of adults with RA and the ACR Pediatric-30 for use in trials of children with JRA. 93 Each attempts to dichotomously categorize patients as improved or not improved, using a core set of variables assembled into an algorithm. Composite variables avoid the multiplicity problem without requiring adjustment of the type I error level (described later) due to multiple hypothesis testing.

Response Variables Based on Claims Allowed The claims that the FDA allows for antirheumatic and antiinflammatory therapies for RA and JRA include reduction in signs and symptoms, major clinical response, complete clinical response, remission, prevention of disability, and prevention of structural damage (see http://wwwfda.gov/ cber/gdlns/rheumcln.pdj). The reduction in signs and symptoms claim is usually the first to be granted for marketing approval. This claim

A N A LY SIS

0 Fell N I CAL

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is typically established in trials of at least 6 months' duration unless the product belongs to an already well-characterized pharmacologic class, in which case trials of 3 months' duration are sufficient to establish efficacy for signs and symptoms. For trials in adults, the FDA recommends that the ACR-20 criteria be used. In pediatric rheumatology, the FDA suggests that the ACR Pediatric30 be used for JRA. The major clinical response claim is awarded to agents that are able to show a response at the ACR-70 level, rather than the 20% improvement needed for a signs and symptoms claim. This claim is based on statistically significant improvement response rates by the ACR-70 definition compared with background therapy in a randomized controlled group. Trial duration should be a minimum of 7 months for an agent that is expected to have a rapid onset of action and longer for agents with less rapid effects. The complete clinical response claim is granted to a drug that produces a remission for at least 6 continuous months by the ACR-20 criteria and by radiographic arrest. Complete clinical response indicates that the patient is in remission but is still taking antirheumatic drugs. Typically, trials for a complete clinical response last a minimum of 1 year. Remission is defined as continuation of the same result after all antirheumatic drugs have been withdrawn. The remission claim is granted if remission by the ACR definition and radiographic arrest (no radiographic progression by the method of Larsen and colleagues94 or by the modified method of Sharp and associates95 ) are maintained over a continuous 6-month period while the patient is off all antirheumatic therapy. A drug need not be a cure to be awarded a remission claim. A remission claim can be granted even if the patient relapses after 6 months or more of remission. Trials aimed at a remission claim should be at least 1 year in duration. Wallace and colleagues56 developed a preliminary definition of clinical remission for use in JRA. The prevention of disability claim is granted to drugs for which the primary outcome is a functional ability measure, such as the Childhood Health Assessment Questionnaire or the Arthritis Impact Measurements Scale. In addition, the full effect of JRA on a patient is not captured without the use of a more general healthrelated measure of quality of life. For this reason, data from a validated measure such as the Medical Outcome Study Short-Form Health Survey (SF_36),96,9 7 the Childhood Health Questionnaire, or the Pediatric Quality of Life Inventory Scales (Peds QL)98,99 should also be gathered, and the patient's condition should not worsen on these measures over the duration of the trial. The prevention of structural damage claim is granted to drugs that show either a slowing of radiographic progression or the prevention of new erosions demonstrated by radiography or other measurement tools such as magnetic resonance imaging. These trials should be at least 1 year in duration. Certainly, other clinical efficacy response variables are possible, and in pediatric rheumatology the ACR Pediatric-30 is likely to be inappropriate for the study of rheumatic conditions of childhood other than JRA.

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Whatever variables are chosen, they must possess a host of validity characteristics. These include responsiveness (sensitivity to change within the trial's duration), face (clinical sensibility), content (comprehensiveness), construct (biologic sensibility, or how the variable is hypothesized to behave as compared to how it does behave), and criterion (does it agree with the gold standard, if one exists) validity.lOo In addition, variables should be reproducible (reliability) and, if more than one variable is chosen, nonredundant with one another.

Analysis Sets (Patients) Not all patients who enter a trial complete the protocol as it is written. The analysis plan must state how subjects who drop out, are noncompliant, or in some other manner do not follow the protocol specifications will be handled. The formation of analysis sets should be aimed at minimizing bias and avoiding an increase in the possibility of an erroneous conclusion that a difference is present between groups when, in fact, it is not (type I error, described later). The per-protocol set (also called valid cases set, efficacy sample, or evaluable subjects sample) comprises those subjects who closely follow and complete the protocol. In practice, consideration of only the per-protocol set results in the loss of valuable information from patients who perhaps completed most of the study or had only one or two major protocol violations related to, for example, concurrent medication. Therefore, the full-analysis set is also used for the primary analysis. The full-analysis set refers to the intent-totreat approach and is derived from all randomized patients, including those who dropped out early or had a major protocol violation. Historically, the intent-to-treat analysis meant that all patients, whether they dropped out, were noncompliant, or otherwise deviated from the written protocol, were evaluated for outcome at the time that they would have had their last visit (because one intended to treat them until then). The concept is embodied in the brief saying, "Once randomized, analyzed." However, this approach results in the introduction of substantial bias and is problematic in rheumatology and other specialties in which patients, once off trial, are lost to follow-up and receive various other medications and procedures. It is now common to use a modified intent-to-treat analysis, the last-observation-carried-fonvard (LOCF) approach. This technique involves using the last value obtained for a response variable (no matter when in the trial it was measured) as if it were measured at the scheduled final visit. In this way, the data from noncompleters who were exposed to the drug long enough to experience treatment effects (if any) can be combined with the data from the per-protocol set. The intent-to-treat approach allows for minimal exclusion of some patients, such as those who, after randomization, never received any of the investigational medication.

UNDERSTANDING AND DESCRIBING DATA In any type of clinical investigation, the investigators collect data and want to be able to summarize, interpret, and con-

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vey it to other parties. In order to do this, it is important to understand how measurements are made, how data can be displayed, and how the types of data determine the appropriate statistical test. The types of measurements (variables) determine which statistical test to use.

Scales of Measurement: Categorical, Ordinal, and Continuous Data The scale or level of data has important implications for how information is displayed and summarized. All data may be classified into one of the following measurement scales: categorical, ordinal, or continuous (numeric).

Categorical Variables For categorical (qualitative) variables, sometimes called nominal variables (i.e., "in name only"), each subject can be placed into one of the categories. Variables with two possible outcomes, such as Yes/No or Male/Female, are called dichotomous. Categorical variables are categorized in terms of proportions or percentages (e.g., the study population was 75% female and 25% male). The best ways to display categorical data include contingency tables and bar charts.

Ordinal Variables On an ordinal scale, the variables used have an inherent order. Subjects can be placed in "ranked" or "ordered" categories. Examples of ordinal variables include the severity scores of swelling (0 to 3+), Apgar scores, and tumor staging. Order exists among the categories, but the difference between adjacent categories is not uniform throughout the scale. Figure 6-3 shows an example of an ordinal variable, the standard method used to grade swelling by pediatric rheumatologists. The difference between swelling severity scores of 0 and 1 is not the same magnitude as the difference between scores of 2 and 3. Ordinal variables are best summarized using percentages and proportions. The entire set of data measured as an ordinal scale may be summarized by a median value.

Continuous Variables Continuous variables are observations in which the differences between numbers have meaning on a numeric scale. These are quantitative measures. Examples are age, height, weight, blood pressure, survival time, and laboratory values such as glucose, sodium, and potas-

0 - - - - - 1 + - - - - - 2+ - - - - - 3+

None No joint swelling

Mild Moderate Mild. definite Definite swelling swelling but with no with obscuring blurring of normal of skeletal landmarks skeletal outlines

Severe No discernible skeletal landmarks

• Figure 6-3 Example of an ordinal level variable. An ordinal scale is used to assess the severity of swelling in a joint.

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sium levels. Although continuous variables all have meaning on a numeric scale, differing degrees of precision are required for different types of studies. For instance, age in a study of adults may be estimated to the closest year; in children, age may have to be estimated to the closest month, and in neonates, to the closest day or hour. Characteristics measured on numeric scales can be displayed in tables and graphs. Means and SDs (discussed later) are used to summarize continuous variables.

When to Convert Higher Levels of Data to Lower Levels As a rule, one should work with the highest level of data possible, because of increased quantitative precision and because parametric statistics are, in general, more powerful than nonparametric equivalents (see later discussion). Yet, there are times when, for example, numeric data should be converted to ordinal or nominal data before further analyses are conducted. Situations in which "lowering" the level of data may be appropriate include the following:

• In a multicentered study in which different methods are used to generate a numeric value (e.g., the antinuclear antibody titer when different substrates are used). In this situation, one may be forced to "dichotomize" patient results, describing them as simply "normal" or "elevated," and conduct the analysis using statistics appropriate for a nominal rather than a continuous variable. • ff the experimenter suspects measurement error in the data. An example is compliance with a prescribed drug dosage or with a clinical trial or physical therapy program. It may be necessary to divide the patients dichotomously and classify each as "compliant" or "noncompliant." • If reliability (reproducibility) of the measurement tool is unknown or likely to be poor. In pediatrics, the reliability of measurement on visual analogue scales is suspected to be low in young children. Rather than reading the result in centimeters from the left side of the scale, investigators frequently place a grid that is divided into 10 equal segments over the visual analogue scale line and read the result as a whole number from 0 to 10. This effectively converts a continuous variable to an ordinal level outcome. • In clinical trials when one wishes to use a set of response variables (of any data level) to dichotomously divide patients into "responders" and "nonresponders." Examples have been presented earlier in this chapter.

Concepts Related to Measurement of Variables: Validity, Variability, and Bias In clinical research, it is obvious that not all patients treated identically will experience an identical response. This is known as the variability that is common to virtually all human experimentation. Certain important terms are associated with describing how this variability may have arisen. In some situations, its sources can be mini-

mized or eliminated altogether. Variability is sometimes called error. Error may be broadly classified into nonrandom and random error. Nonrandom error is also called bias or systematic error. It results in a lack of validity of a measure and therefore influences the accuracy of the measure. In general, validity is equated with accura9. Random error refers to imprecision. In Figure 6-4, the different types of random error and systematic error are graphically demonstrated.

Potential Sources of Variability in Measurement of Individuals Variability may arise among individuals from a number of factors, including diurnal variation; changes related to factors such as age, diet, and exercise; and environmental factors, such as season or temperature. Variability may also arise from measurement characteristics, including poor calibration, inherent lack of precision of the instrument, and misreading or misrecording of information from the instrument.

External Versus Internal Validity External validity may be equated with generalizability. It determines the population settings to which measurement and treatment variables can be generalized. Internal validity defines how valid the conclusions are within the patient sample studied; it is a basic minimum requirement. without which any study is uninterpretable. The question of external validity is meaningless without first establishing whether the study is internally valid. Obviously, both types of validity are important. However, they may be at odds, in that study design features that increase one may tend to decrease the other.

Bias An excellent, concise discussion of biases can be found

at http://www.musc.eduldclicrebmlbias.html. Space considerations prevent a thorough discussion of all types of

Accuracy and Precision

Accuracy Only

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Precision Only

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• Rgure 6-4 Combinations of accuracy and precision in describing a continuous variable. Accuracy is impaired by bias or systematic error, precision by random error.

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bias that can enter into clinical studies. Sources of bias that may occur in clinical studies include selection, measurement, unacceptability, confounding, recall, referral, volunteer, withdrawal, attention, investigator, and verification, among others. To complicate matters further, the same type of bias may go by different names or be a subset of some other bias (see later discussion). Many are self-explanatory and need little explanation. A few of the more important types of bias are discussed here. Selection bias-the distortion of study effects resulting from the sampling of subjects-includes volunteer bias, nonresponse bias, and bias resulting from loss to followup. Another subtype of selection bias is referred to as detection bias. Measurement bias (sometimes referred to as information bias) is distortion of the study effect resulting from inaccurate determination of the study variables (either exposure or disease). Measurement bias may be divided into nondifferential and differential misciassification. Nondifferential information bias can occur if the exposure is not accurately assessed. This type of bias may occur in occupational research, for example, if job titles are used as a surrogate for exposure status. Another form of nondifferential measurement bias is unacceptableness bias, in which the exposure may be under-reported by patients if it is unacceptable behavior. This is likely to have an impact on all subjects, not just subjects with the disease of interest. Differential misclassification bias includes recall bias, in which the recall of information about exposure is influenced by whether the person has the disease (Le., cases may have more accurate memory of events leading to disease than controls who have no disease). Interoiew bias can occur if the circumstances under which different groups of subjects are interviewed are not compatible. These circumstances include time from exposure to interview, setting of the interview, person doing the interview, manner in which questions are asked (prompting), and whether the subject has knowledge of the research hypothesis. Case-control studies are particularly vulnerable to informationbias. Confounding bias is a distortion of the study effect that results from mixing of the exposure associated with the disease with the effects of one or more extraneous variables. An extraneous variable that wholly or partially accounts for the apparent effect of the exposure or that masks an underlying true association is called a confounder. Examples of confounding are (1) an apparent association between an exposure and a disease that may actually be due to another variable and (2) an apparent lack of association between exposure and disease that results from failure to control for the effect of some other factor. An example of confounding bias in pediatric rheumatology can be found in a recent report by Brunner and colleagues. 101 These investigators attempted to identify risk factors for damage in childhood-onset systemic lupus erythematosus (SLE). An association was found between damage and disease duration, indicating a possible (and logical) cause-and-effect relationship between the two. However, once the data were corrected for the confounder disease activity over time, disease duration disappeared as a predictor of damage.

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To assess the pOSSibility of confounding, the standard technique of stratifying the data by the potential confounder may be used. One looks for an association between the exposure (as a possible causal factor) and the disease, then compares those subjects who have the confounder with those who do not to see whether an association exists. Another common method is to use Mantel-Haenszel procedures to calculate an overall relative risk in which the results from each stratum are weighted by the sample size of the stratum. 102 Only established risk factors for the disease should be investigated as potential confounders. In brief, these can be dealt with in the design of the study (i.e., by matching) or by stratification or multivariate analysis (see later discussion).

Desalblng Data and the Frequency Distribution of Continuous Variables Descriptive statistics are commonly used to graphically represent individual data points or to summarize groups of data, regardless of the data level. Many exploratory and epidemiologic studies use only descriptive statistics, rather than inferential statistics (tests of hypotheses). Graphs such as dose-response curves represent descriptive statistics. Rates and ratios are commonly used in epidemiologic studies to describe disease frequency and distribution. A rate (or proportion) implies that the numerator is part of the denominator and is usually associated with a time element (e.g., an annual case-fatality rate of 11/120 implies that the 11 deaths came from the total of 120 cases). The numerator of a ratio is not part of the denominator (e.g., the female/male ratio among patients with oligoarticular-onset JRA is 6: 1). Statisticians employ many types of distributions for describing and analyzing data. These include the binomial (BernoullO, geometric, chi-square, Poisson, t, and F distributions, among others. The frequency distribution of continuous variables is most commonly referred to in the medical literature and is the only distribution discussed in detail in this chapter. Its parameters form the basis of much of the descriptive statistics used in the reporting of data from clinical investigations. A frequency distribution of a continuous variable is simply an x-y plot of the possible values that a variable can take on (x-axis) versus the number of observations having the particular values (y-axis). If the frequency distribution is normally distributed it is called a gaussian distribution (Fig. 6-5).

Measures of Central Tendency, Skewness, and Kurtosis Every distribution of continuous variables has an arithmetic mean (average), which is calculated by adding the observations and dividing the sum by the number of observations. The median of any distribution is the centermost value. If the distribution has an even number of observations (Le., there is no center value), the median is calculated by averaging the two most center values. The median is also the 50th percentile. The mode is the

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• Figure 6-5 The normal or gaussian distribution (bell-shaped curve), showing the approximate percentage of observations expected to be found within one and two standard deviations (SO) from the mean value. Also note the critical values for one- and two-tailed tests of hypotheses.

most frequently observed value. The mean, median, and mode are all called measures of central tendency. A distribution has only one mean and one median, but numerous modes are possible; this leads to forms such as bimodal and multimodal distributions. In a normal distribution, the mean, median, and mode are all the same value. Figure 6-6 demonstrates the effect of positive skewing on the measures of central tendency. The skewness is said to be positive because there are too many observations in the upper (shaded) tail (Le., toward the right side of the distribution). This type of skewing typically occurs in distributions that have a fixed lower boundary but no upper boundary (e.g., results of liver function tests). Negative skewing is the mirror image of Figure 6-6 and has the opposite effect on central tendency measures. An example is the age at onset of disease among patients with oligoarticular ]RA. Kurtosis is a measure of the peakedness of a distribution.

Measures of Spread or Variation The frequency distribution of continuous variables can be described by its mean and its standard deviation (SD). The SD is a measure of the spread of values. Abbreviations in common use for the mean include x for the sample mean and Il for the underlying population mean from which the sample was drawn. The SD in a formula is designated s for the sample SD and 0 for the population SD; it is the square root of the distribution's variance. Variance is calculated by subtracting the mean from each of the individual values in the distribution, squaring the differences (to eliminate the negative sign), summing the squares, and dividing the result by the

number of observations minus 1. The sample variance is abbreviated S2, and the variance of the population from which the sample was drawn is 0 2 • If a frequency distribution is normally distributed, the distance ± 1 SD from the mean includes 68.3% of the observations, ±2 SD includes 95.8% of the observations, and ±3 SD includes 99.7% of the values. Actual distributions from clinical investigations may include more or fewer of the observations at the SD cut points than these theoretical percentages indicate. To demonstrate an SD, consider the following example. The mean number of swollen joints among 551 children who were entered into trials of second-line agents was 16.1, with an SD of 11.6. Therefore, 376 (68.3%) of the children in these trials should have swollen joint counts between 28 and 45 06.1 ± 11.6). Note that if one were to consider 2 or 3 SDs from the mean, the range of values included would drop below 0, again pointing to the theoretical nature of the SD rather than actual values. The impossible values are an indication that the distribution is not perfectly normal.

Z Scores: Placing a Single Value Within a Distribution of Values Frequently, clinical investigators find it useful to locate exactly where an individual patient's value for some variable lies within a distribution of values. Because the normal distribution depends on two parameters, the mean and the SD, there is an infinite number of normal curves, based on the variable being measured. However, all tables of the normal distribution are for the distribution described by a mean of 0 and an SD of 1. Therefore, any variable with a mean not equal to 0 and an SD equal to 1 must be rescaled so that these parameters are met. The solution is to convert the variable to a standard normal variable, Z (also called a standard normal deviate). For example, in a clinical trial of calcium supplementation in postpubertal females with ]RA, eligibility criteria may include the requirement that the patient's bone mineral content (by dual-energy X-ray absorptiometry [DEXA]) must be less than 1.5 SD below the mean of the normal population. A Z score can be calculated by subtracting the population mean from the measured value in the individual and dividing the result by the SD of the

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population: Z = (x; - /l)/a, where Xi is the individual's value. One may transform the Z scale back to the original scale by the formula Xi = /l + aZ. Thus, if the population mean is 2143 g and the population SD is 308 g, a patient whose bone mineral content is less than 1681 g (Le., 2143 - [308 x 1.5] respecting the negative direction) qualifies for the study with regard to this eligibility criterion. A Z score also can be calculated using the sample mean and SD. In addition, two means can be compared to determine whether they are statistically significant via the Z test if the sample size is large. Any continuous numeric variable can be converted to the Z scale.

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Although the median, mode, and range (described earlier) are helpful, the mean and SD may be quite meaningless in this situation. A commonly used method is to group the ranked values in a non-normal distribution into quartiles, which are similar to percentiles, but with only four categories: Q1 = 25%, Q2 = 50%, Q3 = 75%, and Q4=100%. The spread, or dispersion, of a non-normal distribution is described in terms of the interquartile range. This is the difference between the highest value in the third quartile (Le., the 75th percentile) and the highest value in the first quartile (i.e., the 25th percentile). In other words, the formula for the interquartile range is Q3 - Q1.

Standard Error of the Mean The standard error of the mean (SEM) represents a different concept from the SD. Mathematically, it is expressed as SEM = SD/Yn, where n is the sample size. Because samples drawn from an underlying population do not each produce the same mean value (but tend to cluster around the same value), one must calculate the range of where the true (unknown) population mean lies. FrOm the formula, it can be seen that the greater the n (Le., the larger the denominator), the smaller the SEM. Thus, the SEM gives the clinical investigator an idea of how "tightly" the estimated mean from the sample represents the true, underlying mean. Investigators often ask statisticians what should be plotted when presenting the data as a mean and its accompanying measure of variability, the SD or the SEM. Because the SEM is always less than the SD, investigators tend to plot it rather than the SD. A rule of thumb is that the SD should be used when comparing values from individual subjects to a population distribution. The SEM is used when plotting mean values of two groups of subjects.

Confidence Intervals As stated earlier, the SD encompasses the variability of

individual observations and the SEM indicates the variability of means. The mean ± 1.96 SD estimates the range of values within which 95% of the observations from subjects can be expected to fall (see Fig. 6-5). Similarly, the mean ± 1.96 SEM estimates the range in which 95% of the means of repeated samples from the same population should fall. If the mean and the SEM are known, the 95% CIs can easily be estimated. These limits indicate the range of values within which the investigator is 95% sure that the true mean of the underlying population lies. One can eas!Iy calculate any CI level (e.g., 90% CI, 99% CI) by using the critical values that cut off specific areas of the curve. CIs are frequently used in addition to statistical hypothesis testing. They can be calculated for the chisquare test, the t test, regression, and a variety of other tests of statistical inference.

Describing Non-normal Distributions Not all parameters used to describe normal distributions are helpful when one is attempting to describe distributions that are nongaussian (Le., do not follow a bell-shaped curve or reasonable approximation).

STATISTICAL TESTS OF INFERENCE COMMONLY USED IN CLINICAL INVESTIGATIONS This chapter does not attempt to describe comprehensively the myriad statistical procedures that are readily available to the clinical investigator through such computer programs as Statistical Analysis System (SAS) or Statistical Package for Social Sciences (SPSS). Rather, a basic introduction to statistical concepts is provided, followed by a description of the inferential and other procedures found most commonly in the literature. Formulas are not stressed, because virtually all statistical procedures are now conducted with the use of computer programs.

Basic Concepts Relevant to Analysis Statistical approaches may be divided into frequentist methods and bayesian approaches. Frequentist methods refer to P values and CIs, which can be interpreted as the frequency of specific outcomes from the same experimental situation if it is repeated many times. That is, what are the chances of this outcome (and outcomes even more extreme) if one repeats the experiment many times? Bayesian analysis permits a calculation of the probability that, for example, a treatment is superior according to the observed data and prior knowledge. It begins with a posterior probability distribution for some parameter, which is derived from the data, and a prior probabili~y distribution for that parameter. The posterior distribution is used as the basis for statistical inference. 103 This chapter emphasizes the frequentist school, because the majority of statistics in today's literature follow frequentist rather than bayesian theory. The types of variables in the study and the number of variables studied determine the choice of the appropriate statistical approach. The first step is to determine which variables are independent (predictor or explanatory) variables and which are dependent (outcome or response) variables. An independent variable is the variable that is the explanatory factor or thought to be the cause. A dependent variable (DV) is one whose value is the outcome in the study or the response or is thought to be the effect. The second step is to determine the measurement scale of the variable: categorical (nomina!), ordinal (ranked), or continuous numeric, definitions for which were provided earlier. The third step is to deter-

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mine whether the study observations are independent of each other. In the design of a clinical study, one must determine whether the groups to be compared are independent or paired. Samples in which the values of one group cannot be predicted from the values of the other group are said to consist of independent groups. In other words, the patient group and the control group represent different individuals rather than the same individual measured at two different times. With paired (matched) groups, the values of one group may be predicted from values of the other. In a paired experiment, a patient may be measured before and after therapy, in which case the patient acts as her or his own control, or a patient may be paired with another individual who has been matched with respect to all of the independent variables (e.g., age, duration of disease) that may affect the DV (response). In animal studies, in which genetically identical animals are frequently used in research, paired experiments are the rule. However, in human clinical studies, it is rare that two groups can be matched for all of the independent variables that may influence the outcome variable. An investigator may wish to match the groups as closely as possible, to eliminate bias, but still treat the groups as if they were independent, thus improving the overall quality of the experimental design, as described earlier. The nature and distribution of the values of the variables also determine whether parametric or nonparametric tests can be used. The use of a parametric test is based on certain assumptions. The major assumption is that the variable of interest follows a normal distribution. It may be possible to transform variables that are not normally distributed. This technique expresses the values of observations on another scale, such as a natural log scale. This may allow the use of parametric statistical tests when the actual values obtained in the study do not follow a normal distribution. Another alternative is to use a nonparametric test. Nonparametric methods are based on weaker assumptions in that they do not assume a normal distribution or equality of variance between the different groups. There are nonparametric procedures for most statistical needs, but, because they are not based on the assumption of normality, nonparametric tests are more conservative. Unfortunately, they are also less powerful (Le., less able to reject the null hypothesis when it is false) than their parametric counterparts.

Two Types of Statistical Error and P Values Type I error is the probability of rejecting a null hypothesis when it is true (i.e., concluding that there is a difference when, in fact, there is none). It is abbreviated as ex (alpha error level). The P value is the calculated type I error level based on the data; it is defined as the likelihood that a difference at least as large as the observed difference could have occurred by chance alone. That is, it is analogous to a false-positive result in diagnostic tests (discussed earlier). Whether the P is capitalized is arbitrary and varies among publishers and journals. P values that exceed the predefined type I error level (e.g., P = .08 when ex was set at .05) are called not statistically significant; values at or below the preset type I error level

(e.g., .001) are called statistically Significant. The ex or type I error level is set; the P value is calculated. The debate about when to adjust P values to deal with the issue of multiplicity, or multiple hypothesis testing, appears far from resolved, and spirited debate continues, particularly in new technologies, such as microarray data. 104-106 When one is conducting exploratory studies not aimed at establishing definite cause-effect relationships, P need not be corrected for fear of missing a possible true association or difference. False-positive results can later be discarded in confirmatory, pivotal studies. In confirmatory studies aimed at adding pivotal evidence to a cause-effect relationship, there is no need to correct the P value for the main test of hypothesis (i.e., that on which sample size was based). However, results of secondary, exploratory hypotheses should present both uncorrected and corrected P values. An alternative to correcting the P value is to set ex lower (e.g., at .01 instead of .05) in anticipation of conducting multiple hypothesis testing. There are numerous techniques for correcting P values for multiple comparisons. By far, the most widely used (perhaps because of it'> simplicity) is the Bonferroni correction, despite its conservativeness. To adjust a P value using the Bonferroni correction, the P value obtained is multiplied by the number of statistical tests. Thus, a P value of .05 obtained in a series of 10 tests of hypotheses becomes (.05 x 10), or .5. Alternatively, when the experiment is designed, the ex error level can be divided by the number of anticipated tests (in the example, .05 .;- 10 = .005), with values of P greater than this level referred to as nonsignificant. Type II error is the probability of failing to reject a false null hypothesis in favor of the alternative hypothesis (i.e., concluding that there is no difference when, in fact, there is a difference). It is commonly abbreviated as ~ (beta error level). Table 6-5 is a summary of the types of decision errors, illustrating the concepts of the null hypothesis and ex and ~ errors. Traditionally, type I error levels are set lower than type II error levels (e.g., .05 and .2, respectively). In other words, the experimenter is more willing to make a type II error than a type I error. The conventional rationale for this approach is that type I errors are more serious, because they can result in the abandonment of an established, beneficial therapy in favor of a new therapy when no such change is warranted. Power, the ability of a statistical test to identify a true difference if in fact one eXists, is expressed mathematically as 1 minus ~. It is a consideration in the design of an experiment, because the power of the test is affected by the sample size. The distribution of the test statistic is divided into two areas: acceptance and rejection. These concepts are graphically shown in Figure 6-7. If the null II _ . TABLE

6 ')

True Situation

Oul< OUII' 01 Study Accept Ho Correct Type II error

H", null hypothesis; H" alternative hypothesis.

Type I error Correct

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• FIgurre &-7 Theoretical visual representation of acceptance and rejection regions, alpha and beta error regions, and power.There are four possibilities when one compares the means (or other summary descriptors of a distribution of values) of two (or more) populations or samples. (1) First, one may correctly conclude that there is no difference between the two means (I.e., correctly accept, or fail to reject, the null hypothesis (HoI of no difference). In this case the mean of, for example, the treated group would fall within the distribution on the left anywhere in the acceptance region (white), but not in the rejection region (black) and also not in the stippled region (beta).This implies that the second mean arose from a population having the same underlying mean as the population that gave rise to the first mean, and the experimenter correctly recognized this situation. (2) Second, one may correctly conclude that there is a difference between the two means (I.e., correctly reject Hoin favor of the alternative hypothesis [HI or HJ that there is a difference between the two means). In this case, the lIlean of the treated group would fall within the rejection region (black) or further to the right. This implies that the second mean arose from a population with a different underlying mean from that of the population that gave rise to the first mean, and the experimenter correctly recognized this fact. (3)Third, the investigator may incorrectly conclude that there is a difference between the two means when In fact there is not a difference (I.e., incorrectly reject Hoin favor of HI when, i'n fact, it should not be rejected). In this case, the value of the second mean happened to fall into the rejection, or alpha region, even though it arose from the same population as the first mean.This is known as atype I error, and its probability of occurrence is based on the alpha error level set by the experimenter a.e., how much chance is one willing to take of concluding that there is a difference when in fact there is not?).This will determine the size or area of the rejection region. Atype I error implies that the second mean arose from a population with the same mean as the population that gave rise to the first mean, but the experimenter failed to recognize this fact because the second mean fell far out in the tail of the distribution, as shown in the graph. (4) Finally, the investigator may incorrectly conclude that there is no difference between two means when, in fact, there is a difference (I.e., incorrectly accept, or fail to reject, Howhen it is actually false). In this case, the second mean fell somewhere in the beta region, leading the experimenter to believe, incorrectly, that the second mean came from the same population that gave rise to the first mean.This is known as a type " error, and its probability of occurrence is based on where the experimenter sets the power (1 - the beta error level) of a test. Power will determine the size of the beta area on the graph and is usually heavily dependent on sample size. Atype II error implies that the second mean arose from a population with adifferent mean from that of the population that gave rise to the first mean, but that the experimenter failed to recognize this fact because the second mean fell somewhat close to the first mean (I.e., in the beta region) own.

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some guesswork, and the resulting calculation may not always yield the correct sample size needed to answer a specific question. This problem occurs when the investigator's assumptions do not hold true for the sample that is actually enrolled in the study. Sample size should always be calculated during the development of the clinical investigative protocol. Sample size is most frequently calculated with the use of computer programs, but the investigator and the statistician must still be able to make various assumptions that they think are likely to be met during the study. For chi-square tests (discussed later), the investigator needs to know the outcome of interest (which should be specifically defined), an estimate of the magnitude of effect (Le., how much difference can one expect between, for example, a control group and a treated group), the desired type I error level (usually .05), and the type II (~) error level (i.e., 1 - power). With these pieces of information, the calculations are relatively straightforward and can be ascertained from tables or with the use of appropriate computer programs. To calculate the sample size needed for a parametric test, such as the t test, one must also estimate the variance in the variable of interest. The variance estimate may come from published data or from a pilot study that was designed to preliminarily assess the question under consideration. Because many sample size calculations result in the requirement of an unrealistic number of patients, the statistician is often asked to find ways to decrease the number of patients needed. Sample size may be decreased by increasing the acceptable type I error level, by increasing the acceptable type II error level, by increasing the size of difference reqUired to detect a statistically significant difference (which should also be clinically significant), and by choosing an outcome variable with a smaller amount of variance. The most common ways to do this include improving the precision of the measurements of the outcome variable, training investigators, using better equipment, and repeatedly measuring the outcome.

Post Hoc Power Analysis

hypothesis is rejected, one concludes that the evidence supports a significant difference between the groups. If the null hypothesis is not rejected, one concludes that there is no such difference. The lower the P value, the higher the level of significance.

In the event that an investigation yields nonsignificant differences, the concern is that the investigator has committed a type II error. The options to address this situation include calculation of the size of the difference one could detect as statistically significant with sufficient power (e.g., 80%), given the sample size and variance obtained in the study; this is termed the minimum detectable difference. Three other options are calculation of the power of the study to find the actual (observed) difference between groups statistically significant, calculation of the power of the study to find clinically meaningful differences, and calculation of the sample size that would be necessary to find the observed difference statistically significant.

Sample Size

Minimum Detectable Difference

The estimation of sample size requires considerable statistical skill as well as knowledge of the underlying basic assumptions being made by the investigator. It involves

The first option is used frequently and requires further explanation. Minimum detectable difference calculations estimate the amount of difference between groups that the

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investigator would be able to detect given the actual size of the sample and the variance. If the minimum detectable difference is much larger than would be considered clinically significant, the investigator may conclude that the investigation did not include a sufficient number of patients to detect a clinically meaningful difference as statistically significant. If the minimum detectable difference is smaller than the difference that is considered clinically significant, the test was adequately powered and the investigator may conclude that in fact there is no difference between the samples.

Confidence Intervals (Limits) on Statistical Tests of Inference CIs (described earlier) are frequently calculated for a statistical hypothesis test. They may be calculated for the t test, chi-square test, analysis of variance, regression, and most other tests of inference. A 95% CI is a range of values within which, the experimenter believes, there is a 95% probability that the true underlying (unknown) mean (or difference in means) lies. The most frequently reported CI is at the 95% level. The confidence limits are related to the P value. If one calculates the CI of a test that compares two means or difference in means, and zero is within in the range of the 95% CI, then the statistical test (P value) should not be significant, because there is some probability that the true difference between the two means is zero.

number of successes in N independent trials, given that the probability of success on anyone trial is y?" For example, one may ask, "What is the probability that a fair coin will produce 7 heads in 10 flips of the coin given that the probability of a "success" (heads) is 0.5 on each toss?" The binomial test yields an exact probability (P value) for the 7 successes as well as the probability of obtaining results even more extreme (Le., 8 of 10, 9 of 10, and 10 of 10 heads). The binomial test has limited applicability in describing the statistical probability that a therapy is beneficial, because the odds of success typically are not known. In pediatric rheumatology, the question may be, "What is the probability that 50 patients with ]RA treated with methotrexate will experience improvement as determined by a given index or measure?" The problem is that one is typically unsure of the exact probability of a success in a single independent trial. In some situations, the probability of success is arbitrarily given the value of .5 (Le., 50% chance), and the binomial test is done to either confirm or fail to confirm that level of probability of success.

Goodness-of-Fit Chi-Square Test

that a statistically significant difference may not necessarily indicate clinical significance. Particularly if the sample size is large, many tests may result in a statistically significant finding when in fact there is a relatively small degree of clinically significant difference between the two groups. Biologic significance, as compared with statistical significance, has come into the forefront with the testing of new immune response modifiers (biologic agents). For example, the sought-after effect of a drug (e.g., to reduce the number of CD4-positive T lymphocytes) may be significant yet produce no clinical effect. The solution to this problem is to include not only measures of surrogate markers of efficacy (e.g., laboratory values) but also outcomes that allow for interpretation of the clinical significance of such a biologic effect.

The goodness-o/fit chi-square test is related to Pearson's chi-square test (discussed later), in which observed proportions are compared with expected values. The goodness-of-fit chi-square test can be used to test the significance of a single proportion or of a theoretical model, such as the mode of inheritance of a gene. A reference population is often used to obtain the expected values. Suppose the frequency of an allele that is thought to produce risk for polyarticular ]RA is known to be 2 in 100 in the general population (ignoring population stratification for this example). However, the observed frequency of the allele in a sample of patients with polyarticular ]RA is found to be 10 in 100. Is this much deviation from the expected value significant? Briefly, one calculates how well the observed frequencies fit the model from the general population by determining the difference between each set of observed and expected values, squaring them, dividing by their respective expected values, and adding the results. In the example, the sum of (observed - expected)" + expected values = 00 - 2)2 + 2 [for those with the allele] + (90 - 98)2 + 98 [for those without the allele] = approximately 33. A chi-square table is consulted (as described in greater detail later), and the value of 33 is found to be highly statistically significant.

One-Sample Tests

One-Sample tTest

Statistical hypothesis testing may be completed on studies involving one or more groups. The most frequent approach to analYZing data from a clinical investigation that involves only one group is to compare that group with a known population or expected value.

When a statistical inference is desired on a single mean, the one-sample t test may be used. The test is similar to Student's t test for comparing two means, described later. Suppose one wishes to determine whether the mean height of 9- to 10-year-old girls with SLE is significantly less than that of the general population of 9- to lO-yearold girls. The critical ratio for t is set up as follows:

Statistical Versus Clinical Versus Biologic Significance An important concept that is frequently overlooked is

Binomial Test of Proportions Perhaps the most frequently used test for comparing one sample to a known population is the binomial test. This test asks the question, "What is the probability of x

t

=

(.~- /lo) / (s - --.In)

where x is the mean of the sample of patients with SLE, Jlo is the general population mean, s is the sample SD, and

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6 DESIGN, MEASUREMENT, AND ANALYSIS OF CLINICAL INVESTIGATIONS

n is the sample size. One then consults a t table list of critical values and determines whether t is significant at some predetermined level in consideration of the degrees of freedom or independence (which here is n - 1).

Two-Sample Tests The two-sample test to be used is determined by the level of the data and by certain other assumptions, as defined later.

Chi-Square Test with One Degree of Freedom

It.

TABLE 6--6

the expected values in cells a, b, c, and dare 15, 73, 68, and 342, respectively. The next step is to find the difference between each pair of observed and expected values, square it to eliminate the negative sign, and divide by the expected value. To obtain the chi-square statistic, the results from each cell (ij) are summed:

X2

=

r [ (Ojj -

E/ / Eij

l

A short-cut formula for calculating the chi-square with 1 df is

X2

For categorical (nominal) data and ordinal data with very few ranks, the most frequently used hypothesis test is the Pearson chi-square (X2) test. This nonparametric statistical test of inference is for assessing the association between the two variables. It is most commonly performed on contingency tables such as a 2 x 2 cross-tabulation, which has one degree of freedom (l df). The numbers in the cells represent counts (frequencies), and each cell must he independent of all other cells (Le., an individual patient can contribute only once to the entire table). For example, to observe the association between HLA-DR8 and oligoarticular JRA, a 2 x 2 table can be constructed with HLA-DR8 positive or negative as the column headings and oligoarticular JRA present or absent (the latter representing control subjects) as the row headings (Table 6-6). The chi-square statistic is based on how much difference there is between "observed" and "expected" frequencies. The null hypothesis is that there is a random distribution of outcome in each "exposure" group-that is, that the columns are independent of the rows. Expected values are calculated from row and column totals. In Table 6-6,

=

(ad - bc)W.;- (a + b)(c + d)(a + c)(b + d)

where N is the total study population. The significance of the resulting chi-square statistic is determined from a table of critical values. There are several useful points to remember about the interpretation of the statistic. For chi-square with 1 df (i.e., 2 x 2 tables), the statistic becomes significant at the .05 level if the value is 3.841 or greater, and the larger the chi-square value, the more significant it is. Most tables of critical values report two-tailed probabilities; the P value is divided by 2 to find the one-tailed probabilities. Chi-square analysis with greater than 1 df (i.e., tables larger than 2 x 2) requires larger values to be significant.

Continuity Correction ofYates If the total N for a 2 x 2 chi-square table is less than about 40, the Yates continuity correction is used to compensate for deviations from the theoretical (smooth) probability distribution. The resulting chi-square value is smaller and the resulting statistical inference is more conservative. The technique involves subtracting 72 from the absolute value of each 11 E...II Mathematically, this is stated as follows:

°-

Example of the Calculation of Chi-Square with One Degree of Freedom'

As50dated Allele (HLA·DR 8) Condition (Ollgoartlcular Juvenile Rheumatoid Arthrltls)

Pnsent

Present

Cell. a

Absent (controls)

observed expected Cell c observed expected

Column Totals (c) of Obsen'ed Values

83

Absent

Row Totals (rJ of Observed Values

Cell b

= 42 = 15

observed = 46 expected = 73

88

Cell d

= 41 = 68

165

observed = 369 expected = 342 415

410

N= 498

Expected value in a cell is the row total x column total divided by the total N, or, (rt x c,)/N Expected value in cell a = (83 x 88) / 498 ;: 15 Expected value in cell b = (88 x 415) / 498;: 73 Expected value in cell c = (83 x 410) / 498 ;: 68 Expected value in cell d = (410 x 415) / 498 ;: 342 X2 = (42 - 15)2 + (46 -73)' + (41 - 68)2 + (369 - 342)' = 71 15 73 68 342 A chi-square value of 71 is significant at the .000001 level. The odds ratio (Le_, adlbc) = 8.2. Adapted from Nepom BS, Malhortrd U, Schwarz DA, et ai: HLA and T cell receptor polymorphisms in pauciarticu!ar-onset juvenile rheumatoid arthritis. Arthritis Rheum 34: 1260-1267. 1991. Copyright © 1991 Wiley-Liss, Inc. Reprinted by permission of Wiley-Liss. Inc.. a subsidiary of John Wiley & Sons, Inc.

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risk, with the results from each stratum being weighted by the sample size of the stratum.

or

x = (lad 2

bcl - N12)2 + (a + b)(c + d)(a + c)(b + d)

Rsher's ExactTest Fisher's exact test is used as a replacement for the chi-

square test when the expected frequency of one or more cells is less than 5. This test is commonly used in studies in which one or more events are rare.

McNemar'sTest The chi-square test assumes independence of the cells, as noted earlier. However, experimental designs exist for observing categorical outcomes more than once in the same patient. McNemar's test (also known as the paired or matched chi-square) provides a way of testing the hypotheses in such designs. McNemar's chi-square statistic can be calculated with the following formula:

X2McNemar

=

(b -

C)2

I

(b

+ C)

or, with the continuity correction, X2CMcNemar =

(Ib - cl - 1)2 + (b + c)

An example is shown in Table 6-7. Two different concentrations of an analgesic lotion are given to 51 patients with arthritis. The null hypothesis is that the proportion of patients who receive relief from analgesic lotion 1 is the same as that from lotion 2. The results show that the null hypothesis cannot be rejected according to the McNemar test.

Mantel-Haenszel Chi-SquareTest This procedure is known as a stratified chi-square test and is frequently used to detect confounding variables. The procedure involves breaking the contingency table into various strata and then calculating an overall relative

II.

TABLE 6 7

EXdlllple 01 the MINellldr Chi Square fest

Fifty-one patients with arthritis pain in both hands are treated with two different lotions containing different concentrations of an analgesic. One lotion is placed on the left hand and the other on the right hand of each patient. Each patient rates each hand as experiencing pain relief or no relief The null hypothesis is that the same proportion of patients will receive relief from lotion 1 as from lotion 2.

lotion 1

lotion 2 Relief No Relief

Relief

No Relief

11 10

24

6

The McNemar chi-square test with the Yates correction is used: X'CMcNc,,", ( 16 - 10 I - I)' / 6 + 10 = 0.562. Interpret from regular x' table with one degree of freedom: 0.562 is less than 3.841. Therefore, do not reject the null hypothesis.

Common Errors with Chi-Square Tests Perhaps because of its frequent use, the chi-square test is often employed or interpreted inappropriately. Some of the more common mistakes include unnecessary conversion of continuous or ordinal level data to categorical data in order to use the chi-square test, nonindependence of the cells in the table (exception is when McNemar's chisquare test is being used), use of the chi-square rather than Fisher's exact test when expected cell frequencies are lower than 5, and confusion of statistical significance by chi-square values with clinical or biologic importance.

Student's tTest What the chi-square test is to categorical data, the t test is to continuous data. This test is used for comparing two sample means from either independent or matched samples. It asks the question, "Is the difference between ~ and Xc statistically significant, where ~ is the mean of the treated group and Xc is the mean of the control group?" This difference must be standardized, just as was done in the case of the standard normal variable procedure earlier, so that one set of t tables of critical values can be used. In the case of independent samples, the numerator of the t statistic is the difference in means and the denominator is the standard error of the difference. This is calculated as -.J s2 p Clint

+ lin)c

where s2 is the pooled variance, n t is the sample size of the treat~d group, and nc is the sample size of the control group. The degrees of freedom are calculated as n, + nc - 2, and a table of critical t values, for either one-tailed or two-tailed tests (depending on the hypothesis being examined), is consulted to determine whether the t statistic is significant. The matched t test is more efficient (Le., more powerful) than the independent test. The computer calculates the difference (retaining the sign) for each matched pair: d j = Xli - X 2i ' where i repres~nts each of n successive pairs. The mean difference (d) and the estimated standard error of the difference (s/-.Jn) are calculated. The null hypothesis. (0 = 0) is tested by calculating the t statistic: tpaired = d + (s/-.Jn). The degrees of freedom are equal to n - 1, where n is the number of pairs. A table of critical t values is consulted to determine whether the test statistic is significant.

Nonparametrlc t Tests The t tests described earlier are parametric tests. That is, they make assumptions about the underlying distributions, including normality and equality of variances between groups. The t test is a very robust test; it is still valid even if these assumptions are substantially violated. Modern data-analysis computer software programs provide relevant statistics and tests of underlying assumptions for application to a parametric test, and the resulting displays may warn the investigator that the results of the test

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may not be valid. If the violations are severe, the investigator may transform the data using, for example, either natural logarithms (described earlier) or nonparametric tests. Nonparametric tests ignore the magnitude of differences between values taken on by the variables and work with ranks. No assumptions are made about the distribution of the data. In the case of the t test, either the MannWbitnry U test is used for independent data or the Wilcoxon signed-rank test is used for paired data.

K-Sample Tests Clinical investigations involving more than two samples (groups) require that modifications be made to the analysis plan to accommodate the need for multiple comparisons.

Chi-Square Test with More Than One Degree of Freedom When categorical data are analyzed, there may be more than two categories for one or both variables (i.e., the table may be larger than 2 x 2). However, if the chisquare test statistic is found to be significant in a table larger than 2 x 2, it is frequently difficult to determine which proportions were different. One must then attempt to either collapse the number of cells in the table or break the table up into several smaller tables. This may requite adjustment of the resulting P values because of multiple comparisons. The degrees of freedom of contingemcy tables larger than 2 x 2 are equal to the number of rows minus 1 plus the number of columns minus 1. For example, a 2 x 3 table has (2 - 1 + 3 - 1), or 3, degrees of freedom.

Analysis of Variance One-Way Analysis ofVariance The use of repeated t tests to detect differences among more than two means is considered unacceptable because the resulting P value does not accurately describe the chance one has taken of committing a type I error. The one-way analysis of variance (ANOVA) is used for the purpose of comparing more than two sample means. Simply stated, ANOVA divides the total variance among all subjects into two portions, the amount of variance that is a result of the difference between the groups of subjects, and the amount of variance that results from differences within each group. The ratio of the amount between and the amount within each group is known as the F ratio. The corresponding test of significance is known as the F test. If statistical significance is achieved, the investigator must go one step further. The significance may have arisen because just two means were different from one another, or perhaps all the means were different from one another. To determine exactly which means were different, tests must accommodate the fact that multiple comparisons are being made. This is determined by applying a multiple comparison. Commonly used multiple comparison tests include Tukry's honest significant difference test, the Newman-Keuls test, Scheffe's multiple contrasts test, and, if one wishes to make multiple comparisons to

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only one group (e.g., control group, standard of care), Dunnett's test.

Multi-Way ANOVA ANOVA procedures have an additional capability that can increase the efficiency of analyses when one wishes to compare the influence of two or more independent variables on one DV simultaneously. Suppose one wished to test the effects of methotrexate and a physical therapy (PT) program on the disease status of a group of patients with polyarticular JRA. One could carry out two separate studies, conduct t tests for treatment effects on the methotrexate-treated patients and the PT-treated patients, and compare each with placebo or no PT. This approach requires substantial numbers of patients to meet samplesize requirements for each study. However, a two-way ANOVAfactorial design could make much more efficient use of the available subjects and provide information about the interaction (effect modification) between methotrexate and PT. In this situation, patients could be randomized to both treatments, yielding four groups (methotrexate alone, PT alone, both methotrexate and PT, and neither treatment). In addition to providing information about the effect of each treatment alone (j.e., the two main effects), a two-way ANOVA factorial design examines the effect of the interaction between the two treatments. ANOVA techniques can be extended to threeway, four-way, and beyond, provided the sample size is large enough.

Nonparametric ANOVA ANOVA procedures discussed to this point are parametric tests and, as such, make various assumptions about the underlying distribution. If these assumptions are substantially violated, the nonparametric equivalent of ANOVA, the Kruskal-Wallis test, can be used. This test is subject to the same sample-size limitations as the chisquare test. If the sample size in any group is less than 5, one must use Fisher's exact test and exact probabilities, as described earlier.

Correlation and Regression One of the most important measures of statistical correlation is the Pearson product-moment correlation. This statistic is appropriate for estimating the relationship between two variables, x and y, both of which are measured along a continuous scale. Correlation is a two-way model that does not require assumptions of causality. The correlation (r) can vary between -1 and +1. The magnitude of the correlation demonstrates the strength of the relationship between the two variables. The larger the absolute value of the correlation, the more strongly associated are x and y. In the extreme, where r = +1 or -1, all the data values fall perfectly on a straight line. As r approaches zero, the data demonstrate greater scatter about a best-fit line for their relationship. The sign of the correlation indicates the direction of the relationship. A positive sign means that the two variables are directly related (j.e., they tend to increase or decrease together).

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A negative sign for r indicates that the two variables are inversely related (Le., the value of one tends to decrease as that of the other increases). Correlation assumes that the joint distribution of x and y is bivariate normal. That is, y is normally distributed at all values of x, and vice versa. If this assumption is violated substantially, the nonparametric Spearman rank correlation, which yields a Spearman's rho (r j, is used. Because Spearman rank correlation deals with ranks, it can be used with continuous variables that violate assumptions and with ordinal data. Regression is a one-way model in which predictor or explanatory independent (x) variables are thought to affect the dependent outcome (y) variables, but not vice versa. In simple regression models (Le., models that include only a single predictor), as well as in multiple regression models, the direction of the effects must be prespecified. The simple linear regression equation is y = a + bx, where a is the intercept and b is the coefficient. By using various values of x in the equation, the predicted value of y for a given x can be determined. Simple regression models serve as building blocks for the larger, more complex, and more realistic models, including polynomial regression models and structural equation models.

Multiple linear Regression The technique whereby a multitude of independent variables (x j' x2' x3' etc.) can be simultaneously investigated for their influence on a linear related DV (y) is known as multiple linear regression. The method models the DV as a linear function of all the (k) independent variables. That is, y

=

a + bjx j + b 2x 2 + b3x 3 + ... + bkx k

This method is particularly helpful in evaluating extraneous variables as possible confounders of the linear relationship between two continuous variables. In other words, linear regression permits the investigator to assess the separate unconfounded effects of several independent variables on a single DV The Xi terms can be continuous or categorical variables. The b i terms are the regression coefficients. Each b i is "corrected" simultaneously for the linear relationship between its associated Xi and all the other xis, as well as for the linear relationship between the other Xi'S and y, An overall flo value is calculated for the model. It represents the percentage of the total variance of y that is accounted for by the linear relationship with all the Xi'S. A common mistake is to refer to multiple linear regression as a multivariate technique; technically it is not, because it deals with multiple independent variables rather than multiple DVs.

Multiple Logistic Regression Multiple logistic regression is distinguished from multiple linear regression in that the outcome variable (DV) is dichotomous (e.g., diseased or not diseased). Its aim is the same as that of all model-building techniques: to derive the best-fitting, most parsimonious (smallest or most efficient), and biologically reasonable model to

describe the relationship between an outcome (DV) and a set of predictors (independent variables), Here, the independent variables are called covariates. (Multiple logistic regression is not technically a multivariate technique, because it deals with only one DV) Importantly, in multiple logistic regression, the predictor variables may be of any data level (categorical, ordinal, or continuous). A major use of this technique is to examine a series of predictor variables to determine those that best predict a certain outcome. A pediatric rheumatology example of the use of this technique can be found in the paper by Ruperto and associates,63 in which predictor variables that are measurable during the very early stages of JRA (e.g" number of active joints during the first 6 months of illness, erythrocyte sedimentation rate [ESR]) were tested to determine their relative predictive ability for either a favorable or a less favorable outcome (Le., a dichotomous DV) at least 5 years later. An excellent reference guide to this technique is provided by Hosmer and Lemeshow. 107

Analysis of Covariance The analysis of covariance (ANCaVA) combines the principles of ANaVA with those of regression. A chief advantage of this technique is that, unlike ANaVA, the independent variables can be of any data level. ANcaVA is often used to adjust for initial (baseline) differences between or among groups. In other words, one of its chief purposes is to eliminate systematic bias. For example, suppose two groups of patients had unequal numbers of swollen joints at baseline (even though the study may have been randomized). The initial number of swollen joints is then used as the covariate, ANcaVA adjusts the post-treatment means of the groups to what they would have been if all groups had started out equally on the covariate, The other purpose of ANCaVA is to reduce the withingroup (or error) variances, thus making the test more efficient (powerful). For example, suppose a clinical trial investigates the effect on the ESR of a biologic agent and an active comparator. Subjects are randomly assigned to receive one or the other treatment, and the change in ESR is observed. Within each treatment group, there is considerable variation in ESR, reflecting individual differences among patients in the degree of active inflammation. In other words, ESR and active inflammation are covarying (covariates). If one could statistically remove this part of the within-group variability by allowing the degree of inflammation to be the covariate in the analysis, a smaller error term would result, and the test would gain power. ANcaVA provides a method to do this. In summary, ANcaVA provides a method for adjusting for differences at baseline between groups and reduces the amount of variation within groups that is caused by covariates, thus increasing power and capability to detect differences.

Survival Analysis Survival (life table) analysis was developed primarily for the study of how long a particular cohort of subjects survives. The term survival data is now used in a broader

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sense for data that involves time to a certain event, such as time to failure of a drug or time before remission. 55 There are two basic types of life table analysis: the fixedinterval (actuariaf) model and the Kaplan-Meier survival analysis. The latter is used much more frequently in medicine than the former. In actuarial analysis, the lengths of each interval shown on the x-axis are all equal (e.g., 1 year). This is the technique used by life insurance companies to estimate the probability of a person's surviving to a certain age. In the Kaplan-Meier approach, the end of an interval is demarcated by an event. The horizontal components of the lines are not equal, as they are in the actuarial technique. An example of the actuarial method in pediatric rheumatology can be found in a study by Giannini and colleagues lO8 of the time to occurrence of eye disease among patients with certain major histocompatibility complex alleles. An example of the KaplanMeier approach can be found in the study by Lovell and associates,77 in which time to failure in subjects given placebo was compared with time to failure in those given etanercept. Methods exist for comparing the difference of the life table graphs; the most frequently used is the generalized Wilcoxon test. Figure 6-8 is a graphic representation of a comparison between the characteristic lines of an actuarial model and a Kaplan-Meier analysis. An outstanding reference for survival analysis techniques is that of Lee and Wang. 109

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or within raters, indicates that the values for the measure are nonreliable or nonreproducible. Of course, this has dire consequences for the interpretation of the results and for statistical interpretation. Various tests exist for expressing the degree of agreement between and within raters. The most frequently used test to express rater agreement when the outcome is dichotomous is the kappa test ratio (known also as Cohen's kappa, or K). The K statistic is given by the following formula: K = (observed agreement - agreement expected by chance) -:- (maximum possible agreement - agreement expected by chance). K scores range from -1, indicating perfect disagreement, to +1, indicating perfect agreement; a score of 0 indicates the agreement expected by chance. K scores are often expressed as percentages: less than 20% considered negligible agreement; 20% to 40%, minimal; 40% to 60%, fair; 60% to 80%, good, and greater than 80% excellent. lJo Data with three or more categories (Le., ordinal data) require the use of the more complex weighted kappa test. Kendall's W, or coefficient of concordance, can also be used. W values range from 0, which indicates poor agreement, to +1, which indicates perfect agreement among all raters. W cannot be negative, because not all the raters can disagree completely if there are more than two.

Intradass Correlation

Measures of Agreement Among and Within Raters It is often necessary to express in statistical terms how

well various raters agree with one another (inter-rater agreement) or with themselves (intra-rater agreement). These are commonly referred to as measures of reliability or reproducibility. Lack of agreement, either among

100

Cl

80

.5 .~ ;:, III

~Ql

If more than two raters are to be compared for reliability, the intraclass correlation is more appropriate than conducting repeated two-way comparisons between pairs of raters (there is a correction for correlation between raters that becomes apparent when the range of measurement is large). It evaluates the level of agreement among all raters, and the measures (scores) must be parametric in nature. The data are placed in a matrix in which the columns are the raters and the rows are the number of subjects (or the number of variables) being measured. The coefficient represents the amount of agreement: 1 is perfect agreement, and 0 is no agreement. Analysis of variance on the matrix produces an F value (described previously) and tells the investigator whether the raters are significantly different from one another. IJJ

60

Multivariate Analyses

:=

[ '0 40

Actuarial method

1:

~

Ql Q.

20

Kaplan-Meier method

o

2

3

4

5

6

Years since beginning treatment

• FItIIIIIt 6-8 Comparison of Kaplan-Meier and actuarial survival curves, showing atheoretical example of the percentage of patients surviving after 0 to 6 years of treatment. (Modified from Kramer MS: Clinical Epidemiology and Biostatistics: APrimer for Clinical Investigators and Decision-Makers. BerlinHeidelberg~NewYork, Springer-Verlag, 1988, p. 246, © 1988 Springer-Verlag.)

This section provides a basic concept of multivariate statistics and an overview of the more popular and increasingly used multivariate tests. Interested readers are referred to the text by Stevens JJ2 for in-depth discussions of the concepts and tests presented here. Multivariate statistics are appropriate when the experimental design simultaneously investigates two DVssuch as bone mineral density and bone mineral content during a trial of calcium supplementation in prepubescent girls with polyarticular JRA. Testing of these two DVs in two trial groups (calcium supplementation and no supplementation) by, for example, the t test would not be appropriate because the tests are not independent of one another; that is, the two DVs are highly correlated

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with each other (and if one is known, the other can be guessed). Furthermore, just as the interaction among independent variables in a factorial ANOVA provides new information, so too does the use of multivariate tests that consider more than one DV simultaneously. Multivariate techniques may use nominal, ordinal, or continuous data.

dicting group membership. Again, as in stepwise regression, computer programs can add and subtract variables from the equation (based on significance of Wilk's lambda test) until the combination that best discriminates the groups is arrived at.

Hotelllng's T2 Test

Factor analysis is used for data exploration to reveal patterns of interrelationships among variables that are not readily apparent, for confirmation of hypotheses, and for reducing the number of variables to a manageable level. In situations involving many different observations concerning the same patient or groups of patients, factor analysis can be used to determine whether it is possible that some of these observations are a result of just a few underlying factors. That is, the correlation among many DVs may be explained by some underlying factor or factors. For example, the fact that a young boy is experiencing swollen joints, a rash, intermittent fevers, and a drop in hemoglobin with an increase in white blood cell count is a result of underlying factors: he is experiencing the onset of systemic JRA, and pathologic processes are taking place in his hematopoietic system. When groups of patients are studied, the symptoms tend to "load" on the underlying factors differentially. Factor loading is expressed in a factor loading matrix, in which each row of the matrix is a variable and each column is a factor. Such a matrix examines how highly each variable correlates with, or loads on, each factor. Each variable may load onto one or more variables. Next, one must decide which factors are most important to keep and which can be discarded as not contributing enough to the explanation of the variables. This is done by calculating an eigenvalue, which is the amount of variance in the data that is explained by a particular factor. The procedure to this point is called principal component analysis. Additional steps in factor analysis include rotation of axes to determine which are general factors (most variables load significantly on them) and which are bipolarfactors (some variables load positively and some load negatively on them). Factorial complexity is determined by observing how many variables load significantly onto two or more factors.

Just as the t test is used when one wishes to compare one DV in two different groups, Hotelling's T2 test is used when there are two groups with multiple DVs. The process involves the comparisons of, for example, the vectors of the means in the treated and in the control group. A centroid for the groups is calculated, which is the point at which the mean values of the two DVs intersect for the control group when they are plotted on an x-y graph. The SD and the amount of correlation between the variables are used to calculate whether the T2 statistic is significant. Multivariate significance implies that there is a linear combination of the DVs that is significantly separating the groups. However, significance of the T2 statistic may arise from one or more of the DVs under consideration. Discriminant function analysis (described later) is used to determine which variables are contributing the most to the significant finding.

Multivariate Analysis ofVariance Just as ANOVA was used for the comparison of the means of more than two means, so too is the multivariate analysis of variance (MANOVA), rather than Hoteiling's T2, used in situations with more than two groups and multiple DVs. Its use instead of separate univariate ANOVAs is related to accounting for intercorrelations among the DVs. Vectors of means are calculated, and the centroid for each group is compared with the grand centroid (similar to the comparison of variance within groups versus variance between groups tested in univariate ANOVA). Similarly, the within-group variability must be computed for each of the DVs. There are numerous ways to calculate the significance of MANOVA, the most common of which is Wilk's lambda. As with Hoteiling's T2, significance can arise from one or several of the variables, and discriminant function analysis is needed to sort it out.

Discriminant Function Analysis In situations in which many DVs exist, statistically significant differences among the groups can arise from the effect of one, several, or all of the variables. Discriminant function analysis identifies the variables that are most important in accounting for the observed differences. In addition, discriminant function analysis allows determination of those groups that differ more in some DVs than in others. The process derives an equation (function) that best discriminates among the groups. The equation is similar to a regression equation and is the first variable multiplied by its weight, plus the second variable multiplied by its weight, and so on. In this case, rather than predicting a value of a DV, as in regression, one is pre-

Factor Analysis

Multivariate Analysis of Covariance The multivariate analysis of covariance (MANCOVA) is an extension of univariate ANCOVA in which group means at follow-up are adjusted for differences at baseline and within-group variance is reduced by removing variation caused by covariates. The objective of MANCOVA is to determine whether several groups differ on a set of DVs after the follow-up means have been adjusted for any initial differences on the covariates at baseline.

Canonical Correlation Canonical correlation is a multivariate procedure, an extension of multiple regression, that is used to examine the nature of the association or interrelation between two sets of variables. Canonical correlation breaks down the

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complex association into additive pieces to determine the number and nature of independent relationships existing between two sets of variables.

Sample Size for Multivariate Tests A rule of thumb is that there should be at least 10 subjects for each DV investigated in the study. A study in which the subject/variable ratio is smaller is likely to be unreliable.

JUDGING THE QUALITY OF A REPORT OF A CUMICAL INVESTIGATION The most helpful and up-to-date series of guides to the reader of clinical reports was published in the journal of the American Medical Association in 1993-2000. This "Users I Guides to the Medical Literature" series8--40 provides logical checklists of questions for readers attempting to weigh the evidence from many different types of clinical studies. In brief, each Guide asks three basic questions: • Are. the results of the study valid? • What were the results? • Will the results help me in caring for my patients? Practical examples from everyday clinical situations are then used to illustrate how one determines the answer and eventually weighs the evidence from the report. Because not all epidemiologic studies deal with patients, judgin, the quality of an epidemiologic investigation requires an approach that is similar to but separate from judging clinical investigations.

Juclgl'" the Evidence from a Olnlcal Trial and the CONSORT Statement Although the Users' Guides just cited contain information for judging clinical trials, more detailed guides are available. In 1995, a group of medical journal editors, clinical epidemiologists, and statisticians developed a consensus statement about how randomized controlled trials should be reported-the Consolidated Standards of Reporting Trials (CONSORD statement. Since the previous edition of this text, the statement has been revised,113 and a study has be¢n done to determine its impact on reporting of trials,u4 The statement contains a checklist of 21 items that deal chiefly with methods, results, and discussion. It identifies key pieces of information necessary to evaluate the internal and external validity of a report. A flow diagram is also recommended; using a two-group, parallel design, randomized, controlled trial as an example, it provides a graphic display of allocation and status of patients throughout the trial. Some modification of the statement's recommendations is usually necessary because of differences in study design. Overall, however, it provides an outstanding template on which to formulate or judge the report of a clinical trial. Guidelines for determining authorship of articles that are generally accepted by editors of medical journals have now been published. ll5

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28. McAlister FA, Laupacis A, Wells GA, Sacken DL: Users' guides to the medical literature. XIX: Applying clinical trial results. B: Guidelines for determining whether a drug is exerting (more than) a class effect. Evidence-Based Medicine Working Group. JAMA 282: 1371-1377, 1999. 29. Bucher HC, Guyatt GH, Cook OJ, et al: Users' guides to the medical literature. XIX: Applying clinical trial results. A: How to use an article measuring the effect of an intervention on surrogate end points. Evidence-Based Medicine Working Group. JAMA 282: 771-778, 1999. 30. Richardson WS, Wilson MC, Guyatt GH, et al: Users' guides to the medical literature. XV: How to use an article about disease probability for differential diagnosis. EVidence-Based Medicine Working Group. JAMA 281: 1214-1219, 1999. 31. Guyatt GH, Sinclair J, Cook OJ, Glasziou P: Users' gUides to the medical literalUre. XVI: How to use a treatment recommendation. Evidence-Based Medicine Working Group and the Cochrane Applicability Methods Working Group. JAMA 281: 1836-1843, 1999. 32. Barratt A, Irwig L, Glasziou P, et al: Users' guides to the medical literature. XVU: How to use gUidelines and recommendations about screening. Evidence-Based Medicine Working Group. JAMA 281: 2029--2034, 1999. 33. Randolph AG, Haynes RB, Wyatt JC, et al: Users' guides to the medical literature. XVIII: How to use an article evaluating the clinical impact of a computer-based clinical decision support system. JAMA 282: 67-74, 1999. 34. McAlister FA, Straus SE, Guyatt GH, Haynes RB: Users' guides to the medical literature. XX: Integrating research evidence with the care of the inclividual patient. Evidence-Based Medicine Working Group, JAMA 283: 2829--2836, 2000. 35. Hunt DL, Jaescbke R, McKibbon KA: Users' guides to the meclicalliterature. XXI: Using electronic health information resources in evidence-based practice, Evidence-Based Medicine Working Group. JAMA 283:1875-1879, 2000. 36, McGinn TG, Guyal! GH, Wyer PC, et al: Users' guides to the medical literature. XXII: How to use articles about clinical decision rules. Evidence-Based Medicine Working Group. JAMA 284: 79--84, 2000. 37, Giacomini MK, Cook OJ: Users' guides to the medical literature. XXIII: Qualitative research in health care, A: Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 284: 357-362, 2000. 38. Giacomini MK, Cook OJ: Users' guides to the medical literature, XXIII: Qualitative research in health care, B: What are the results and how do they help me care for my patients? Evidence-Based Medicine Working Group. JAMA 284: 478-482, 2000. 39. Richardson WS, Wilson MC, Williams JW Jr, et al: Users' gUides to the medical literature, XXIV: How to use an article on the clinical manifestations of disease. Evidence-Based Medicine Working Group. JAMA 284: 869--875, 2000. 40. Guyatt GH, Haynes RB, Jaeschke RZ, et al: Users' guides to the medical literature. XXV: Evidence-based medicine: principles for applying the Users' Guides to patient care. Evidence-Based Medicine Working Group. JAMA 284: 1290-1296,2000. 41. Sung NS, Crowley WF Jr, Genel M, et al: Central challenges lilCing the national clinical research enterprise. JAMA 289: 1278--1287, 2003, 42. Bloom FE: Presidential address. Science as a way of life: perpleXities of a physician-scientist. Science 300: 1680-1685, 2003. 43. Petiti OM: Meta-analysis, Decision Analysis, and Cost Effectiveness Analysis. Oxford, UK, Oxford University Press, 1994. 44. Moses LE: Statistical concepts fundamental to investigations. N Engl J Med 312: 89Q-897, 1985. 45. Hill AB: The environment and disease: association or causation? Proc R Soc Med 58: 295-300, 1965. 46. Noll RB, Kozlowski K, Gerhardt C, et al: Social, emotional, and behavioral functioning of children with juvenile rheumatoid arthritis. Arthritis Rheum 43: 1387-1396, 2000. 47. Noll RB, Gartstein MA, Vannatta K, et al: Social, emotional, and behavioral functioning of children with cancer, Pediatrics 103: 71-78, 1999. 48. Inman RD, Johnston ME, Hodge M, et al: Postdysenteric reactive arthritis: a clinical and immunogenetic study follOWing an outbreak of salmonellosis. Arthritis Rheum 31: 1377-1383, 1988. 49. Arguedas 0, Fasth A, Andersson-Gare B: A prospective population based study on outcome of juvenile chronic arthritis in Costa Rica. J Rheumatol 29: 174-183, 2002, 50. Hashkes PJ, Balistreri WF, Bove KE, et al: The long-term effect of methotrexate therapy on the liver in patients with juvenile rheumatoid arthritis. Arthritis Rheum 40: 2226-2234, 1997. 51. Ravelli A, Manzoni SM, Viola S, et al: Factors affecting the efficacy of intraarticular corticosteroid injection of knees in juvenile idiopathic arthritis. J Rheumatol 28: 2100-2102, 2001. 52. Ravelli A, Martini A: Early predictors of outcome in juvenile idiopathic arthritis. Clin Exp Rheumatol 21 (5 Suppl 31): S89-S93, 2003. 53, Brunner HI, Lovell OJ, Finck BK, Giannini EH: Preliminary definition of disease flare in juvenile rheumatOid arthritis. J Rheumatol 29: 1058--1064, 2002. 54. Rider LG, Giannini EH, Harris-Love M, et al: Defining clinical improvement in adult and juvenile myositis, J Rheumatol 30: 60}-{i17, 2003. 55, Ruperto N, Ravelli A, Murray KJ, et al: Preliminary core scts of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis, Rheumatology (Oxf) 42: 1452-1459, 2003. 56. Wallace CA, Ruperto N, Giannini EH; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology International Trials Organisation;

Pediatric Rheumatology Collaborative Study Group: Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 11: 2290-2294, 2004, 57, Gare BA, Fasth A: The natural history of juvenile chronic arthritis: a popUlation based cohort study. 1I: Outcome. J Rheumatol 22: 308--319, 1995. 58. Flato B, Lien G, Smerdel A, et al: Prognostic factors in juvenile rheumatOid arthritis: a case-control study revealing early predictors and outcome after 14.9 years, J Rheumatol 30: 386-393, 2003, 59. Oen K: Long-term outcomes and predictors of outcomes for patients with juvenile idiopathic arthritis, Best Pract Res Clin Rheumatol 16: 347-360, 2002. 60, Oen K, Malleson PN, Cabral DA, et al: Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort. J Rheumatol 29: 1989-1999, 2002. 61. Oen K, Malleson PN, Cabral DA, et al: Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J Rheumatol 30: 585-593, 2003. 62. Ruperto N, Levinson JE, Ravelli A, et al: Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. I: Outcome status. J Rheumatol 24: 94'i-951, 1997. 63, Ruperto N, Ravelli A, Levinson JE, et al: Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. II: Early predictors of outcome. J Rheumatol 2-1: 952-958, 1997. 64. Murray K, Thompson SO, Glass ON: PathogeneSiS of juvenile chronic arthritis: genetic and environmental factors. Arch Dis Child 77: 530-534, 1997. 65. Glass ON, Giannini EH: Juvenile rheumatoid arthritis as a complex genetic trait. Arthritis Rheum 42: 2261-2268, 1999. 66. Jarvis IN, Dozmorov I, Jiang K, et al: Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis. Arthritis Res Ther 6: RI5-R32, 2004. 67, Prahalad S, Ryan MH, Shear ES, et al: Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs. Arthritis Rheum 43: 2335-2338, 2000. 6B. Savolainen A, Saila H, Kotaniemi K, et al: Magnitude of the genetic component in juvenile idiopathic arthritis. Ann Rheum Dis 59(2): 1001, 2000. 69. Saila HM, Savolainen HA, Kotaniemi KM, et al: Juvenile idiopathic arthritis in multicase families. Clin Exp Rheumatol 19: 218--220, 2001. 70. Forre 0, Smerdel A: Genetic epidemiology of juvenile idiopathiC arthritis. Scand J Rheumatol 31: 123-128,2002. 71. Thomson W, Donn R: Juvenile idiopathic arthritis genetics: what's new? What's next? Arthritis Res 4: 302-306, 2002, 72. Rosen P, Moroldo MB, tovell OJ, et al: Discordant phenotypes for methotrexate response in juvenile rheumatoid arthritis. Arthritis Rheum 46 (Supp)): S470, 2002. 73. Katz PP: Introduction to special patient outcomes in rheumatology issue of Arthritis Care and Research, Arthritis Care Res 49 (5 Supp)): SI-SI4, 2003. 74. Hull RG: Guidelines for management of childhood arthritis. Rheumatology (OxD 40: 1309-1312, 2001. 75, Temple R: Current definitions of phases of investigation and the role of the FDA in the conduct of clinical trials, Am Heart J 139: SI33-S135, 2000, 76. Weiner DL, Yuh L: Biovavailability studies, In Buncller CR, Tsay J-Y (eds): Statistics in the Pharmaceutical Industry. New York, Marcel Dekker, 1994. pp 215-245. 77. Lovell OJ, Giannini EH, Reiff A, et al: Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatolob'Y Collaborative Study Group, N Engl J Med 342: 763-769, 2000. 78. Honkanen YE, Siegel AF, Szalai JP, et al: A three-stage clinical trial design for rare disorders. Stat Med 20: 3009-3021, 2001. 79. Giannini EH: Can non-fundable trials be conducted anyway? The case for open, randomised, actively controlled trials in rheumatology, Ann Rheum Dis 57: 128--130, 1998, 80. Shaikov AV, Maximov AA, Speransky AI, et al: Repetitive use of pulse therapy with methylprednisolone and cyclophosphamide in addition to oml methotrexate in children with systemic juvenile rheumatoid arthritis: prel iminary results of a longterm study. J Rheumatol 19: 612-616, 1992. 81. Ruperto N, Murray Kj, Gerloni V, et al: A randomized trial of parente",1 methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Althritis Rheum 50: 2191-2201. 2004. 82. Giannini EH: The N of 1 trials design in the rheumatic diseases. Arthritis Care Res 1: 109-115, 1998. 83. Temple R, Ellenberg SS: Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: Ethical and scientific issues. Ann Intern Med 133: 455-463, 2000, 84. Vickers AJ, de Craen A]: Why use placebos in clinical trials? A narrative review of the methodological literature, J C1in Epidemiol 53: 157-161, 2000. 85. Emanuel EJ, Miller FG: The ethics of placebo-controlled trials: a mitkUe ground. N Engl J Med 345: 915-919, 2001. 86. Freedman B, Glass KC, Weijer C: Placebo orthodoxy in clinical research. II: Ethical, legal, and regulatory myths. J Law Med Ethics 24: 252-259, 1996. 87. Freedman B: Placebo-controlled trials and the logic of clinical purpose. lim 12: 1-6, 1990. 88. Freedman B, Weijer C. Glass KC: Placebo orthodoxy in clinical research. I: Empirical and methodological myths. J Law Med Ethics 24: 243-251. 1996,

C HAP T E R 6 DESIGN, MEASUREMENT, AND ANALYSIS OF CLINICAL INVESTIGATIONS 89. Beaton DE, Bombardier C, Katz IN, Wright JG: A taxonomy for responsivene"s, J Clin Epidemiol 54: 1204--1217, 2001. 90. Fortin PR, Stucki G, Katz IN: Measuring relevant change: an emerging challenge in rheumatologic clinical trials, Arthritis Rheum 38: 1027-1030, 1995. 91. Felson DT, Anderson JJ, Boers M, et al: American College of Rheumatology. Preliminary deftnition of improvement in rheumatoid arthritis. Arthritis Rheum 38: 727-735, 1995. 92. van der Heijde OM, van 't Hof M, van Riel PL, van de Putte LB: Development of a disease activity score based on judgment in clinical practice by rheumatologists, J Rheumatol 20: 579-581, 1993. 93. Giahnini EH, Ruperta N, Ravetli A, et al: Preliminary definition of improvemerlt in juvenile arthritis. Arthritis Rheum 40: 1202-1209, 1997, 94. Larsen A, Dale K, Eek M: Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radial Diagn (Stockh) 18: 481-491, 1977. 95. Sharp JT, Young DY, Bluhm GB, et al: How many joints in the hands and wrists should be included in a score of radiologic abnormalities used to as!;tJss rheumatoid arthritis? ArthritL~ Rheum 28: 1326-1335, 1985. 96. Ware JE Jr, Sherbourne CD: The MOS 36-item short-form health survey (SF-36). I: Cooceptual framework and item selectioo, Med Care 30: 473-483, 199t. 97. LandgrafJM: Measuring and monitoring quality of life in children and youth: a 11I!ief commentary. Soz Praventivmed 46: 281-282, 2001. 98. VaJliji lW, Seid M, Kurtin PS: PedsQL 4.0: reliability and validity of the Pe~latric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 39: 80Q-812, 2001. 99. VaI1Tli lW, Seid M, Smith Knight T, et al: The PedsQL in pediatric rheumatology: reliability, validity, and responsiveness of the Pediatric Quality of Life lnv~ntory Generic Core Scales and Rheumatology Module. Arthritis Rheum 46: 714-725, 2002. 100. Hay~ RD, Anderson R, Revicki 0: Psychometric considerations in evaluating health-related quality of life measures. Qual Life Res 2: 441-449, 1993. 101. Brunner HI, Silverman ED, To T, et al: Risk factors for damage in childhood-onset systemic lupus erythematosus: cumulative disease activity

102. 103, 104, 105,

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107, 108.

109, 110. 111. 112. 113,

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and medication use predict disease damage, Arthritis Rheum 46: 436-444; 2002. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. .I Nat! Cancer Inst 22: 719--748, 1959. Brophy JM, Joseph L: Placing trials in context using Bayesian analysis: GUSTO revisited by Reverend Bayes. JAMA 273: 871-875, 1995. Blume J, Peipert .IF:. What your statistician never told you about P-vaJues. JAm Assoc Gynecol Laparosc 10: 439-444, 2003. Pounds S, Morris SW: Estimating the occurrence of false positives and false negatives in microarray studies by approximating and partitioning the empirical distribution of p-values. Bioinformatics 19: 1236-1242, 2003. Gruvberger-Saal SK, Eden P, Ringner M, et al: Predicting continuous values of prognostic markers in breast cancer from microarray gene expression profiles. Mol Cancer Ther 3: 161-168, 2004. Hosmer OW, Lemeshow S: Applied Logistic Regression, 2nd ed. New York, John Wiley & Sons, 2000. Giannini EH, Malagon CN, Van Kerckhove C, et al: Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis. .I Rheumatol 18: 1394--1397, 1991. Lee ET, Wang JW: Statistical Methods for Survival Data Analysis. New York, John Wiley & Sons, 2003. Jekel .IF, Elmore JG, Katz OL: Epidemiology, Biostatistics, and Preventative Medicine. Philadelphia, WB Saunders, 1996. Portney LG, Watkins MP: Foundations of Clinical Research. Applications and P,dctice, Norwalk, CT, Appleton & Lange, 1993, pp 509--516. Stevens .lP: Applied Multivariate Statistics for the Social Sciences, 4th ed. Mahwah, N.I, Lawrence Erlbaum, 2001. Moher 0, Schulz KF, Altman 0: The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group I"dndomized trials. .lAMA 285: 1987-1991,2001. Moher D, .lanes A, Lepage L: Use of the CONSORT statement and quality of reports of mndomized trials: a comparative before-and-after evaluation. .lAMA 285: 1992-1995,2001. Davidoff F, DeAngelis CO, Orazen .1M, et al: Sponsorship, authorship, and accountability. N Engl.l Med 345, 825-826; discussion 826-827, 2001.

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ASSESSMENT OF HEALTH STATUS, FUNCTION, AND QUALITY OF LIFE OUTCOMES: METHODOLOGY AND INSTRUMENTS Clar6n M. Duffy and Daniel J. Lovell

~

The rheumatic diseases of childhood influence many if not all aspects of the child's life-not only physical but also sociaJ,1 emotionaJ,2 intellectual, and economic. 3 Indeed, the impact of childhood rheumatic disease is not only on the child but extends to the entire family.4 Conversely, the family's status and functioning can significantly impact the outcome of the child's illness. 4 This chapter describes the instruments that have been developed to assess this web of influence in a quantitative fashion, and specifically focuses on the measurement of functional status and quality of life, with an emphasis on measures developed or used for juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (IIA).

BACKGROUND What Do We Mean by the Terms "Fundlonal Status" and "Quality of Life"? "Functional status" can broadly be defined as the ability of an individual to perform daily activities. Such ability may be impaired for a variety of reasons and can include both physical and psychological factors. For our purpose, the assessment of functional status emphasizes impairment due to physical factors. The term "quality of life" (QoL) is much more complex. It was originally developed by sociologists to try to determine the effect of material affluence on people's lives. This sociologic approach was developed in the United States during World War II. The concept broadened so that it eventually included education, social welfare, economics, and industrial growth. s This broad societal approach was also incorporated into questionnaires that were developed to assess the status of an individual within this broad framework of concern. Many of these areas of concern or domains, although important to an individual, are well outside the influence of disease 174

and health care interventions. It is for this reason that other terminology to describe QoL was developed. Various authors have used terms such as health-related quality of life (HRQoL), life satisfaction, self-esteem, wellbeing, general health, functional status, and life adjustment to describe those aspects of QoL that relate to the overall global health status of human beings.' There remains considerable confusion about the actual terminology and definitions in this field. For the purpose of this chapter, discussion of QoL will be restricted to HRQoL. However, both functional status and HRQoL are complex concepts that contain numerous subcomponents. There are differences among the experts as to what constitutes HRQoL and, as a consequence, various instruments have been developed to measure it. Such instruments may be divided into generic and disease-specific measures. Generic HRQoL measures are those that purport to be broadly equal across different types and severity of disease, across different medical treatments or health interventions, and across different demographic or cultural subgroups. They are designed to capture aspects of health and disease that cross broad diagnostic categories and social or demographic subgroups. Disease-specific HRQoL measurements are those designed to assess specific diseases or patient populations; such instruments are usually more responsive to changes in individual subject status. The last 25 years have seen the development and validation of a variety of instruments to measure functional status, as well as generic and disease specific HRQoL. These instruments were first developed in adult rheumatology, but in the last 15 years tools specifically designed to be used in childhood-onset rheumatic diseases have been developed.

Why Measure Quality of Life? QoL measurements have been used for a wide variety of purposes. One of the earliest and currently one of the

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strongest motivations for measurement of HRQoL is to allow comparisons of health gains or efficiency of healthrelated interventions across broad population groups, in order to be able to compare health gains achieved in treating different patient groups. This information has been used in measurement of health outcomes in a variety of health-related systems of care to assist in priority setting and allocation of limited health care resources. 5-7 In the field of rheumatology, HRQoL has gained wide popularity because it has been shown to measure outcomes that are of direct interest and importance to patients, to provide effective measurements of patient status, to be predictive of patient outcome, and to produce reliable and effective measures of treatment impact. 8-11 To further complicate this already complex field, there are a number of terms and measurement techniques that have been imported from the field of questionnaire development that are foreign and certainly not intuitively easily understood by health care personnel. The most important concepts and terms are included in Table 7-1.

HlerafChy of Outcomes Critical to understanding this area is having a clear vision of the hierarchy of outcomes and outcome measures. The first level of outcome assessment is the measurement of

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disease activity. This is the aspect of outcome assessment that has been the traditional focus of trials in rheumatology. Disease activity measures include those parameters most familiar to clinicians, such as joint counts, morning stiffness, and erythrocyte sedimentation rate. The major drawback to measures in this area is that they are not really what the patient is interested in. However, measures of disease activity are still widely used in clinical trials, because inhibition of the disease process or activity is an essential component of an effective therapeutic intervention (especially for pharmacologic interventions). At this time, measurement of disease activity is a necessary but not a sufficient approach to measuring patient outcome. Furthermore, when the performance characteristics of the traditional disease activity measures used in rheumatology were Scientifically assessed, many instruments were found to be unreliable, redundant, insensitive to change, or not correlated with long-term patient outcome. 9 The next level up the hierarchy is the measurement of functional status. The focus here is on measuring the ability of the person to perform physical activities of daily life, such as dressing, walking, climbing stairs, and self-care. Obviously, this is an area of more relevance to the patient. Several instruments have been developed and validated to quantify functional status in patients with ]RA. These are discussed in greater detail later in this chapter.

Glossary of Terms Commonly Used in Quality of Lile (Qol) Literature

Ce11ln1i effect: Situation in which the highest score on an instrument does not represent the best status a subject can have: patients with the higheSt score can still improve more.

Centellt validity: Extent to which items in the instrument comprehensively assess the domain of interest.

ConveJ1ent valid"':

Correlation of instrument scores to accepted but not gold standard parameters measuring the same domain.

Crlterlon validity: Comparison of results on an instrument as a "gold standard": such a gold standard does not exist for QoL. DlsallIIlnant Instrument: Designed to most effectively differentiate groups of people. Domatns or dimensions: Area of behavior or experience that is being measured. EvalUUve Instrument: Designed to most effectively detect change in the status of a person over time.

Face .1IdIty: Estimation of whether an instrument appears to be measuring what it is intended (seldom quantitated).

to

measure: does it look reasonable?

Floor effects: Situation in which the lowest possible score on an instrument does not represent the worst status a subject can have; patients with the worst score can still deteriorate further. ~llabll"': Extent to which an instrument can yield accurate and reliable results when used in circumstances or subjects different from those in which it was originally validated: for example, able to be used in varying socioeconomic, ethnic, and geographic disease types or disease severity.

1'ttodeI! ' A theoretical framework of what is being measured and how the instrument should perform. PItIent: preference: Instruments designed so that each individual selects those parameters on the instrument that are most important to them. Predlctlve valid"': Extent to which a score on an instrument at one point predicts patient outcome at a later time.

ReJlabll..,: Extent to which a measuring procedure yields the same results on repeated trials if all the conditions remain unchanged. R ~ (sensIt/v/tJ to change): Extent to which scores on an instrument given at different times in the same subject (or subjects) will change if there is a true change in the status of the subject. ~ or proxy reporter: Someone who answers on behalf of another and reports what they think the subject would answer for themselves (e.g., parent reporting for a child).

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The next higher level in this hierarchy is the measurement of QoL. Although some authors have made distinctions between "QoL" and "health status," many others use these terms interchangeably, and they may not have separate meanings. 1l In general, QoL is the more commonly used term. Measures at this level are in accordance with the view of the World Health Organization that health is a state of physical, mental, and social well-being. 12 Disease-specific HRQoL measures, such as the Health Assessment Questionnaire (HAQ) or the Arthritis Impact Measurement Scale (AIMS) were developed to incorporate the broad World Health Organization concept of health but by addressing areas that are affected by rheumatic disease. For example, the HAQ includes questions addressing mortality, functional status, physical discomfort, psychologic discomfort, treatment side effects, and economic impact. 9 Despite concerns regarding the ability to measure QoL in children,13 major advances have been made in the development and validation of disease-specific HRQoL tools for children with rheumatic diseases. These instruments also are discussed later. The development of a core set of measures for application in clinical trials in JIA has been extremely important. 14 This core set incorporates the types of instruments already alluded to (Table 7-2).

PROCESS OF INSTRUMENT DEVELOPMENT The development and validation process for functional assessment or QoL instruments has been well established, but for most health care providers the terminology and statistical approaches are unfamiliar. Certainly, it is clear that the development of a new functional assessment or QoL instrument is labor intensive, requires sequential studies, entails input from a wide range of individuals, and needs frequent revisions of the original tool before completion. For example, more than 20 iterations were required in the development of the HAQ. The developmental process for two of the functional assessment tools validated for children with JRA each required 3 to 5 years of work. 15-18 Given the broader scope of content, QoL instruments for JRA have taken at least as long. I 9-2l The process used to develop and validate health measurement questionnaires has been described in textbooks 22 and published articles,23 and, indeed, several articles have described thoroughly the

I!:.

TABLE 7~2 (ore Set of Criteria for Evaluating Change in Treatment Trials of Children With IRA

Physician global assessment of disease activity Patient/parent assessment of overall well-being Functional ability (CHAQ) Number of joints Wilh active arthritis Number of joints with limited range of motion ESR Improvement: At least 30% improvement from baseline in 3 of any 6 variables, with no more than 1 of the remaining variables worsening by > 30% From Giannini, Ruperto, Ravelli, et al." ESR, eJYlhrocyte sedimenlalion rate.

steps used for instruments specifically focused on children with rheumatic diseases. 19.24 A key question to be addressed by anyone who is considering development of a new survey instrument or questionnaire is whether there is truly a need. At this time, there are hundreds of validated questionnaires, and review of the literature may well reveal one that could serve the purpose. Researchers tend to magnify the deficiencies of existing measures and signitlcantiy underestimate the effort required to develop an adequate new measure. 22 There are several compendia of measuring scales. 2'-27 If one or more existent scales are found, then these scales need to be evaluated. If the conclusion is that no existent questionnaire is satisfactory, then much work awaits the brave souls who choose to develop a new tool (Table 7-3). Given this background, the rest of this chapter describes the various tools available in pediatric rheumatology. For a more complete description of these instruments, the reader is referred to the instruments themselves or to published reviews. ll ,28.29

BACKGROUND ON AVAILABLE INSTRUMENTS FOR CHILDHOOD RHEUMATIC DISEASES As discussed already, there is an increasing need to incor-

porate estimates of physical, social, and mental functioning into health assessment, particularly in the assessment of chronic diseases,30-33 in an attempt to provide an all-encompassing measure of QoL. QoL not only includes both health status and functional status but should also attempt to incorporate some aspect of the patient's own perception of what particular aspects of life affect them significantly and to what extent this is influenced by the disease. 33 These facts have been incorporated into the development of measurement tools for adult rheumatic diseases·w--36; and have been demonstrated to be reliable, valid, and responsive in a variety of conditions37-42; and are now believed to be required for inclusion in clinical trials. 43 ,44 Since 1986, various groups have attempted to develop the deftnitive measure for application in JRA. The length of time involved clearly suggests that this is a complex task. The ideal instrument should be practical and easy to use; should be capable of completion by the parent and/or the child within a short time; should measure physical function; should also, as suggested by Singsen,4' measure psychological function and social function, including school, family, and behavioral issues; and should include a measurement of pain. None of the instruments developed to

1'1, 1..1

TABLE 7 -3 Relluiu~d PlOpl'rtil's of the Ideal Instrument for Juvenile Idiopathic Arthritis

Reliable Valid Responsive (sensitive to change) Discriminative ability Easy to use and score Applicable to a wide age range and to a heterogeneous population Measures physical function comprehensively Measures quality of life (including psychosocial functioning) comprehensively

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date meets all of these criteria. However, each instrument has unique characteristics that make it distinct, and therefore each one may have different indications for use. In the following sections, each instrument is discussed with an emphasis on its development, its measurement properties, and the settings in which it might be used. Most instruments developed to date for childhood rheumatic diseases have their application in JRA (Table 7-4). However, some have been developed or have been modified for use in other childhood rheumatic diseases. Both types are discussed here.

INSTRUMENTS FOR JUVENILE RHEUMATOID

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TABLE 7-4 Instruments Developed dnd/or Used in Juwnile Rheumdtoid Arthritis

Measures of Physical Function Childhood Health Assessment Questionnaire (CHAQ) Juvenile Arthritis Assessment Scale (JAFAS) and Report (JAFAR) Juvenile Arthritis Self-Report Index (JASI)

Measures of Quality of ute Juvenile Arthritis Quality of Life Questionnaire (JAQQ) Childhood Arthritis Health Profile (CAHP) Quality of My Life Questionnaire (QoMLQ) Childhood Health Questionnaire (CHQ) Pediatric Quality of Life Inventory Scales (Peds QL)

ARTtfRmS Disease-specific measures of functional status developed for ]RA include the Childhood Arthritis Impact Measurement Scales (CHAIMS),46 the Childhood Health AsseS1lment Questionnaire (CHAQ),16 the Juvenile Arthritis Functibnal Assessment Scale (JAFAS) and Report (JAFAR),17 and the Juvenile Arthritis Self-report Index (JASI).24.47 Disease-specific measures of QoL include the Juvenile Arthritis Quality of Life Questionnaire (JAQQ)l9 and the Childhood Arthritis Health Profile (CAHP).20,21 More recently, there has been a greater focus on the use of generic instruments to assess QoL in children with JRA. Such measures include the Quality of My Life Questionnaire (QoMLQ),48 the Child Health Questionnaire (CHQ)49 and the Pediatric Quality of Life Inventory (Peds QL) (Table 7-4).50 All of these instruments are discussed briefly here, and Table 7-5 summarizes their comparative properties.

The Childhood Arthritis Impact Measurement Scales The CHAIMS was the first disease-specific measure developed for JRA. 46 This was a modification of the

1!fI • • H.BIE 7-5

Puam_

AIMS.34 However, its measurement properties were poor except for the pain dimension and, as a result, it has not had widespread use.

The Childhood Health Assessment Questionnaire The CHAQ16 was derived from the adult HAQ.9,3S It comprises two indices, Disability and Discomfort. The Disability Index assesses function in eight areas--dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities-distributed among a total of 30 items. In each functional area, there is at least one question that is relevant to children of all ages. Each question is rated on a four-point scale of difficulty in performance, scored from a to 3. The Disability Index is calculated as the mean of the eight functional areas. Discomfort is determined by the presence of pain, as measured by a 100-mm visual analogue scale (VAS). In addition, a 100-mm VAS measures patient/parent global assessment of arthritis. In the original validation study,16 mean scores for patients were 0.84 for the Disability Index and 0.82 for

Comparative Properties of Instruments Developed and/or Used for Juvenile Rheumatoid Arthritis'

Reliability Validity Responsiveness Discriminative ability Applicable to a wide range Applicable to a heterogeneous population Measures physical function Measures quality of life Measures pain Tested widely Easy to use

CHAQ

JAFAR

JASI

JAQQ

CAHP

QoMLQ

CHQ

Peels QL

Strong Strong Weak Moderate Very strong

Strong Strong Weak Moderate No

Strong Strong Moderate Strong No

NA Strong Very strong Weak Very strong

Moderate Moderate NA Moderate Moderate

Moderate Moderate NA NA Moderate

Strong Strong Moderate Moderate Strong

Strong Strong Moderate Moderate Very strong

Very strong

Strong

No

Very strong

NA

NA

Very strong

Strong

Moderate No Moderate Very strong Strong

Moderate No Moderate Moderate Strong

Very strong No No No No

Strong Strong Strong No Strong

Strong Strong No No No

No Moderate No No Strong

Moderate Strong Moderate No Moderate

Moderate Strong Moderate No Moderate

·Although most instruments have been developed using patient~ defmed as having juvenile rheumatoid arthritis (JRA) as the criteria of the American College of Rheumatoll>gy. they are probably equally applicable to patients defined by the International League of Associations for Rheumatology as juvenile idiopathic arthritis (JIA). "No. property absent; Weak, property present but weak; Moderate, property present and moderately strong; Strong. property present and strong; Vel)' strong, property present al1d vel)' strong; NA. not applicable. CHAQ. Childhood Health Assessment Questionnaire; JAFAR, Juvenile Arthritis Functional Assessment Report; JASI, Juvenile Arthritis Self-report Index; JAQQ, Juvenile Arthritis Quality of Life Questionnaire; CAHP, Childhood Arthritis Health Profile; QoMLQ, Quality of My Life Questionnaire; CHQ, Child Health Questionnaire; Peds QL. Pediatric Quality of Life Inventol)'.

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the Discomfort Index. Reliability was very good. Convergent validity was also very good, with excellent correlations with Steinbrocker's functional class, active joint count, disease activity index, and degree of morning stiffness. Mean scores for parents and children were not significantly different from one another and were highly correlated, suggesting that parents can reliably report for their children. The CHAQ was completed by parents in all cases, and also by children 8 years of age and older, in a mean of 10 minutes. Responsiveness was established later,51 The CHAQ has been shown to be a useful instrument for outcome evaluation in longitudinal studies.,2-M It has also been used in a variety of settings and translated into a number of different languages while still maintaining excellent reliability, validity, and parent--child correlations. li6--75 One study did suggest that it had poor responsiveness/Ii and in two recent trials it was shown to have reasonable responsiveness. 77 •78 Several studies have demonstrated its usefulness in the evaluation of rehabilitative interventions,?9-&! Other studies suggest that it is highly predictive of the presence of significant pain. 85.86 Efforts to better understand its measurement attributes suggest that a change of 0.13 represents a minimal clinically important change score, while scores of 0.13, 0.63, and 1.75 represent mild, mild to moderate, and moderate disability, respectively.87 Although the CHAQ does not measure psychosocial function in its present form, an earlier version showed reasonable measurement properties in this domain88 ; however, this aspect has not been maintained in the version in current use. The CHAQ has excellent reliability and validity and reasonable responsiveness. It also has good discriminative properties, can be administered to children of all ages, is available in several languages, and is of great use in the clinical setting for long-term follow-up of children with JRA. Therefore, it is of value for longitudinal studies as well as clinical trials and has become the preferred measure in both settings.

The Juvenile Arthritis Functional Assessment Scale and Report The Juvenile Arthritis Functional Assessment Scale 0AFAS)89 preceded the publication of JAFAR.15 JAFAS is an observer-based scale, whereas JAFAR is a report completed by the patient or parent. Items for both instruments were derived from the AIMS, the HAQ, and the McMaster Health Index Questionnaire. 90 JAFAS requires standardized simple equipment and can be administered in about 10 minutes by a health protessional who times the child's performance on 10 physical tasks. Good reliability and convergent validity have been demonstrated. The major limitation ofJAFAS is the requirement of a trained observer and standardized equipment. JAFAR comprises one dimension and contains 23 items which assess ability to perform physical tasks in children older than 7 years of age on a three-point scale scored from 0 to 2; thus, the score range is 0 to 46, with the lower score indicating better function. Two separate versions are available, one for the child 0AFAR-C) and one for the parents 0AFAR-P). In 72 children with JRA (and their parents), mean scores for JAFAR-C and JAFAR-P were 4.39 and 4.38, respectively, and were significantly

L I FE 0

UTe 0 M E S

different from controls. Reliability was good for both versions. Construct validity was good, with predictable correlations among JAFAR-C, JAFAR-P, JAFAS, and pain. Convergent validity was also good, with moderate correlations with disease activity index and active joint counts. Similar measurement properties were found in an English study, in which both versions of JAFAR were highly correlated with one another and with active joint count, pain, Steinbrocker class, and stiffness score, but not with measures of psychological dysfunction?l A Dutch translation of the JAFAR also showed good measurement properties, although the CHAQ did slightly better than the JAFAR in this particular study.li9 Sensitivity to change or responsiveness was demonstrated in a small trial of intravenous immunoglobulin in polyarticular JRA.92 JAFAR has also proved to be a useful measure of functional ability in studies on osteopenia93.94 and sleep disturbance')' in JRA. The JAFAR has excellent reliability and validity. Data from a small controlled trial suggest that it is responsive, but further work is needed in larger trials to clearly establish this property. It cannot be administered to children younger than 7 years of age, and this prohibits its use in children with early onset of JRA. Nonetheless, it is a practical instrument that is of great use in the clinical setting and in the longitudinal follow-up of most children with JRA.

The Juvenile Arthritis Self-Report Index The JASI 24 was developed with a specific focus on physical activity in children older than 8 years of age with JRA. Its emphasis is on responsiveness, and it is aimed primarily at rehabilitation interventions. Through a detailed process, as suggested by Kirshner and Guyatt,23 an instrument with 100 items, distributed in five categories of physical function (self-care, domestic, mobility, school, and extracurricular), was developed. The score range is from 0 to 100, with higher scores indicating better function. A seven-point Likert scale of difficulty in performing tasks was included. As a secondary component, JASI Part 2, patients identify up to five tasks that are most problematic, and these tasks are evaluated on sequential follow-up. This maneuver makes this component of the JASI potentially more responsive and patient specific. In a validation study, the JASI was shown to have good measurement properties. 47 It was completed for the most part by the patients in a mean time of 49.8 minutes (including 10 minutes of instruction). The mean JASI Part 1 score for the group was 78.2 (range, 20 to 100), suggesting overall excellent function. There was reasonable spread of scores, suggesting that the JASI has discriminative ability. Reliability was demonstrated with excellent intraclass correlations. Construct validity was established by demonstration of predicted correlations with other measures used. In a subsample of patients, level of agreement was good between JASI scores and observation of performance of tasks by a therapist. JASI Part 2 was also reliable, but less so. The JASI has been developed in a meticulous fashion, resulting in excellent reliability and validity. Data for JASI Part 11 suggest that it is responsive, although further data are needed to clearly establish this property. However, it

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cannot be administered to children younger than 8 years of age, and this prohibits its use in children with early onset of JRA. Also, because it is comprehensive, it takes a long time to complete, and this may make it less attractive for clinical use. Nonetheless, the JASI is a comprehensive instrument with excellent measurement properties whose greatest value is probably as a research tool for longitudinal studies.

The 'uvenile Arthritis Quality of Ufe Questionnaire The JAQQ19 was developed by follOWing standard principles of item generation. 23 The parents of 91 patients with JRA and juvenile spondyloarthropathy were interviewed to generate items. For those 9 years of age and oldet, parents and children were interviewed separately, a pr@cess that produced a very high level of agreement between patients and parents over a wide array of perceived difficulties. 96 Additional items on psychosocial function were added by the incorporation of a previously developed psychosocial instrument,97 Generated items were subsequently reduced by application of scores assigned by patients, parents, and a panel of experts and then categorized into four dimensions (gross motor function, fine motor function, psychosocial function, and general symptoms), each with approximately 20 items. A seven-point Likert scale of frequency of difficulty with the particular item in question was then applied; scores range from 1 to 7, with higher scores indicating worse function. Respondents score all items and are also asked to identify up to five items in each dimension with which they are having difficulty; they may also volunteer their own items for each dimension. The mean score for the five highest-scoring items in each dimension is computed as the Dimension Score (range, 1 to 7); the Total JAQQ Score is computed as the mean of the four Dimension Scores (range, 1 to 7). The J~QQ was completed by 30 patients in 20 minutes initially, and then in 5 minutes on retesting 5 weeks later, showing good construct validity, with moderate correlations with measures of disease activity and excellent correlations with pain. Correlations for the psychosocial dimension were less, as predicted, being best with pain. Responsiveness was demonstrated by cQrrelations of change scores, which were moderate with sum of joint severity score and physician global assessment of change and excellent with pain. Responsiveness was also demonstrated by the ability of the JAQQ to discriminate among patients based on physician global assessment of change. After this initial study,19 the item number was reduced to 74----;gross motor function, 17 items; fine motor function, 16 items; psychosocial function, 22 items; and general symptoms, 19 items. A pain dimension, added as a supplement to the JAQQ, included a 100-mm VAS, a five-point Likert scale, and, for children younger than 10 years of age, a five-point happy/sad face modeI.98 Face and content validity of this version was confirmed in 20 pediatric rheumatologists and therapists. Construct validity and responsiveness were established. 99 Responsiveness was further established before and after commencement of new drug therapy (a mean of 8 weeks apart).100 Responsiveness of the JAQQ was also shown to be maintained over time 101 and to be a~ least as good as that of the CHAQ or CHQ.102 English and French versions are availahle, and a Dutch translation has been validated. 103

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The JAQQ has been developed in a detailed fashion, resulting in excellent validity and responsiveness. It can be administered to children of all ages and disease onset types, in a reasonable period of time with minimal assistance, and can be scored quickly by hand; this makes it practical for use in the clinical setting. Perhaps its biggest drawback is that for each child essentially a different instrument is completed, based on its unique scoring system. This may make comparison between groups difficult, compromising the test's discriminative ability, and is the subject of ongoing study. Nonetheless, the JAQQ has excellent responsiveness and therefore is a very useful instrument for clinical trials.

The Childhood Arthritis Health Profile The CAHp 20 was developed to capture the broad range of health states in children with JRA including physical and psychosocial function. It is a parent report that is selfadministered and consists of three modules--generic health status measures, JRA-specific health status measures, and patient characteristics. The initial report focused on the development, validity, and reliability of the functional scales, both JRA specific and generic. Three functional scales--gross motor function, fine motor function, and role activities (play, family, friends).-were determined for the JRA-specific scales. Internal reliability was demonstrated by good inter-item correlations within scales and minimal item scale variation. Correlation coefficients for the JRA-specific scales with one another ranged from 0.84 to 0.97, whereas those for the generic functioning scales were 0.73, demonstrating validity of these scales and further suggesting that the JRA-specific scales provide additional information beyond that of the generic functioning scales. In a follow-up report,21 differences in the )RA-specific scales were compared with clinician-rated disease severity and activity. Significant differences were seen across disease severity and activity for gross motor function, fine motor function, usual role activities affected by JRA, and school functioning. This study confirmed the discriminative ability of the CAHP. The CAHP is a promising instrument but as yet too few data have been published to determine its usefulness. Because of its comprehensiveness and complexity, it is unlikely to be of practical use in the clinical setting. Nonetheless, because of its discriminative ability, it is likely to find a role as a research tool for longitudinal studies.

The Quality of My Ufe Questionnaire The QoMLQ was developed in an attempt to distinguish between difficulties resulting from the disease itself and those difficulties that are generic. 48 It comprises two separate 100-mm VAS, anchored with the descriptors "Worst" and "Best," that direct respondents to indicate their "quality of life," both aspects caused by the disease itself and those caused by overall difficulties not necessarily directly related to the disease. This approach demonstrated the importance of distingUishing between these factors, because clear differences were noted among respondents between the two scales. This is a short and easy to use generic instrument that has been demon-

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strated to be highly reliable and valid. 4R However, it needs further study.

The Child Health Questionnaire The CHQ49 is a generic instrument that comprises a number of different forms. The form used most commonly in children with ]RA is the Parent Form 50 (PF 50), which contains 50 items distributed in several dimensions: global health, physical activities, everyday activities, pain, behavior, well-being, self esteem, general health, and family. These sections are complemented by general questions about the child and the caregiver. Two separate scores can be computed that estimate physical and psychosocial function; both are scored from 0 to 100, with the higher score indicating better function. In a recent study of short-term outcome in 116 children with ]IA observed for less than 2.5 years, Selvaag and colleagues 104 demonstrated poorer physical status but minimal psychological impairment in]IA patients relative to controls using the CHQ. The CHQ is an instrument that has received significant attention, particularly from the Pediatric Rheumatology International Trials Organization (PRINTO), which has validated it for use in 32 languages. 73 It was used in combination with the CHAQ in a trial of methotrexate, where it was shown to be highly responsive. 7R However, one study suggested that the ]AQQ may be at least as responsive as the CHQ for studies in JIAIOZ For the reasons outlined earlier, and because of its generalizability, the CHQ has become the preferred measure of QoL for ]IA trials.

The Pediatric Quality of Life Inventory The Peds QL is a modular instrument designed to measure HRQoL in children and adolescents aged 2 to 18 years. 50 It contains a generic core integrated with a disease-specific core. The generic core has undergone various iterations, the most recent of which, the Peds QL 4.0 Generic Core Scales, contains 23 items distributed in four scales: physical, emotional, social, and school functioning. The Peds QL 3.0 Rheumatology Module contains 22 disease-specific items distributed in five scales (pain, daily activities, treatment, worry, and communication). It is completed by both the children and their parents and consists of developmentally appropriate forms for varying age groups. When it is completed separately, parentchild concordance has been demonstrated to be good. The module takes approximately 15 minutes to complete. Each item is scored on a five-point scale (0 to 4), with a higher score indicating worse function. A mean Scale Score is computed based on the number of items scored. This is then extrapolated in a reverse fashion to a scale of 0 to 100, with a higher score indicating better function. Total Scale Scores are computed as the mean across all items scored in that scale. This process is the same for the Generic Core Scale and the Rheumatology Module. This instrument was shown to have excellent reliability, validity, and responsiveness in a study of 271 children with various rheumatic diseases, 91 of whom had ]RA, and their parents. !Os Reliability varied with the age of the child, being less good for younger children. Reliability was also not as

LI FE

OUTCOM ES

good for the Rheumatology Module. Responsiveness has not been tested in a trial setting. Nonetheless this instrument represents an important addition to the pool of outcome measures available for use in]RA, and further studies are being followed with interest.

INSTRUMENTS AVAILABLE FOR USE IN RHEUMATIC DISEASES OTHER THAN JUVENILE IDIOPATHIC ARTHRITIS There has been considerable recent international effort to develop appropriate measures for use in inflammatory myopathies in both adults and children. This effort has culminated in the development of measures of disease activity and damage 106 and a core set of measures for childhood-onset and adult-onset diseases. 107 ,IOH The core set for juvenile dermatomyositis (TDM) was conducted simultaneously with a similar effort for juvenile systemic lupus erythematosus (SLE).IOR The development of specific functional status or HRQoL measures in either disease, specific to children, has not been as active as for ]RA. Through an initial survey of 267 physicians in 46 countries worldwide, followed by a nominal group technique using 40 physicians from 34 countries, 37 response variables for ]DM were examined. lOR Ultimately, a core set for JDM was arrived at and comprised muscle strength testing, muscle enzyme testing, functional ability, physician and parent/patient global assessments, and a global score tool. This instrument has recently undergone validation testing in an attempt to define improvement in the core set. 109 Such improvement is defined as a minimum of 15% improvement in the domains of muscle strength and physical function, a minimum of 20% improvement for physician and patient global assessments and overall global assessment, and a minimum of 30% improvement in muscle enzymes. In addition, however, a specific outcome measure has been developed for ]DM, the Childhood Myositis Assessment Scale (CMAS).lIO This is a therapist-administered assessment of muscle strength, endurance, and function with excellent measurement properties. It is scored on a scale of 0 to 52, based on the ability of the child to perform specific tasks scored by an observer. The CMAS has been shown to have outstanding intraand inter-observer reliability. It has been shown to have good validity and good correlations with manual muscle testing. It also has reasonable responsiveness and is undergoing further study. The CHAQ has also been validated for use in ]DM patients. It was shown to have excellent test-retest reliability, validity, and responsiveness lll - 1l4 and to be of value as a measure of outcome. liZ As a component of the initiative discussed for ]DM, a similar effort was conducted for juvenile SLE. 1OH In this component of the study, 41 response variables were tested. Ultimately, measures of disease activity included specific SLE immunologic tests and renal function measures, as well as physician and parent/patient global assessments, an overall global assessment, a measure of growth and development, and a measure of HRQoL (most likely the CHQ, but this has not been finalized). Brunner and associates pre-

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viously validated the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) for juvenile SLE 115 and in a recent study demonstrated the responsiveness of the European Consensus Lupus Activity Measurement (ECLAM) for juvenile SLE, suggesting that it might be more sensitive than the SLEDA[ in this population. 116 Two recent studies described the extent of damage in juvenile SLE117.118 using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index. Further work is ongoing to develop new measures or test existing measures of function or HRQoL in both ]DM and]$LE.

CONCLUSION This chapter outlined the essential properties required of any instrument for application in children with rheumatic diseases and discussed the various instruments that have been developed. The focus was predominantly on outcome measures that have been developed for ]RA. The properties of these various instruments were compared (Table 7-5). It is clear that they differ significantly from one another and have been developed with different objectives in mind, so that each has unique qualities. Four measures-CHAIMS, CHAQ, ]AFAR and ]ASI-have a specific focus on physical function, whereas the others-]AQQ, CAHP, QoMLQ, CHQ, and Peds QL-attempt to measure HRQoL in addition to physical function. The ]ASI has excellent measurement properties. Because it is comprehensive and takes considerable time to cOfllplete, it is probably best applied as a research tool, rather than a tool for clinical use. The ]AFAR also has excellent measurement properties and has been tested widely; however, its use may be limited because it cannot be administered to a broad enough age range. The CHAQ has excellent measurement properties and has uhdergone the most Widespread use. It is simple to use and can be completed within a brief period. It is versatile and can be used in clinical trials and outcome studies, in a number of diseases, and is also applicable to a wide age range. It not only is of great value as a research tool but also can be used in the clinical setting. For these reasons, it has a distinct advantage and has become the preferred measure of functional status for ]RA. The ]AQQ is also comprehensive, although it can be completed quickly. It can be administered to all age groups and is highly responsive. Its most appropriate role is in clinical trials, the specific purpose for which it was designed; however, it may also have a role in longitudinal studies. The CAHP also has excellent measurementproperties, particularly in its discriminative ability. It is comprehensive but cannot be completed quickly, so its role will most likely be as a research tool for longitudinal studies. Both the QoMLQ and the Peds QL have distinct merits. The QoMLQ is simple to use but may not be comprehensive enough for most purposes; this may limit i:ts use. The Peds QL is a comprehensive instrument with excellent measurement properties that can be completed relatively qUickly. Therefore, it merits further study to ascertain whether it should be the preferred measure of HRQoL for ]IA and other pediatric rheumatic

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diseases. That distinction is currently held by the CHQ, which also has excellent measurement properties. However, the CHQ may not be responsive enough, and the ]AQQ and Peds QL might be better. This issue needs further study. To date, although the thrust to develop instruments for application in diseases other than ]IA continues, this effort lags somewhat behind. The CMAS appears to be an excellent measure of functional status in ]DM, and the CHAQ appears to have an important role in this disease. However, a concentration of effort needs to be applied to the study of juvenile SLE in this regard. Such work is ongoing. The past several years have been a very exciting and active time of research. Work is still ongoing to improve these instruments and to clarify the role each should hold in the future, not only in ]RA but also in other pediatric rheumatic diseases.

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Brook RH, Appel FA: Quality of care assessment: choosing a model for peer review. N Engl J Med 288: 1323, 1973. 31. Feinstein AR, Josephy BR, Wells CK: Scientific and clinical problems in indexes of functional disability. Ann Intern Med 105: 413, 1986. 32. Guyatt GH, Veldhuyzen Van lanten SJO, Feeny DH, et al: Measuring quality of life in clinical trials: a taxonomy and review. Can Med Assoc J 140: 1441, 1989. 33. Gill TM, Feinstein AR: A critical appraisal of the quality of Quality of Life measurements. JAMA 272: 619, 1994. 34. Meenan RF, Gertrnan PM, Mason JH: Measuring health status in arthritis: the arthritis impact measurement scales. Arthritis Rheum 23: 146, 1980. 35. Fries JF, Spitz P, Kraines RG, et al: Measurement of patient outcome in arthritis. Arthritis Rheum 23: 137, 1980. 36. 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J Rheumatol 9: 789, 1982. 42. Pincus T, Callaghan LF, Brooks RH, et al: Self-report questionnaire scores in rheumatoid arthritis compared with traditional physical, radiographic and labol"dtory measures. Ann Intern Med 110: 259, 1989. 43. Felson DT, Anderson JJ, Boers M, et al: The American College of Rheumatology core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 36: 729, 1993. 44. Tugwell P, Bombardier C, Buchanan WW, et al: Methotrexate in rheumatoid arthritis patients: impact on quality of life-assessed by traditional standarditem and individualized patient preference health status questionnaires. Arch intern Med 150: 59, 1990. 45. Singsen BH: Health status (arthritis impact) in children with chronic rheumatic diseases: current measurement issues and an approach to instrument design. Arthritis Care Res 4: 87, 1991. 46. Coulton Cj, lborowsky E, Lipton J, et al: Assessment of the reliability and validity of the arthritIs impact measurement scales for children with juvenile arthritis. Arthritis Rheum 30: 819, 1987. 47. Wright VF, Longo Kimber J, Law M, et al: The Juvenile Arthritis Functional Status Index (jAS(): a validation study. J Rheumatol 23: 1066, 1996. 48. Feldman BM, Grundland B, McCullough L, Wright V: Distinction of quality of life, health-related quality of life, and health status in children referred for rheumatology care. J Rheumatol 27: 226, 2000. 49. Landgraf JM, Abetz L, Ware JE: Child Health Questinnaire (CHQ); A User's Manual. Boston, MA, The Health Institute, New England Medical Center, 1996. 50. Varni jW, Seid M, Rode CA: The Peds QL: measurement model for the Pediatric Quality of Life Inventory. Med Care 37: 126, 1999. 51. Singh G, Brown B, Athreya B: Functional status in juvenile rheumatoid arthritis: sensitivity to change of the childhood health assessment questionnaire labstractl. Arthritis Rheum 34: S81, 1991. 52. Andersson Gare B, Fasth A, Wiklund I: Measurement of functional status in juvenile chronic arthritis: evaluation of a Swedish version of the Childhood Health Assessment Questionnaire. Clin Exp Rheumatol 11: 569, 1993. 53. Andersson Gare B, Fasth A: The natural history of juvenile chronic arthritis: a population based cohort study. II: Outcome. J Rheumatol 22: 308, 1995. 54. Ruperto N, Ravelli A, LevisonJE, et al: Long term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. II: Early predictors of outcome. J Rheumatol 24: 952, 1997. 55. Minden K, Kiessling U, Listing J, et al: Prognosis of patients with juvenile chronic arthritis and juvenile spondyloarthropathy. J Rheumatol 27: 2256, 2000.

56. Guillaume S, Prieur AM, Coste J, Job-Deslandre C: Long-term outcome and prognosis in oligo-articular onset juvenile idiopathic arthritis. Arthritis Rheum 43: 1858, 2000. 57. lak M, Pedersen FK: Juvenile chronic arthritis into adulthood: a long-term follow up study. Rheumatology 39: 198,2000. 58. Lomater C, Gerloni V, Gattinara M, et al: Systemic onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive patients foHowed for 10 years. J Rheumatol 27: 491, 2000. 59. Spiegel LR, Schneider R, Lang BA, et al: Early predictors of poor functional outcome in systemic onset juvenile rheumatoid arthritis: a multicentre cohort study. Arthritis Rheum 43: 2402, 2000. 60. Oen K, Malleson P, Cabral 0, et al: Disease course and outcome of juvenile rheumatoid arthritis in a multicentre cohort. J Rheumatol 29: 1989, 2002. 61. Fantini F, Gerloni V, Gattinara M, et al: Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year follow up. J Rheumatol 30: 579, 2003. 62. Flato B, Lien G, Smerdel A, et al: Prognostic factors in juvenile rheumatoid arthritis: a case-control study revealing early predictors and outcome after 14.9 years. J Rheumatol 30: 386, 2003. 63. Foster HE, Marshall N, Myers A, et al: Outcome in adults with juvenile idiopathic arthritis. Arthritis Rheum 48: 767, 2003. 64. Bowyer S, Roettcher PA, Higgins GC, et al: Health status of patients with juvenile rheumatoid arthritis at 1 and 5 years after diagnosis. J Rheumatol 30: 394, 2003. 65. Oen K, Malleson P, Cabral D, et al: Early predictors of long-term outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J Rheumatol 30: 585, 2003. 66. Doherty E, Yanni G, Conroy RM, et al: A comparison of child and parent ratings of disability and pain in juvenile chronic arthritis. J Rheumatol 20: 1563, 1993. 67. Len C, Goldenberg./, Bosi Ferraz M, et al: Crosscuitural reliahility of the Childhood Health A"essment Questionnaire. J Rheumatol 21: 2349, 1994. 68. Fantini F, Corvaglia G, Bergomi P, et al: Validation of the Italian version of the Stanford Childhood Health Assessment Questionnaire for measuring functional status for children with chronic arthritis. Clin Exp Rheumatol 13: 785, 1995. 69. Van der Net J, Prakken ABJ, Helders PJM, et al: Correlates of disablement in polyarticular juvenile chronic arthritis: a cross sectional study. Br J Rheumatol 35: 91, 1996. 70. Goycochea-Robles MV, Garduno-Espinosa .I, Vilchis-Guizar E, et al: Validation of a Spanish version of the Childhood Health A"essment Questionnaire. J Rheumatol 24: 2242, 1997. 71. Arguedas 0, Andersson-Gare B, Fasth A, et al: Development of a Costa Rican version of the Childhood Health Assessment Questionnaire. J Rheumatol 24: 2233, 1997. 72. Flato B, Soskaar 0, Vinje 0, et al: Measuring disability in early juvenile arthritis: Evaluation of a Norwegian version of the Childhood Health Assessment Questionnaire. J Rheumatol 25: 1851, 1998. 73. Ruperto N, Ravelli A, Pistorio A. et al: Cross-cultuml adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ> and the Child Health Questionnaire (CHQ) in 32 countries. Clin Exp Rheumatol 19 (Suppl 23): Sl-S9, 2001. 74. Pouchot J, Larbre]p, Lemelle I, et al: Validation of the French version of the Child Health Questionnaire in juvenile idiopathic arthritis. Rev Rhum 69: 468, 2002. 75. Madl SM, Al Mayouf SM, Grainger CG, Bahabri SA: The Arabic version of the Child Health Questionnaire modified for Arabic children. Saudi Med J 25: 83, 2004. 76. Ruperto N, Ravelli A, Migliavacca 0, et al: Responsiveness of clinical measures in children with oligoarticular juvenile chronic anhritis. J Rheumatol 26: 1827, 1999. 77. Lovell OJ, Giannini EH, Reiff A, et al: Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 342: 763-769, 2000. 78. Ruperto N, Murray K, Gerloni V, et al: A randomized trial of methotrexate in medium versus high doses in children with juvenile idiopathic arthritis who failed on standard dose. Arthritis Rheum 49 (Suppl): S232, 2002. 79. Fan JS, WesselJ, Ellsworth J: The relationship between strength and function in females with juvenile rheumatoid arthritis. J Rheumatol 25: 1399, 1998. 80. Wessel J, Kaup C, Fan J, et al: Isometric strength in children with arthritiS: reliability and relation to function. Arthritis Care Res 12: 238, 1999. 81. Miller ML, Kress AM, Berry CA: Decreased physical function in juvenile rheumatoid arthritis. Arthritis Care Res 12: 309, 1999. 82. Bekkering WP, ten Cate R, van SUijlekom-Smit LW, et al: 111e relationship between impairments in function and disabilities in independent function in children with systemic juvenile idiopathic arthritis. J Rheumatol 28: 1099, 200 1. 83. Epps H, Hurley M, Utley M: Development and evaluation of a single value score to assess global range of motion in juvenile idiopathic arthritis. Arthritis Rheum 47: 398, 2002. 84. Takken T, van der Net J, Helders PJ: Relationship between functional ahility and physical fitness in juvenile idiopathic arthritis patients. Scand .I Rheumatol 32: 174, 2003. 85. Sallfors C, Hallberg LR, Fasth A: Gender and age differences in pain, coping and health status among children with chronic arthritis. Clin Exp Rheumatol 21: 785, 2003.

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ASSESSMENT OF HEALTH, FUNCTION, AND QUALITY OF LIFE OUTCOMES

86, Den K, Reed M, Malleson P, et al: Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis, ] Rheumatol 30: 832, 2003, 87, Dempster H, Porepa M, Young N, Feldman BM: The clinical meaning of functional outcome scores in children with juvenile arthritis, Arthritis Rheum 44: 1768, 2001. 88, Billings AG, Moos RF, Miller ]], et al: Psychosocial adaptation in juvenile rheumatic disease: a controlled evaluation, Health Psychol 6: 343, 1987, 89, Lovell 0], Howe S, Shear S, et al: Development of a disability measurement tool for juvenile rheumatoid arthritis, Arthritis Rheum 32: 1390, 1989. 90. Chambers LW, MacDonald LA, Tugwell P, et al: The McMaster Health Index Questionnaire as a measure of the quality of life for patients with rheumatoid d Child Behaviour Profile. Burlington, VT, Queen City, 1983, 98. MaUl)\iIksela Fl, Olkkala KT, Korpela R: Measurement of pain in children with self-reporting and behavioural assessment. Clin Pharmacal Ther 42: 137, 1987, 99. Duffy CM, Arsenault L, Watanabe Duffy KN, et al: Validity and sensitivity to chanlle of the Juvenile Arthritis Quality of Life Questionnaire (JAQQ) [ab,tractJ. Arthritis Rheum 36 (Supp!): S144, 1993. 100. Duffy CM, Arsenault L, Watanabe Duffy KN, et al: Relative sensitivity to change of the Juvenile Arthritis Quality of Life Questionnaire following a new lteaunent [abstract). Arthritis Rheum 37 (Supp!): 5196, 1994. 101. Duffy CM, Arsenault L, Watanabe Duffy KN, et al: Relative sensitivity to chanJle of the Juvenile Arthritis Quality of Life Questionnaire on sequential follow up [abstractJ. Arthritis Rheum 38 (Supp!): S178, 1995. 102. Duffy CM, Watanabe Duffy KN, Gibbon M, et al: Accuracy of functional outcome measures in defining improvement in juvenile idiopathic arthritis [abstract). Ann Rheum Dis 59: 724. 2000. 103. Takken T, van del' Net], Kuis W, Heidel'S PJ: Aquatic fitness training for children with juvenile idiopathic arthritis. Rheumatology 42: 1408, 2003.

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104. Selvaag AE, Flato B, Lien G, et al: Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the Child Health Questionnaire. J Rheumatol 30: 1602, 2003. 105. Varni lW, Seid M, Smith Knight T, et al: The Peds QL in Pediatric Rheumatology: reliability, validity and responsiveness of the Pediatric Quality of Life Inventory Generic Core Scales and Rheumatology Module. Arthritis Rheum 46: 714, 2002, 106. Isenberg DA, Allen E, Farewell V, et al: International consensus on outcome measures for patients with idiopathic inflammatory myopathies: development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology 42: 1, 2003. 107. Miller FW, Rider LG, Chung YL, et al: Proposed core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatology 40: 1262, 2001. 108. Ruperto N, Ravelli A, Murray K], et al: Preliminary core set of measures for disease activity and damage assessment in juvenile systemic lupus erythematosu, and juvenile dermatomyositis. Rheumatology 42: 1, 2003. 109. Rider L, Giannini EH, Harris-Love M, et al: Defining clinical improvement in adult and juvenile myositis, J Rheumatol 30: 603, 200} 110, Lovell 0], Lindsley CB, Rennenbohm RM, et aI: Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies: 11. The Childhood Myositi, Assessment Scale (CMAS): a quantitiative tool for the evaluation of muscle function. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group. Arthritis Rheum 42: 2213, 1999. 111. Feldman BM, Ayling-Campos A, Luy L, et al: Measuring disability in juvenile dermatomyositis: validity of the Childhood Health Assessment Questionnaire, J Rheumatol 22: 326, 1995. 112. Huber AM, Lang B, LeBlanc C, et al: Medium and long-term functional outcomes in a multi-center cohort of children with juvenile dermatomyositis. Arthritis Rheum 43: 541, 2000, 113. Huber AM, Hicks ]E, Lachenbruch PA, et al: Validation of the Childhood Health Assessment Questionnaire in the juvenile idiopathic myopathies. J Rheumatol 28: 1106, 2001. 114. Takken T, Elst E, Spermon N, et al: The physiological and physical determinants of functional ability measures in children with dermatomyositis, Rheumatology 49: 591, 2003. 115. Brunner HI, Feldman BM, Bombardier C, Silverman ED: The SLEDAI, SLAM and BILAG are sensitive to clinical change in childhood-onset sy'temic lupus erythematosus. Arthritis Rheum 42: 1354. 1999. 116, Brunner HI, Silverman ED, Bombardier C, Feldman BM: European Consensus Lupus Activity Measurement is sensitive to change in childhoodonset sy'temic onset lupus erythematosus. Arthriti, Rheum 49: 335, 2003. 117. Brunner HI, Silverman ED, To T, et al: Risk factors for damage in childhoodonset systemic lupus erythematosus: cumulative disease activity and medication u,e predict disease damage. Arthritis Rheum 46: 436, 2002. 118, Ravelli A, Duarte-Salazar C, Buratti S, et al: Assessment of damage in juvenile-onset systemic lupus erythematosus: a multi-centre cohort ,tudy. ArthritiS Rheum 49: 501, 2003.

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8

A GENERAL ApPROACH TO MANAGEMENT OF RHEUMATIC DISEASES IN CHILDREN Balu H. Athreya and Carol B. Lindsley

IJif

Rheumatic diseases are chronic, multisystem diseases characterized by an unpredictable course with periods of exacerbation and remission. Care of affected children requires consultations with medical and surgical specialists. Many of these disorders cause muscle weakness and joint contractures with functional disabilities. Therefore, children with rheumatic diseases often require physical and occupational therapy, counseling, and social services (Table 8-1). Treatment of these diseases with anti-inflammatory agents, immunosuppressives, and the new biologic immune modulators is discussed in various chapters dealing with individual disease categories. This chapter discusses general principles of management of issues, other than medical, that are common to all chronic diseases. This includes discussions on compliance issues, strategies to improve self-image and coping skills, schoolrelated issues, transition to adult care, physical and occupational therapy, and one specific aspect of well-child care-immunization. There are multiple dimensions to the effects of chronic illness on children and on members of their families.! Several early studies suggested a negative impact of chronic illness on psychosocial deveiopment,I-3 family,4 school life,s.6 and family finances. 7 •H Studies focusing on children with rheumatic diseases growing up before the availability of modern drugs showed that 30% to 50% entered adult life with active disease. 9.10 Severe disability was common in this young adult population with decreased physical functions, poor health perception, and pain. ll ,12 All of the psychosocial and physical problems assume greater importance when such children reach adolescence!3 or when they grow up to be adults with continuing disease activity. For all of these reasons, a program of care for children with rheumatic diseases should plan for the whole child and the future and should be comprehensive (e.g., family-centered, community-based, coordinated, and cost-effective) (Table 8-2).14 More recent studies have not substantiated earlier pessimistic outcomes for children with rheumatic diseases. Even earlier studies that emphasized the continuing disease activity and functional problems of young

184

adults growing up with juvenile rheumatoid arthritis QRA) showed that many of these patients completed college, worked full time, and raised chiidren. ll ,I5--17 Recent well-designed studies seem to indicate that JRA is not necessarily a psychosocial stressor, and families of children with JRA are, in general, resilient.!8,19 Although these studies suggest that psychosocial intervention is not needed for every child with arthritis, they also show that some of these children do suffer disabilities, have reduced function and employment status and decreased social acceptance,21) and have overall adjustment problems and internalization of symptoms. 21 Current research efforts suggest that planning for care for these children should be based on new concepts of disablement, should be evidence-based, and should be individualized. New concepts of the "disablement" process include four distinct constructs: active pathology, impairment, functional limitation, and disability.22 Each of these stages offers potential for intervention. In addition, there may be other factors, such as coping skills, access to care, economics, and the family's psychosocial climate, that contribute to this disablement process and therefore are appropriate targets for intervention. In planning for the management of functional and psychosocial disabilities in chronic illness, one must address the issue of why some patients and families are vulnera-

I-, • 1ABLE 8 -I ,-

(olllponenb of M,lIIdgemenl of RlwllIIldli( Oisedses in (hildren

Medical and surgical management Family-centered, community-based, coordinated care (school, outreach) Psychosocial management (social services, mental health services, financial) Musculoskeletal rehabilitation (physical therapy, occupational therapy, orthopedics) Well-child care issues (growth and development, nutrition, immunization, anticipatory guidance) Continuity of care Cost-effective care

C HAP T E R 8

I'll • -

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185

TEAM CARE

IABLE l'l-2 Steps in Implementing [,unity-Centered, \ (llIlmunity-Based (an'

Tertiary Center Recognizing the pivotal role of the child and the family in the planning of care Developing resources in the community where the child lives Recognizing parents and professionals as equals in a partnership of care Emptlwering the family with information through education and support Encouraging pediatricians to assume a greater role in casecOOirdination, become knowledgeable about available local resources, and work with community agencies Increasing communication among disciplines and from patients to hea'lth professionals Breaking barriers to development of such a system

Pediatric Rheumatologist; Rheumatology Nurse; Allied Services; Other Pediatric Specialists; Special Laboratory; Imaging; etc.

I I

Child and Parent

School .....- - Primary Physician

ble and others are not. 18,19 Based on their well-designed study, Noll and colleagues suggested that "randomly occurring, challenging life events do not alter the child's potential for inclusive fitness by denigrating their social status or emotional well-being."23 One concept to explain this qifference in vulnerability suggests that there are some risk factors that tend to push children with chronic illness and their families to dysfunction and disability, and there are resilience factors that tend to give more stability,24,25 An imbalance between these two groups of factors influences outcomes (Table 8-3). Therefore, in planning for the care of these children, emphasis should be on the child and the family, and efforts should be aimed at not only controlling the disease and managing the current problems, but also at planning for the future. Steps should be taken to improve the resilience of patients and families through better education to cope with the vicissitudes of these diseases, improved social and peer support for the children and their parents, and stress management education to help them cope better with their disease and disability. Accurate diagnosis is the first step. Rheumatic diseases may be acute and explosive in onset, or they may evolve over a period of months and years. Only one organ system may be affected, or several systems may be involved, mimicking several other inflammatory and noninflammatory diseases. It may not be possible to place an accurate diagnostic label at first, and yet life-threatening complications and functional disabilities may have to be managed. Great skill and patience are required to support the families in managing their problems in the face of uncertainties in diagnosis and prognosis. Therein reside the <-~hallenges and pleasures of rheumatology.

I:.

I ABI E H 3

Risk factors Resilience factors

• Figure 8-1

From Wallender JL. Varni VW: Adjustment in children with chronic physical disorders' programmatic research on a disability-stress coping module. hI La Greca AM, Siegel LJ. Wallender JL. Walker CE teds), Stress and Coping in Child Health. New York. Guilford, pp. 279-298, 1991.

Community Agencies

Model of team care.

Expertise should be the cornerstone of the care of children with rheumatic diseases. Comprehensive treatment centers should be based in tertiary-care academic centers. The treatment team (Fig. 8-1) should consist of a pediatric rheumatologist, a nurse specialist, physical and occupational therapists, a social worker, and a psychologist, all working with the child's primary care physician. Consultations with an orthopedic surgeon, ophthalmologist, nutritionist, and dentist should be available when required. The child and family should be the central focus of the team. The roles of the primary care physician and the rheumatologist are listed in Table 8-4. Effective communication between the primary care physician and the specialist, and the availability of one contact person at the tertiary center, are the other essential requirements for comprehensive care. 26 Specially trained nurses have fulfilled the contact function effectively in many pediatric rheumatology centers. 27

PATIENT EDUCATION Children with rheumatic diseases and their parents require education on several issues. These issues are

I! II

TABLE l'l-4

Primary physician

Risk and Resilience

Severity of disease and disability Degree of functional independence Daily hassles and struggles Family's ability to solve problems Social support Coping skills

---.,~~

Pediatric rheumatologist

Role of Physicians in the Care Managenwnt feam

Care of intercurrent illness Immunization Developmental issues Anticipatory guidance Working with the community agencies Working with the school system Overall management of the rheumatic disorder Detailed guidelines and directions for the management of a specific problem Ongoing medical explanation for the management decisions Minor counseling Physical therapy/occupational therapy Monitoring for drug toxicity Referral to other subspecialty

186

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discussed in detail in several publications (Appendix 8-1). The mode of teaching has to vary to suit the needs

and skills of parents. Language barriers, cultural backgrounds, and literacy issues must be kept in mind before such programs are organized. Education about the disease, medications, adverse effects of medications, and therapy programs should take place both individually by the pediatric rheumatologist and in groups as part of parent support groups. The belief system of the family should be explored, and all doubts and questions should be addressed. Information required by parents varies with the time that has passed since diagnosis. It also depends on the developmental needs of the child. Therefore, education must be individualized. z8 Information is easily available on the Internet. However, families need help to receive information from reliable sources, such as the Arthritis Foundation (http://www. arthritis. org), and they need assistance with interpretation of the information gathered. Parents and patients in the United States are encouraged to attend educational sessions organized by the American Juvenile Arthritis Organization (AJAO) for patients, siblings, and parents as part of annual regional and national meetings. Similar organizations also exist in other parts of the World (e.g., United Kingdom, Italy, India).

COUNSELING A trusting relationship is the most important requirement for effective counseling. To be trusted, one must be trustworthy. Open, honest communication with the child and the parents is a major component of this relationship. One must listen carefully before offering advice. Collecting information about a child's illness, behavior, and family dynamics may require many visits and observations. One must listen to what the child and family say and observe what they do. Nonverbal cues must be attended to. While treating the impact of the disease on a child and the attendant weaknesses in the family, one must also be on the lookout for their strengths. This strength may lie in the extended family, an interested schoolteacher, or a loving grandparent. It is important to know the strengths, because one can only build on the strengths while finding ways to compensate for the weaknesses. Some families grow in strength in the presence of adversity. Factors that contribute to successful coping should be supported and encouraged. 24 •29 Children with physical disabilities and deformities and children who look different because of a rash or steroid therapy are bound to feel different and selfconscious. Physical disability and fluctuation in disease activity may make it difficult for these children to participate in social and family activities. 30 Emphasis on what they can do and planning activities in which they can participate should help their sense of self-worth and morale. There should be alternative plans and backup arrangements. Involvement of siblings, friends, and classmates in helping a disabled child during activities should help create a successful experience for everyone.

'11 1:.

IABLE H -5

hI( lors ThaI Influence Adheren(('

Cognitive/emotional (e.g., limited ability to understand, depression) Behavioral (e.g., defiance, adolescent independence) Cultural (e.g., alternative concepts of disease model) Social and family issues (e.g., unstable family) Disease-related (e.g., chronicity) Medication-related (e.g., side effects) Organizational (e.g., appointments in the clinic) Economics (e.g., cost of visit) From Kroll T, Barlow]H. Shaw K: Treatment adherence in juvenile rheumatoid anhrilis: a review. Scand.J Rheumatol 28: 10-18, 1999.

ADHERENCE (COMPLIANCE) Children with chronic illness soon become tired of taking medicines day after day with no end in sight. They often ask why they have to do mindless exercises that do not appear to help them in any way. Therefore, compliance with medication and therapy programs becomes a major issue for children with chronic diseases. 31.3 2 The word "compliance" implies that the physician gives orders and the patient obeys. But the ideal situation is an informed patient who chooses to follow the treatment prescribed by a trusted physician after being convinced of the benefits and made aware of the consequences of not following the treatment. In other words, the patient chooses to adhere to the prescribed program. In pediatrics, one must consider the child, the parent, and the caretaker to make sure the treatment plan is followed. Patient and parent education and incorporation of the needs of family members in planning the care are essential to ensure that the patient adheres to the plan. Listening to the specific needs of a child and family and incorporating them into the plan, as well as designing a plan that accounts for the stresses and strengths of the family and their cultural values, increases the likelihood that the plan will be followed. Factors that affect adherence and strategies to enhance adherence are listed in Tables 8-5 and Table 8-6.

SIBLING ISSUES Stress related to living with chronic illness affects every member of the family, including siblings. The role of siblings and their impact on the developmental needs of the patient may vary with the age and cognitive level of siblings, their perception of the child with chronic illness,

-=..

TABLE 8-6

Slr.llegies 10 fadlildle dud Promole Adlwreme

Informational handouts Cues and reminders Positive feedback Discipline Steps to minimize discomfort and inconvenience Dealing effectively with complaints Monitoring disease process for changes Adapled from Rapoff M: Compliance wilh treatment regimens for pediatric rheumatic diseases. Anhritis Care Res 3: 40-47. 1989.

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ApPROACH TO MANAGEMENT OF RHEUMATIC DISEASES IN CHILDREN

paret}fal attitudes, and the demands placed on unaffected siblings. 33•34 Feelings may range from guilt (that siblings are responsible for the sick child in some magical way) to fear of catching the illness and embarrassment. 35 Siblings may resent the extra time and attention given to the affected child and perceived favoritism in matters of discipline. Realistically, parents may not be able to provide adequate time to satisfy the developmental needs of the siblings. This is a particular problem for single parents. Depending on the parental demands, some siblings may take an important role in the medical treatment of the affected child (such as reminding about medications and helping with therapy); others may be protected from this role by their parents. Some siblings may take a more protective role in school and outside the home. Disease severity, parental functioning, family stress, and family support systems are some of the determinants of the effects of chronic illness on siblings. In spite of ambivalent feelings, siblings of children with arthritis function well in life. 36 With the proper approach, they become a great source of extra support, both at home and at school. It is important to evaluate the needs of siblings in caring for children with chronic illness and to help support their needsY Some ideas to reduce the negative impact on siblings are given in Table 8-7.

SCHOOL ISSUES Rheumatic diseases in general do not affect the ability of the child to learn and think, except for conditions that affect the central nervous system, such as systemic lupus erythematosus (SLE). Children with arthritis can and should attend school except in special circumstances. School is a child's job. However, the school system often must institute several adaptations to the standardized schedule. 5•6 In the United States, children with chronic illness and disabilities must be educated in the "least restrictive environment." Individualized education plans ClEPs) have to be formulated at the parent's request, and there are strong "due process" requirements. 38 Depending on the medical condition and the disability, one or more of the "related school services" listed in Table 8-8 may need to be provided for children with special health care needs to ensure proper educational opportunities. 6,39 Special school services are important components of community-based services, They provide physical adap-

~~ /I TABl~

H- 7 Approd(he~ 10 Siblings of Children with ( hrolllc Illness

Include siblings in clinic visits. Talk with siblings and explore their needs. Determine the perception of the siblings on the impact of the illness on family members. Help them deal with their friends' questions. Encourage and enlist sibling participation in developing care plans. Conduct sibling group discussions at local and national support groups.

It III

1ABLE 8-8 III Children

Related School

Service~ Needed

187

by Chronl<
Administration of medications Implementation of medical procedures Emergency preparations Schedule modifications Modified physical education Transportation Building accessibility Toileting/lifting assistance: support therapies Physical therapy Occupational therapy Speech and language therapy Counseling services (school, career, personal) Data from Walker OK, Jacobs FH: Chronically ill children in schools. In Hobbs N. Perrin J (eds): The Constant Shadow: Issues in Chronic Childhood Illness in America. San Francisco, Jossey-Bass, 1984. Modified from Walker OK: Care of chronically ill children in schools. Pediatr Clin North Am 31: 221, 1984.

tations in schools for handicapped access, elevators, classes on the same floor, and a duplicate set of books. Transportation, school counseling, nutrition, adaptive physical education, and homebound instruction are some of the other services that may be needed. 5.39 Many common concerns expressed by children and parents in relation to school, as well as suggested solutions, are given in Table 8-9, The nurse can provide an individualized checklist for parents (Appendix 8-2); this list can be shared with the school nurse or teacher. School nurses are some of the best advocates for children with disabilities and special needs. Well-informed school nurses can work with teachers and physical education instructors and make appropriate modifications within the school. Therefore, communication between the tertiary center staff members (particularly the nurse) and the school nurse is essential. In addition, special educational programs for school nurses are very useful. It is important to recognize that teachers and parents tend to emphasize issues related to activities of daily living (ADL) as limiting school life, whereas children themselves rate peer acceptance and self-concept as more important. 4o Therefore, these children need more help with peer support and better coping skills. Final1y, if a child is considering vocational training or col1ege after high school, early planning is essential. This planning should start at the beginning of secondary school at the very latest. One of the author's successful "graduates" wrote a checklist in preparation for her entry into college (Table 8-10).

TRANSITION Transition to adult care is a process that should start in pediatric rheumatology centers when a child reaches adolescence. 13.41 Preparation of these children requires attention to functional vocational evaluation and training, independent liVing skills, and self-advocacy. Growing up through adolescence into young adult life is a major task for any child. This time becomes a challenge for children with chronic illness and their parents. 13 Adolescents with chronic diseases have to be encouraged

188

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8 ApPROACH TO MANAGEMENT OF RHEUMATIC DISEASES IN CHILDREN

,

II

TABLE 8 9

(ommon SdlOOI (OI11erns for Students with Rheumati( Oiseas('s

DIfficulty

Strategy

Inactivity, stiffness due to prolonged sitting

Sit at side or back of room to allow walking around without disturbing class Change position every 20 minutes Ask to be assigned jobs that require walking (e.g., collect papers) Request elevator permit Schedule classes to decrease walking and climbing Request extra time getting from classes Use wheelchair if needed Keep two sets of book: one in class, one at home Have a buddy help carry books Get a backpack or shoulder bag for books Determine cafeteria assistance plan (helper, reserved seat, wheeled cart) Request an easel-top desk or special chair Use "fat" pen/pencil, crayons Use felt-tip pen Stretch hands every 10 minutes Use tape recorder for note taking Photocopy classmate's notes Use computer for reports Request alternative to timed tests (oral test, extra time, computer) Educate teacher (messy writing may be unavoidable at times) Wear loose-fitting clothing Wear clothes with Velcro closures Get adaptive equipment from occupational therapist Modify locker or request alternative storage place Use lockers with key locks instead of dials Devise alternative signaling method

Climbing stairs or walking long distances

Carrying books or cafeteria tray

Getting up from desk Handwriting (slow, messy, painful)

Shoulder movement and dressing Reaching locker Raising hand

From Raising a Child with Arthritis: A Patient's Guide. Atlanta: Arthritis Foundation, 1998.

to take control of their disease management gradually. This requires preparation of the family and child before adolescence. Both physicians and parents have to let go of the child in a sensitive and gradual way, The parent has to trust, and the child must prove that he or she can be trusted to take care of ongoing management and needs. Adolescent support groups with profeSSional leadership may be helpful. Some of the subjects that should be

( ' . TABI E S I I)

RheulIl
Visit the college before choosing, in order to evaluate the walking distance between buildings, stairs, and elevators and for general accessibility. Know the different climate changes (e,g" if you feel better in the summer, you may want to pick a campus with a warm climate). Also, climate changes can cause flare-ups or increased stiffness, It is always good to get to know a local doctor in your college area or health service before troubles occur, so that he or she knows your past history and can help you right away if there are any problems. If you have the chance to pick your oWn schedule during your first year, make sure you give yourself enough time to get from one class to another (e.g., if you have to walk to buildings from one end of campus to the other), Also try not to overburden yourself with classes and too many credit hours-there will always be bad days, so expect them. If you are not a morning person or if you are a "night owl," schedule your classes in the afternoon, And always-no matter how "bad" the food is-eat as regularly as possible: breakfast, lunch, and dinner, It helps in the long run, even if your stomach does not think so at the time, Take extra medicine with you at the start of school and give yourself time to find the nearest pharmacy.

addressed, both in individual sessions and in group discussions, are preparing for college, sexuality, alcohol and drugs, and vocational planning.

FINANCIAL ISSUES Children with chronic illness account for a large proportion of health care expenditures in the United States,~.42 For instance, families of children with rheumatic diseases may spend hundreds to thousands of unreimbursed dollars out of pocket per year,4,7.8 not including time lost from work. In the current competitive environment, children with chronic illness and disabilities are particularly vulnerable. The high cost that goes with chronic illness, and the pressures to cut costs, may make it difficult to proVide adequate and appropriate care for children with chronic illness and disabilitiesY In the United States, families need to be educated about various types of coverage and how to work with health maintenance organizations (HMOs) and insurance companies. Families need to learn about child welfare systems and social security benefits. They also have to learn to work with their school systems. Parents must be advocates for their children and learn both their own rights and responsibilities and those of their children.3~ Both parents and physician..'i need to work through the political process to bring about changes in financing of medical care that will ensure access to appropriate services for all children with disabilities. 43 A special program developed by the AJAO teaches several skills to parents so that they can become advocates for their children. In this program, a parent and a health professional who works with the child learn to

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list items of care essential for that specific child and learn strategies to achieve those goals.

UNCONVENTIONAL REMEDIES With scientific medicine truthfully acknowledging its ignorance about the etiology of rheumatic diseases and the lack of a cure, it is easy for parents to believe those who promise miracles. This is also the age of alternative medicine. 44 There are pressures from well-meaning friends and relatives to try unproven remedies widely advertised in newspapers and on the Internet. Southwood and colleagues 45 reported that 70% of patients with juvenile arthritis had used unconventional remedies. Even if it is not discussed by patients, it can be assumed that most of them have tried or are trying one or more remedies. It is better to keep an open and noncritical relationship with patients and their family members so that they feel comfortable talking about these remedies. It is important for pediatric rheumatologists to be aware of the currently available alternative remedies, so they can provide proper guidance when patients ask about such methods. This is an opportunity to educate parents on the conduct of scientific studies and to explain to them the difference between controlled trials and testimonials. It is better to let them try some remedies that are innocuous, caution about some potentially dangerous treatments (e.g., megavitamins), and refuse to be part of certain other approaches (e.g., bee-sting therapy). It is always wise to allow room for parents to come back without losing face and feeling humiliated.

f

II

TABLE 8-1 I

189

Principles of Therapy

Relieve pain Cheat, cold, splint). Stretch individual joints. Train coordination of opposing muscles. Re-integrate physiologic movement patterns. Re-educate to improve posture and gait. Improve activities of daily living: Use of traction and/or prone position to reduce hip flexion contracture Use of resting splints for wrist support Shoe inserts and modifications From Hackett J, Johnson B, Parkin A, Southwood T: Physiotherapy and occupational therapy for juvenile chronic arthritis: custom and practice in five centres in the UK, USA and Canada. Br J Rheumatol 35: 695-699, 1996; Scull SA, Dow MB, Athreya BH: Physical and occupational therapy for children with rheumatic diseases. Pediatr Clin North Am 33: 1053---1077, 1986.

tions for referral to therapists are listed in Table 8-12. If more aggressive therapy is required, an outpatient program is indicated with two or three sessions a week. Even with this frequency, carryover into the daily routine is essential to maintain the benefits. Occasionally, children require intensive inpatient rehabilitation, which is becoming increasingly difficult to finance in the United States. Fortunately, the need for such inpatient rehabilitation is becoming less frequent thanks to better medical management. Children whose disability is serious enough to interfere with attendance at a regular school may be able to receive school-based therapy that follows an IEP.

PHYSICAL AND OCCUPATIONAL THERAPY The overall goals of rehabilitation are to maximize function, to prevent deformities, and to help a child achieve developmental milestones-physical, psychosocial, emotional, educational, and vocational. The concept is to help the child and family lead as normal a life as possible. Goals must be set in collaboration with the parents and the child. One has to account for the needs of the family, their strengths and weaknesses, their economic and human resources, their coping styles, and their cultural values. The child's developmental level and interests also must be acknowledged. 46 Physical and occupational therapy programs are vital to the management of rheumatic diseases in children. A variety of modalities and treatment approaches are used without adequate proof of their efficacy. For example, it is not known whether a resting splint to prevent dysfunctional positioning of the wrist during sleep is better than a functional splint worn during activities to prevent misalignment of the wrist joint. Consequently, there are differences of opinion and approachY General principles of therapy agreed upon by most experts are given in Table 8-11. Needs for therapy services may vary with the specific rheumatic disease, whether disabilities are acute or chronic. For minor problems and prevention of contracture, standard exercises to maintain range of motion (ROM) can be taught to parents by the pediatric rheumatologist and the nurses (Figs. 8-2 to 8-11). Usual indica-

• Figure 8-2 Neck. Tum the head toward one shoulder and then the other. Repeat two to three times on each side. (From Raising a Child with Arthritis: A Parent's Guide. Atlanta, Arthritis Foundation, 1998.)

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Inditdtions lor Refell,,1 10 1herdpish

Involvement of multiple joints Severe pain or stiffness of joints and muscles Established contracture, limitation in activities of daily living (even single area) Preoperative management Postoperative management Rapidly progressive disease Prescription for assistive devices (e.g., crutches, wheelchair) Failure to respond to standard exercise Parent-child conflict resulting in poor compliance with therapy

Essential components of treatment should include rest, management of fatigue and pain, posture and positioning, therapeutic exercises, and improving ADL,41l-50 Conditioning exercises and sports activities are discussed later.

Rest It is preferable for children with arthritis to be as active

as possible. General bed rest is rarely prescribed except for children with severe arthritis or myositis and for children with systemic disease associated with myocarditis or pericarditis. In the author's practice, children

~ A

c

• Figure 8-3 Shoulder. A, Lie on the floor with both arms at your sides. Raise one arm over the head, keeping the elbow straight, until the back of the hand reaches the floor. Return the arm slowly to the side. Repeat this exercise with the other arm. Repeat, alternating arms, two to three times. B, Shoulder abduction. Start with the arms down at the sides with palms facing out. Raise the arms out to the sides and up until palms touch, keeping elbows straight. Hold briefly, then return arms to the sides. Repeat two to three times. C, Shoulder rotation. lying down, place arms straight out from shoulder, palms toward ceiling. Bend at the elbow with the fingers pointing toward ceiling. Rolls arms forward so the hands point straight down toward feet (internal rotation). Roll arms backward so the hands point toward the head (external rotation). Repeat two to three times. (From Raising a Child with Arthritis: A Parent's Guide. Atlanta, Arthritis Foundation, 1998.)

• Figure 8-4 Elbow. A, Lie on floor with both arms at sides, palms facing the ceiling. Bring hands to shoulders by bending elbows. Return hands to the floor by straightening elbows. B, Bend elbows and hold them into the sides of the body with forearms parallel to the floor and palms down. Slowly tum forearms so palms face ceiling. Hold to the count of three, and tum arms so palms face the floor again. (From Raising a Child with Arthritis: AParent's Guide. Atlanta, Arthritis Foundation, 1998.)

A

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191

• Figure 8-5 Wrist. A, With the forearms resting firmly on atabletop and the hand hanging over the edge of the table, bend the wrist up as far as possible. Bend the wrist down as far as possible. Hold. Repeat two to three times. B, Plac.e the hand on atable or other flat surfac.e. Raise elbow toward ceiling until wrinkles appear at the wrist. C, Grasp the hand with the opposite hand. Put the palms together, with fingers around the opposite hand. Push the hand backward, stretching the wrist. Hold. Repeat two to three times. (From Raising a Child with Arthritis: AParent's Guide. Atlanta, Arthritis Foundation, 1998.)

~--~~,....---" 1"

, , I

,\\'; ."".. 11 •• - , .-If '-'

A

B

c are allowed to set their own limits based on pain and endurance, with the suggestion that, if necessary, they allow themselves a rest period during the day, usually immediately after school. Localized rest for an acutely inflamed joint is provided with a splint or a bivalved cast. If a splint or cast is applied, the limb should be taken out once or twice a day and ROM exercises or isometric exercises should be performed.

Children with functional disorders and chronic pain syndromes complain of fatigue that interferes with school attendance and participation in sports. This fatigue is often associated with nonrestorative sleep. Pharmacologic and behavioral approaches are needed to help promote sleep and thereby relieve fatigue. Fatigue out of proportion to disease activity deserves close scrutiny to differentiate between medical and psychological causes and may require cognitive and behavioral therapy.

Fatigue

Pain

Fatigue is a common problem for children with rheumatic diseases. It is a particular complaint for children with systemic diseases, anemia, and myocarditis. A defined period of rest during the middle of the day is ideal, although it is not always practical. Treatment of the systemic disease and anemia often corrects the fatigue.

Pain is a major component of many of the inflammatory musculoskeletal conditions. 51 Children with chronic arthritis often do not complain of pain because they become used to living with a certain level of constant pain. In addition to control of inflammation and use of analgesics, other modalities, such as biofeedback and transcutaneous

192

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a I,)

• Figure 8-6 Angers. A, Place hand on atable or flat surface with fingers together. Then, separate the fingers as widely as possible and hold. Repeat two to three times. 8, Curl the fingers tightly while keeping the knuckles straight. Complete the fist by bending the knuckles, then open the hand wide. Repeat two to three times. (From Raising a Child with Arthritis; A Parent's Guide. Atlanta, Arthritis Foundation, 1998.)

B

electrical nelVe stimulation (TENS), may have to be tried, depending on the clinical diagnosis, acuteness or chronicity of pain, the child's developmental status, various effects of the pain on function, and psychosocial issues. Pain caused by an acutely inflamed joint is treated with joint aspiration, intra-articular injection of glucocorticoid (if appropriate), and use of nonsteroidal anti-inflammatory dmgs. In addition, the joint can be placed in a resting splint for a few days until the inflammation subsides. The splint should be removed two or three times a day and the joint moved through ROM actively or passively to avoid atrophy of muscles and joint stiffness. children with myositis and pain need to rest and to be allowed to move to their tolerance. An active exercise program should not be started until pain and tenderness subside. Pain out of proportion to swelling of the joint needs careful evaluation to mle out other diagnoses (e.g., leukemia). In patients with JRA or SLE, severe pain or sudden onset of pain in one joint may indicate septic arthritis. Pain after activity is not uncommon in children with rheumatic diseases. Standard treatment is rest and ice, and an occasional analgesic. Children should be encouraged to be as active as possible and to set their own limits. The author's guideline is that if the joint pain after activity

lasts more than 45 to 60 minutes, the activity level or duration should be decreased.

Chronic Pain Chronic pain is a primary manifestation of rheumatic diseases in general. A unique constellation of nociceptive, affective, cognitive, and behavioral factors interact to make the pain experience more intense for some childrenY It is also important to remember that chronic pain, whether organic in origin or unexplained, can lead to depression, and, conversely, occult depression can manifest as chronic pain. 53 Children with rheumatic diseases may also experience cycles of intense and intractable pain not amenable to a pharmacologic approach. Some of these children experience secondary fibromyalgia with such classic features as tender points and lack of sleep. This pattern affects their emotional stability and function and leads to a vicious circle. In these children, a cognitive-behavioral approach may be indicated. 54 Other techniques, such as TENS, visual imagery, relaxation, and management of time and stress, may be helpful. Approaches to pain control in regional pain, ovemse, and pain amplification syndromes are discussed in appro-

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193

• figure 8-7 Hlp and knee. Lying on the back, bend one knee toward the chest, then lower. Repeat with the other knee. Repeat two to three times with each leg. (From Raising a Child with Arthritis: A Parent's Guide. Atlanta, Arthritis Foundation, 1998.)

• Figure 8-8 Back. Lie on the back with knees bent. Keep the back flat against the floor. Raise both bent knees toward the chest. Place hands behind thighs and pull toward the chest. Lower legs to original position. (From Raising a Child with Arthritis: AParent's Guide. Atlanta, Arthritis Foundation, 1998.)

/~

B~=m

A

• Figure 8-9 A, Thigh. Lie on the back with one leg bent at the knee and one leg straight. Raise the straight leg, keeping the knee as straight as possible. Keep the small of the back on the floor. Lower the leg and repeat with the other leg. B, Knee. Lying on the stomach, bend one knee, bringing the heel toward the buttocks.Then, lower the leg and repeat with the other knee. Repeat two to three times with each leg. (From Raising a Child with Arthritis: A Parent's Guide. Atlanta, Arthritis Foundation, 1998.)

c;;:----_-------,,' ----_..........- _~.--. "~~

_----

.....

A

c

D

• Figure 8-10 Hlp. A, Lie flat on the back with legs straight, about six inches apart. Roll the legs in and out, keeping the knees straight. Repeat two to three times. B, Lie flat on the back with the legs straight, about 6 inches apart. Slide one leg out to the side and retum. Repeat with the other leg. Repeat two to three times with each leg. C, Lying on the stomach, lift one leg. Try to keep the knee straight.Then, lower the leg and repeat with the other leg. Repeat two to three times with each leg. D, Lying on table with knees bent over the edge, bring one knee up to the chest. At the same time, keep the other flat on the table. Hold for a count of 10. Lower the leg. Repeat with the other leg. (From Raising a Child with Arthritis: AParent's Guide. Atlanta, Arthritis Foundation, 1998.)

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• Figure 8-11 A, Ankle. Sit in a

chair with feet on the floor. Rrst, keeping the heels down, lift the toes up as high as possible.Then, keeping the front of the feet on the floor, lift the heels up as high as possible. Rnally, tum the soles of both feet toward each other, then tum them away from each other. Repeat each movement two to three times. 8, Lower leg (calf). Standing an arm's length away from the wall, place both hands on the wall, above the head. Place one leg straight back, keeping the foot flat on the floor and the knee straight; the forward leg should be bent at the knee. Hold until a pull is felt in the back of the straight leg and count slowly to 10. Repeat two to three times with each leg. e, Lower leg. This exercise is performed by the parent or other caregiver with the child lying on the back with legs straight. Place your hand under the child's heel. Grasp the foot and lean the lower part of your arm against the sole of the foot. Bend the foot toward the knee, but do not use too much pressure. With the other hand, grasp the leg between the ankle and knee to steady the leg. Hold for a count of 10 or 15. Repeat with the other leg. (From Raising a Child with Arthritis: AParent's Guide. Atlanta, Arthritis Foundation, 1998.)

l

priate chapters. It is important to remember that emotions, cultural factors, and family dynamics play a major part in pain perception. Therefore, exclusively medical management of pain in these syndromes is unlikely to be successful. This is particularly true in reflex neurovascular dystrophy. 51 ,55 For all of these reasons, it is important to obtain a complete developmental and psychosocial history in children with chronic pain, particularly in children for whom repeated examinations and laboratory results are negative. Children with chronic pain present a management challenge because of the psychosocial factors and the time needed to care for them. Referral to a pain clinic, psychologist, or psychiatrist is sometimes needed.

Posture/Positioning Children with arthritis assume a number of dysfunctional postures unconsciously as their bodies adapt to the pain and limitation of ROM. It is important to remind them to sit with a straight back and shoulders braced. This is particularly important for children with spondyloarthropathies. Attention should be given to the school chair to ensure that good posture is maintained. The position for reading books or work on the computer should provide for good neck and wrist positions. Children with cervical spine involvement should sleep with a single pillow or a very soft pillow. Resting knee or wrist splints may be indicated for use at night to prevent poor positioning of these joints during sleep (Fig. 8-12). Lying

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Lower-extremity resting splint.This posterior shell is wom during the hours of sleep to rest the knees in extension. (From Scull SA, Dow MB, Athreya BH: Physical and occupation therapy for children with rheumatic diseases. Pedlatr Oin North Am 33:1067, 1986, with permission.) • figure .... 12

prone at least 20 minutes a day may help prevent hip flexion contractures (Fig. 8-13).

therapeutic Exerdses Therapeutic exercises serve several functions. 43-50,56 They may be aimed at improving ROM of joints, strengthening muscles, or promoting conditioning and endurance. 56 There are several types of exercises. 50,57 In active exercises, the patient is asked to move the joint. These exercises are useful to stretch and strengthen muscles (e.g., touching toes to stretch hamstrings [Fig. 8-14)). Passive exercises (active-assistive) are performed by the therapist and are useful when there is a flare of arthritis, when a joint has lost motion, and in young children. Resistive exercises are used to strengthen muscles; for example, resistance is applied as the joint moves through its range. Stretching exercises, such as those for the treatment of tight heel cords or hip flexion contracture, are done prefer:lbly by the therapist. Strengthening exercises may be isometric or isotonic. If the muscle is contracted without permitting joint motion, it is isometric. Quadriceps setting for an acutely inflamed joint is an isometric exercise. Isotonic exercises performed against gravity along with ROM and resistive exercises are useful to strengthen muscles. A child should master ROM exercises and muscle strengthening exercises before proceeding to endurance! conditioning exercises and sports activities (Fig. 8-15).

• Figure .... 14 Lower-extremity stretching exercises. Active exercises to stretch hamstrings (A); iliopsoas (B); and heel cords (C and 0). (From Scull SA, Dow MB, Athreya BH. Physical and occupation therapy for children with rheumatic diseases. Pediatr elin North Am 33:1072, 1986.)

Recreational

~ Aerobic Isotonic Isometric Range of motion and stretching

• FIpre .... 13 Prone time. Resting in the prone position on a firm sUrface

is used to stretch hip and knee flexion contractures. (From Scull SA, Dow MB, Athreya BH: Physical and occupation therapy for children with rheumatic diseases. Pediatr elin North Am 33:1058, 1986, with permission.)

Children with arthritis should begin with range-ofmotion exercises. They may progress upward on the pyramid as their disease regresses or is controlled medically. • Figure .... 15 Pyramid of graded progress in an exercise program. (From Hicks IE: Exercise in patients with inflammatory arthritis. Rheum Dis elin North Am 16: 857, 1990.)

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Exercises should be done every day, either in the morning or in the evening, for at least 20 to 30 minutes. This routine may be difficult to accomplish, particularly in the morning in a family in which both parents work and there are other children. It is best for a child to take a warm bath before performing exercises. The parents and child (particularly the adolescent) should be educated on the importance and the techniques of performing home therapy exercises. The therapist should demonstrate the exercise and let the parents practice under supervision. A written description with figures (see Figs. 8-2 to 8-11) is useful. Exercises should be age-appropriate and should accommodate the family's daily schedule. Young children are easily bored with exercises, and insistence by parents on a rigid routine may lead to parent-ehild conflicts. Therefore, efforts should be made to incorporate these exercises into games, recreational activities, and play (Table 8-13).

Adlvltles of Dally Living (ADL) ADL include tasks in self-care, dressing, feeding, and hygiene. Age-appropriate independence in these activities may be difficult for children with arthritis. For children who have difficulties with actions such as turning doorknobs or opening jars, simple and more efficient techniques to perform these activities and other joint protection techniques must be taught. For more severe conditions, adaptive devices may be needed (Fig. 8-16). In certain situations, modifications to the home may be necessary, particularly for children in wheelchairs.

Sports and Exercise Children with rheumatic diseases fatigue easily and have reduced cardiopulmonary reserve. S8 Several factors limit the exercise capacity of these children, including the severity of involvement of joints and muscles, involvement of the cardiovascular or the respiratory system, and anemia. In addition, psychologic factors S9 and parental concerns may add to the lowered physical fitness of these children. 60 Involving children in age-appropriate games and play activities is an ideal way to maintain ROM of joints, increase muscle strength, improve conditioning, and boost self-esteem. Better compliance is an added bonus. Various age-appropriate activities are listed in Table 8-13. Young children can ride in their toy cars or tricycles (Fig. 8-17). By adjusting the height of the seat and making sure they do not slide up and down, ROM of the knee can be improved to gain increased flexion or extension. By reversing the handle, extension of the wrist can be increased (Fig. 8-18). School-aged children should be encouraged to participate in physical education classes to their tolerance. Adapting gym classes and allowing children to set their own limits should encourage participation. However, activities that involve weight bearing or stress on affected joints, such as headstands, somersaults, chin-ups, and handstands, should be avoided. The trampoline is usually

b_ .. lAB. [ I i 13 lor Parl'll!s

Play fxl'rdsl's by Agl' Grou,): A GUllk

Alles 6 mo-3 ,.. Playing in warm water with toys-to move all joints and help pain Toys that pull apart (e.g., pop beads)-to strengthen hand~ and arms Tickle bottoms of feet-to bend knees and hips Put plastic ring over ankle and leg and take it off Pushing and catching a balloon or soft beach ball-to strengthen arms Kicking a balloon or soft beach ball-to bend knees and strengthen legs Squeeze and roll clay-to strengthen hand and bend wrist Tricycle or toys to scoot-to strengthen leg muscles and move the joints of the legs

Ages 4-8,.. Warm bath and playing with toys in the water-to move all joints and help pain Pieces of elastic to pull into funny shapes-to strengthen arms and hands. (Theraband is a thin elastic sheet that can be drawn on and pulled into funny shapes; it is available from physical therapy or dental supply houses.) Any crafts the child likes-to strengthen and move joints of arms and hands Clay to squeeze and roll-to strengthen hand and bend wrist Tricycle or bicycle riding-to move leg in many positions Swimming classes----total body exercise

Alles 9-13,..

/

Swimming-total body exercise Crafts----to strengthen and move joints of arms and hands Bicycling-leg joint movement and strengthening of leg muscles School activities (including gym)-total body movement. (Note: Although children with juvenile rheumatoid arthritis are usually encouraged to take part in gym to their tolerance, there may be times when it is not advisable, or your physician may suggest avoiding specific gym activities. Ask your physician whether your child should be restricted from playing contact sports, doing headstands, etc.) Hitting and catching softballs or volleyballs-arm strength Ballet-total body movement

Alles 13 ,.. and Older By this age, the teenager should be helping to plan the exercise activities; parents, teen, and staff can talk together about what the teen likes to do and what joints need extra moving. Adapted from Giesecke LL, Athreya BH, Doughty RA: Home Care Guide on Juvenile Rheumatoid Althritis (for Parents). Atlantic City, N.J, Children's Seashore House, 1985: Scull SA, Dow MIl, Athreya BH: Physical and occupational therapy for children with rheumatic diseases. Pediatr Clin North Am 33: 1060, 1986.

contraindicated. Contact sports and activities that generate torsional forces on involved joints (e.g., downhill skiing) or repeated impacts should be avoided in children with severe arthritis. In general, cycling and swimming are safe and beneficial for most children with arthritis.

Therapeutic Modalities Heat, cold, splinting, bracing (orthotics), and water exercises are some of the modalities used in the treatment of rheumatic diseases.

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197

• Rgure 8-17 Child in hot-wheels cyde. The seat and the pedals can be adjusted to increase flexion or extension at the knee.

• FIg-.e 8-16 Dressing aids: a dressing stick (A); sock aid (8); and coat hanger "hoop' (C and fJJ are used to train this child for independence. (From Scull SA, Dow MB, Athreya BH: Physical and occupation therapy for children with rheumatic diseases. Pediatr Clin North Am 33:1064, 1986.)

Heat and Cold Both intra-articular temperature and blood flow are increased in inflamed joints. Consequently, the metabolism of articular tissues is altered. 61 However, studies on the value of heat and cold in altering the intra-articular temperature and blood flow and in relief of symptoms have yielded inconclusive results. Based on an extensive review of the literature, Karen Hayes62 came to several conclusions, which are described in the following paragraphs. Both heat and cold appear to be effective in managing pain, stiffness, and limitation of ROM. Heat may be more effective for joint motion and cold more effective for pain reduction. Therefore, a patient with acute disease may benefit from cold as well as from heat; patients with chronic disease may benefit from heat. Preference of the patient may be the best determinant of the modality used. Either deep or superficial heat may be used. A warm tub bath or shower in the morning helps reduce stiff-

• Rgure 8-18

Reversed handle bars force wrist joints into extension.

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ness. A heated pool (88' F to 92' F [31' C to 33' CD is ideal for therapeutic exercises,63 but one must be careful to avoid vasodilatation and hypotension. Children with moderate to severe anemia often do not tolerate warm pools. Moist packs may be useful to relieve muscle spasm. Deep heat in the form of paraffin baths may be beneficial, particularly for the small joints of the hand. Deep heat application, such as diathermy or ultrasound, is not usually recommended for children because of potential damage to the cartilage. Cold packs and ice packs are ideal for acute swelling and pain and for postexercise pain.

Splints Splints, braces, and orthotic devices are used for various purposes, including support for acutely inflamed joints (resting splints), maintenance of joints in functional positions during activity (dynamic splints) (Fig. 8-19), stretching of contracted joints (corrective splints), and provision of shock absorption (shoe inserts). Splints may be made from a variety of compounds such as plaster of Paris, polypropylene, or fiberglass. Materials to be used

depend on the purpose, need for repeated adjustments, and cost.

Resting Splints Resting splints are used to rest acutely inflamed joints. A joint is maintained in a functional position in the splint for most of the day. The splint is removed once or twice a day to exercise the muscles and move the joint through its ROM, if possible. Resting splints are often used to maintain position and prevent deformities at the wrists, knees, and ankles. The most commonly used splints are wrist splints (Fig. 8-20), to maintain the wrist in a functional position during the night, and knee splints (see Fig. 8-12), to prevent knee-flexion contractures. If a knee-flexion contracture is greater than 20 degrees, it may be necessary to use serial casting (corrective splint) or dynamic splinting. Although cervical collars may not be totally efficacious to prevent motion at the atlantoaxial joint, children with cervical spine involvement may benefit from use of a firm collar during car rides.

Functional Splints Functional splints are designed to support joints during ADL and to reduce stress. For example, a molded anklefoot orthosis (AFO) may be used to maintain the stretch of the Achilles tendon during weight bearing. A shoe insert may be used to decrease pain during weight bearing. Some splints produce a constant stretch to the muscles during walking and functioning (dynamic splints). Biomechanical orthotics are small, custom-made devices, such as shoe inserts, that are designed to correct alignment or to relieve pain.

Water Exercises Therapy in water (pool or whirlpool) is one of the best and most acceptable forms of therapy for children with

• Figure 8-19

Dynamic splint.

• Figure I-ZO Wrist cock-up splint. Aresting splint for wrist and fingers. (From Scull SA, Dow MB, Athreya BH: Physical and occupation therapy for children with rheumatic diseases. Pediatr elin North Am 33:1067, 1986.)

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arthritis,6.>,64 The buoyancy of water facilitates weight bearing, Water also can be used to provide resistance to muscle movement. Children can walk in water up to the chest to reduce the load on their hips. A heated pool may be useful to reduce stiffness. Finally, swimming itself is a great exercise, both for ROM and for aerobic conditioning. Water therapy is ideal for children with severe morning stiffness and for postoperative rehabilitation.

Shoe Modification Citing their detailed analysis of feet in JRA, Truckenbrodt and associates65 defined eight major deformities (Table 8-14). The most common are pes planovalgus due to involvement of subtalar joints, pes cavus due to inflammation of the intertarsal joints, and pseudocavus due to inflammation of the upper ankle joint and the talonavicular joint. Soft, comfortable footwear with good arch support (e.g., sneakers), is recommended for most common problems. Cushioning with a foam insole may reduce the force of impact. For children with metatarsal pain, metatarsal bars or rocker-bottom soles may help with push-off.

III,· Il:i.i II

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TABLE 8-15 Strategies for Managing Various Prohlems Associated with Rheumatic Diseases

Problem

Strategy

Morning stiffness

Sleep in a sleeping bag Early-morning shower Pool therapy Therapeutic exercises Active Active-assistive (passive) Resistive Aerobic Posture Splint Brace Stretch Strengthening exercises Active Faradic electrical stimulation Functional training Adaptive devices Shoe inserts Functional orthoses Heel or shoe lift

Decreased range of motion

Position

Muscle weakness

Limitation in activities of daily living Painful feet Leg-length differences Courtesy of S. Bowyer, MD.

Postsurgical Therapy

IMMUNIZATION

The therapist should be involved from the beginning if surgery is planned, Therapists are in a position to recommend the goals of surgery because they have worked with the child and the child's personality and have reviewed the disability and its current functional limitations. Children should be taught to thoroughly exercise the muscles they will be asked to use increasingly after surgery. Early mobilization is essential to prevent loss of motion. Positioning and splinting or use of a passive ROM machine may be required to maintain newly acquired motion. Postoperative therapy may include active and passive ROM, water therapy, and gradual increase in weight bearing. 5o ,66 General strategies to manage various problems encountered in patients with rheumatic diseases are given in Table 8-15.

There are two major questions related to immunization and rheumatic diseases. First, is there any relationship between immunization and onset or exacerbation of these diseases? Second, what are the recommendations for children with rheumatic diseases who are taking various medications? Although some reports suggest that immunization may precipitate an exacerbation or initiation of an arthritic or vasculitic disorder,67-71 other studies do not support this association. n ,7'> In the only available study on the relationship between influenza immunization and arthritis in children, Malleson and colleagues7.> did not find exacerbation of arthritis associated with the influenza virus vaccination. The same study documented that antibody responses were satisfactory even in children receiving glucocorticoid therapy, At present, it appears that the benefits of immunization far outweigh any risk of exacerbation of the disease in most situations,74 Children receiving chronic salicylate therapy and all children with SLE, dermatomyositis with significant muscle weakness, systemic scleroderma with cardiopulmonary or renal disease, or systemic vasculitides may benefit from yearly influenza virus (killed virus) vaccination. Studies also indicate that patients taking glucocorticoids and immunosuppressive drugs respond to influenza vaccine73,75 and pneumococcal vaccine76 with adequate antibody titers. However, such immunization should not give rise to a false sense of security, because immunity is not guaranteed. Children with SLE and splenic hypofunction should receive the pneumococcal vaccine. 76,n The author usually encourages families to keep the regular schedule of immunizations while cautioning them about the possibility of a flare-up. There are, however, a Jew speCial circumstances and precautions:

' Si • -

I ABLE 8-14 Most Frequent Deviations of the Foot in lllvt'nile Chronic Arthritis: Various Combinations Are Possible

Heelfoot (pseudocavus) Pes planovalgus Pes C;WlIS Heelfoot (pseudocavus) Hallux flexus/rigidus Hallux valgus Forefoot adduction Claw toes Hammer toes From Truckenbrodt H, Hafner R, von A1tenbockum c: Functional joint analysis of the foot in juvenile chronic arthritis, Clin Exp Rheumatol 12 (Suppl 10): 591,

1994.

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Active Disease Children with severe, active rheumatic disease should not receive any immunization.

Varicella Varicella can be a major problem for children receiving immunosuppressive therapy, glucocorticoids, methotrexate, and/or biologic agents, For all of these children, suggested management for the prevention of varicella is given in Table 8-16. Varicella vaccination is generally contraindicated in children taking glucocorticoids in doses of 2 mg/kg/day equivalent of prednisone or its equivalent, or 20 mg/day of prednisone or equivalent for longer than 14 days.78 For children receiving smaller doses, the risklbenefit ratio must be assessed. Salicylate should not be used for at least 6 weeks after varicella vaccine administration. The potential for Reye's syndrome in children treated with salicylates in association with varicella or influenza has been widely discussed. 79

Immunosuppressive Therapy Children undergoing immunosuppressive therapy or glucocorticoid therapy should not receive any live vims vaccine. Recommendations made by the Committee on Infectious Diseases of the American Academy of Pediatrics should be followed for these children. 78 The British Society of Rheumatology recommends the' use of influenza A, meningococcus C, haemophilus B, hepatitis B, and tetanus toxoid but warns that the response may be suboptimaJ.74 For adults undergoing glucocorticoid therapy, there is no consensus on what dose is low enough to be considered safe. If glucocorticoids and cytotoxic dmgs have been stopped, live vims vaccines may be given after a minimum of 3 months. It is also important to remember that the new nasal spray vaccine for influenza contains live vims and is therefore contraindicated in immunocompromised patients and their contacts. Only the inactivated parenteral form of the influenza vaccine should be used. Children receiving intravenous immunoglobulin should wait for at least 3 months after the last dose before any immunization to ensure an adequate immune response. 80

I!.

TABLE H 16 V.uicella Prevention Str,ltegy for Children Taking Glmo
Document successful vaccination in the past: measure serum antibody level. If seronegative (susceptible), immunize with varicella vaccine 3 weeks before starting therapy. Susceptible children exposed to varicella should receive varicellazoster immunoglobulin within 72 hI' after exposure, If chicken pox develops, treat with oral or parenteral acyclovir depending on severity and spread; stop Enbrel and methotrexate temporarily; but continue glucocorticoids,

REFERENCES 1. Hobbs N, Perrin 1M: Issues in the Care of Children With Chronic Illness: A Source Book on Problems, Services and Policies. San Francisco, losey-Bass, 1985. 2. Pless lB, Power C, Peckham CS: Long-term psychosocial sequelae of chronic physical disorders in childhood. Pediatrics 91: 1131-1136, 1993. 3. McAnarney ER, Pless IB, Satterwhite B, Friedman SB: Psychological problems of children with chronic juvenile arthritis, Pediatrics 53: 523-528, 1974. 4. McCormick MC, Stemmler MM, Athreya BH: The impact of childhood rheumatic diseases on the family. Arthritis Rheum 29: 872--879, 1986. 5. Lovell DA, Athreya BH, Emery HM, et al: School attendance and pallerns, special services and special needs in pediatric patients with rheumatic diseases. Arthritis Care Res 3: 196, 1990. 6. Walker DK: Care of chronically ill chlldren in schools. Pediatr Clin North Am 31: 221-233, 1984. 7. AIlaire SH, DeNardo BS, Szer IS, et al: The economic impact of juvenile rheumatoid arthritis. j Rheumatol 19: 952-955, 1992. 8. Newacheck PW, Taylor WR: Childhood chronic illness: prevalence, severity, and impact Am 1 Public Health 82: 364-371, 1992. 9, Gare BA, Fasth A: The natural history of juvenile chroniC arthritis: a population based cohort study. n: Outcome. 1 Rheumatol 22: 308-319, 1995. 10. Wallace CA, Levinson lE: luvenile rheumatoid arthritis: outcome and treatment for the 1990s. Rheum Dis Clin North Am 17: 891-905, 1991. 11. Peterson LS, Mason T, Nelson AM, et al: Psychosocial olllcomes and health status of adults who have had juvenile rheumatoid arthritis: a controlled, population-based study. Arthritis Rheum 40: 2235-2240, 1997. 12. Packham lC, Hall MA: Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology 41:1428-435, 2002. 13. Rettig 1', Athreya BH: Leaving home: preparing the adolescent with arthritis for coping with independence and the adult rheumatology world. In Isenberg D, Miller .1.1 (eds): Adolescent Rheumatology. London, Martin Dunitz, 1998, 14. Brewer Ellr, McPherson M, Magrab PR, Hutchins VL: Family-centered, community-based, coordinated care for children with special healthcare needs. Pediatrics 83: 1055-1060, 1989. 15. Miller 11 3rd: Psychosocial factors related to rheumatic diseases in childhood. .I Rheumatol 20 (Suppl 38): 1-11, 1993. 16. Packham lC, Hall MA: Long-term follOW-LIp of 246 adults with juvenile idiopathic arthritis: education and employment. Rheumatology 41: 1436-14.W, 2002. 17. Packham lC, Hall MA: Long-tenn follow-up of 246 adults with juvenile idiopathic arthritis: social function, relationships and sexual actiVity. Rheumatology 41: 1440-1443, 2002. 18. Routh DK: Commentary: juvenile rheumatoid arthritis as a stressor. .I Pediarr Psychol 28: 41--43, 2003. 19. Dahlquist LM: Commentary: are children with lRA and their families at risk or resilient? 1 pediatr Psychol 28: 43-46, 2003. 20. Reiter-Purtill 1, Gerhardt CA. Vannatta K, et al: A controIled longitudinal study of the social functioning of children with lRA. j Pediatr Psychol 28: 17-28, 2003. 21. LeBovidge .IS, Lavigne lV, Donenberg GR, Miller ML: Psychological adjustment of children and adolescents with chronic arthritis: a meta-analytiC review. j Pediatr Psychol 28: 29-39, 2003. 22. van der Netl, Prakken AB, Helders 1'1, et al: Correlates of disablement in juvenile chronic arthritis: a cross-sectional study. Hr j Rheumatol35: 91-100, 19%. 23. Noll RB, Kozlowski K, Gerhardt C, et al: Social, emotional, and behavioral timctioning of children with juvenile rheumatoid arthritis. Arthritis Rheum 43: 1387-1396, 2000. 24. von Weiss RT, Rapoff MA, Varni JW, et al: Daily hassles and sodal support as predictors of adjustment in children with pediatric rheumatic diseases. .I Pediatr Psycho! 27: 155-165, 2002. 25. Wallender lL. Varni VW: Adjustment in children with chronic physical disorders: programmatic research on a disability-stress coping module. In La Greca AM, Siegel Ll, Wallender jL, Walker CE (eds): Stress and Coping in Child Health. New York, Guilford, pp 279-298, 1991. 26. Mervyn FA: "They get this training but they don't know how you feel." Horsham, UK, National Fund for Research into Crippling Diseases, 1975. 27, Athreya BH: Regionalized arthritis resources. Arthritis Rheum 20 (Supp1): 604, 1977. 28. Rosenstock 1M, Strecher Vj, Becker MH: Social learning theory and the Health Belief Model. Health Educ Q 15: 1751-1783, 1988, 29. Akikusa JD, Allen RC: Reducing the impact of rheumatic diseases in childhood. Best Pract Res Clin Rheumatol 16: 333-345, 2002. 30. Sallfors C, Fasth A, Hallberg LR: Oscillating between hope and despair: a qualitative study. Child Care Health Dev 28: 495-505, 2002. 31. Rapoff MA, Lindsley CB, Christophersen ER: Parent perception of problems experienced by their children in complying with treatments for juvenile rheumatoid arthritis. Arch Phys Mecl Rehabil 66: 427--429, 1985. 32. KroIl T, Barlow lH, Shaw K: Treatment adherence in juvenile rheumatoid arthritis: a review. Scand ) Rheumatol 28: 10-18, 1999. 33. Swartz DR: Dealing with ~hronic illness in childhood. Pediatr Rev 6: 67, 1984. 34. Gallo AM, Breitmayer Bj, Knafl KA, Zoeller LH: Stigma in childhood chronic illness: a well sibling perspective. Pediatr Nurs 17: 21-25, 1991. 35. Birenbaum A: On managing a courtesy stigma. 1 Health Soc Behav 11: 196, 1970. 36. Daniels D, Miller 11 3rd, BiIllngs AG, Moos RH: Psychosocial functioning of siblings of children with rheumatic disease. j Pediatr 109: 379-383, 1986.

C HAP T E R 8 ApPROACH TO MANAGEMENT OF RHEUMATIC DISEASES IN CHILDREN 37. Williams PO, Wiliams AR, Graff ]C, et al: A community-based intervention for siblings and parents of children with chronic illness or disability: the ISEE study, .J Pediatr 143: 386-393, 2003. 38. Cassidy ]T, Lindsley CB: Legal rights of children with musculoskeletal disabilities. Bull Rheum Dis 45: 1-5, 1996. 39. Spencer CH, Fife RZ, Rabinovich CEo The school experience of children with arthritis: coping in the 1990s and transition into adulthood. Pediatr Clin North Am 42: 1285-1298, 1995. 40. Taylor ], Passo MH, Champion VL: School problems and teacher responsibilities in juvenile rheumatoid arthritis.] Sch Health 57: 186-190, 1987. 41. White PH: Success on the road to adulthood: issues and hurdles for adolescents with disabilities. Rheum Dis Clin North Am 23: 697-707, 1997. 42. NefflM, Anderson G: Protecting children with chronic illness in a competitive marketplace.]AMA 274: 1866-1869, 1995. 43. American Academy of Pediatrics, Committee on Children with Disabilities: Managed care and children with special health care needs: a subject review. Pediatrics 102: 657, 1998. 44. Jonas WB: Alternative medicine: learning from the past, examining the present, advancing to the future. ]AMA 280: 1616-1618, 1998. 45. Southwood TR, Malleson PN, Roberts-Thomson P], Mahy M: Unconventional remedies used for patients with juvenile arthritis. Pediatrics 85: 150-154, 1990. 46. Hafner R, Truckenbrodt H, Spamer M: Rehabilitation in children with juvenile chronic arthriti~. Baillieres Clin Rheumatol 12: 329-361, 1998. 47. Hackett], Johnson B. Parkin A, Southwood T: Physiotherapy and occupational therapy for juvenile chronic arthritis: custom and practice in five centres in the UK, USA and Canada. Br] Rheumatol 35: 695-699, 1996. 48. Scull SA, Dow MB, Athreya BH: Physical and occupational therapy for children with rheumatic diseases. Pediatr Clin North Am 33: 1053-1077, 1986. 49. Emery HM, Bowyer SL: Physical modalities of therapy in pediatric rheumatic dise'dses. Rheum Dis Clin North Am 17: 1001-1014, 1991. 50. Hicks JE, Nichols ]], Swezey RL: Handbook of Rehabilitative Rheumatology. Atlanta, American Rheumatism Association, 1988. 51. Varni .TW. Bernstein BH: Evaluation and management of pain in children with rheumatic diseases. Rheum Dis Clin North Am 17: 985, 1991. 52. Rapoff MA , Lindsley CB: The pain puzzle: a visual and conceptual metaphor for understanding and treating pain in pediatric rheumatic disease, ] Rheumatol 27 (Suppl 58); 29-33, 2000. 53. McGrath P], Unruh AM: Pain in children and adolescents. New York, Elsevier Amsterdam, 1987, pp 289-316. 54. Waleo GA, Varni .TW, Ilowite NT: Cognitive-behavioral pain management in children with juvenile rheumatoid arthritis. Pediatrics 89: 1075-1079, 1992. 55. Sherry DO, Weisman R: Psychologic aspects of childhood reflex neurovascular dystrophy. Pediatrics 81: 572-578, 1988. 56. Rhodes V]: Physical therapy management of patients with juvenile rheumatoid arthritis. Phys Ther 71: 910-919, 1991. 57. Basmajian]V: Therapeutic Exercises, 4th ed. Baltimore, Williams & Wilkins, 1984, pp 303-308. 58. Giannini M], Protas E]: Aerobic capacity in juvenile arthritis patients and healthy children. Arthritis Care Res 4: 131-135, 1991. 59. Malleson PN, Bennett SM, MacKinnon M, et al: Physical fitness and its relationship to other indices of health status in children with chronic arthritis. J Rheumatol 23: 1059-1065, 1996. 60. Klepper SE, Darbee], Effgen SK, Singsen BH: Physical fitness levels in children with polyarticular juvenile rheumatoid arthritis. Arthritis Care Res 5: 93-100, 1992.

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61. Castor CW, Yaron M: Connective tissue activation. YIn: The effects of temperature studied in vitro. Arch Phys Med Rehabil 57: 5-9, 1976. 62. Hayes KW: Heat and cold in the management of rheumatoid arthritis. Arthritis Care Res 6: 156-166, 1993. 63. McNeal RL: Aquatic therapy for patients with rheumatic disease. Rheum Dis Clin North Am 16: 915-929, 1990. 64. Campion MR: Hydrotherapy in Pediatrics, 2nd ed. Oxford, ButterworthHeinemann, 1991. 65. Truckenbrodt H, Hafner R, von Altenbockum C: Functional joint analysis of the foot in juvenile chronic arthritis. Clin Exp Rheumatol 12 (Suppl 10): S91-S96, 1994. 66. Swann M: The surgery of juvenile chronic arthritis: an overview. Clin Orthop 259: 70-75, 1990. 67. Benjamin CM, Chew GC, Silman A]: Joint and limb symptoms in children after immunisation with measles, mumps, and rubella vaccine. BMJ 304: 1075-1078, 1992. 68. Institute of Medicine: Adverse effects of pertussis and rubella vaccines. In Howson CP, Howe CJ, Fineberg HV (eds): A Report of the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines. Washington, DC, National Academy Press, 1991. 69. Tingle AJ, Allen M, Petty RE, et al: Rubella-associated arthritis: I. Comparative study of joint manifestations associated with natural rubella infection and RA-27/3 rubella immunisation. Ann Rheum Dis 45: 110-114, 1986. 70. Castresana-lsla C], Herrera-Martinez G, Vega-Molina ]: Erythema nodosum and Takayasu's arteritis after immunization with plasma derived hepatitis B vaccine.] Rheumatol 20: 1417-1418, 1993. 71. Mader R, Narendf'dn A, Lewtas], et al: Systemic vasculitis following influenza vaccination: report of 3 cases and literature review. J Rheumatol 20: 1429-1431, 1993. 72. Ray P, Black S, Shinefield H, et al: Risk of chronic arthropathy among women after rubella vaccination. Vaccine Safety Datalink Team. ]AMA 278: 551-556, 1997. 73. Malleson PN, Tekano ]L, Scheifele OW, Weber ]M: Influenza immunization in children with chronic arthritis: a prospective study. ] Rheumatol 20: 1769-1773, 1993. 74. Davies K, Woo P, British Paediatric Rheumatology Group: Immunization in rheumatic diseases of childhood: an audit of the clinical practice of British Paediatric Rheumatology Group members and a review of the evidence. Rheumatology 41: 937-941, 2002. 75. Park CL, Frank AL, Sullivan M, et al: Influenza vaccination of children during acute asthma exacerbation and concurrent prednisone therapy. Pediatrics 98: 196-200, 1996. 76. Battafarano OF, Battafarano N], Larsen L, et al: Antigen-specific antibody responses in lupus patients following immunization. Arthritis Rheum 41: 1828-1834, 1998. 77. Lipnick RN, Karsh J, Stahl Nl, et al: Pneumococcal immunization in patients with systemic lupus erythematosus treated with immunosuppressives. J Rheumatol 12: 1118-1121, 1985. 78. Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2003, pp 69-81. 79. Hurwitz ES, Barrett M], Bregman 0, et al: Public Health Service study of Reye's syndrome and medications: report of the main study. ]AMA 257: 1905-1911, 1987. 80. Rowley AH, Shulman ST: Current therapy for acute Kawasaki syndrome. ] Pediatr 118: 987-991, 1991.

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APPENDIX 8-1 RESOURCES FOR FURTHER INFORMATION ON RHEUMATIC DISEASES FOR PATIENTS AND PARENTS 1 1. American Juvenile Arthritis Organization Resource Catalog (l998)-Arthritis Foundation 1330 W. Peachtree Street, Atlanta, GA 30309 USA http://www.arthritis.org Check on Juvenile Authirtis

6. National Dissemination Center for Children with Disabilities P,O, Box 1492 Washington, DC 20013 USA http://www.nichcy,org

2. Lupus Foundation of America, Inc. 1300 Piccard Drive, Suite 200 Rockville, MD 20850 USA http://www,lupus.org

7. On TRAC-Taking Responsibility for Adolescent/Adult Care British Columbia's Children's Hospital Room 2, D20 4480 Oak Street Vancouver, BC V6H 3V4 Canada http://www.acsa-caah.ca/pdjlanglon_trac.pdf

3. Scleroderma Foundation 12 Kent Way, Suite 101 Byfield, MA 01922 USA http://www.scleroderma.org 4. Spondylitis Association of America 14827 Ventura Boulevard, Suite 119 PO Box 5872 Sherman Oaks, CA 91403 USA http://www,spondylitis.org 5. Family Village-A great Web site for information on all chronic diseases and rare syndromes. Gives information for resources in England also. http://wwwfamilyvillage.wisc,edu I

Verified December 2004

MONOGRAPHS/BOOKS 1. Raising a Child with Arthritis: A Parent's Guide.

Atlanta, Arthritis Foundation, 1998. 2, Tucker LB, Denardo BA, Stebulis JA, Schaller JG. Your Child with Arthritis: A Family Guide for Caregiving. Baltimore, The John's Hopkins University Press, 1996.

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APPENDIX 8-2 EXAMPLE OF A SCHOOL COMMUNICATION FORM PEDIATRIC RHEUMATOLOGY PROGRAM

(Date)

(Date of Birth)

(Student's Name)

_______is followed by Rheumatology for . This chronic disease is characterized by joint . We recommend the following swelling, pain and stiffness and fatigue. In addition, this student has services be provided by the school: r:l Modified physical education to include: r:l Activities to tolerance, allow student to set own limits r:l No contact sports r:l Swimming is encouraged r:l No repeated stress or pounding to affected joints r:l No weight bearing on wrists and arms, such as handstands, cartwheels, rings r:l Adaptive physical education r:l Two (2) sets of books r:l Use of elevators if available r:l Extra time between classes r:l Provision for locker on each floor if applicable r:l Modified assignments to include use of tape recorder r:l Computer r:l Extended time lines for completion of assignments and tests r:l Use of oral tests r:l No timed tests r:l No grades for handwriting r:l Door-to-door transportation r:l Physical and Occupational Therapist evaluations to plan for accessibility and adaptation needs in school environment (as needed and on a quarterly basis) r:l We request that home instruction be implemented if more than two (2) consecutive school days are missed. r:l IEP that includes all of the above and ongoing aT and PT r:l Other: _ We are enclosing a booklet for teachers. Attached please find a list of common school problems and solutions experienced by students with arthritis. Thank you in advance for your assistance and cooperation regarding this student. Sincerely,

Attending Rheumatologist IEP, Individualized education plan; OT, occupational therapy; PT, physical therapy.

Rheumatology Nurse Specialist

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James T. Cassidy and Ross E. Petty

Chronic arthritis in childhood—characterized as juvenile rheumatoid arthritis (JRA) (Table 9–1), juvenile chronic arthritis (JCA) (Table 9–2), or juvenile idiopathic arthritis (JIA) (Table 9–3)—is one of the most common rheumatic diseases of childhood. It is also one of the more frequent chronic illnesses of children and an important cause of short- and long-term disability. Although it has been customary to refer to this disorder as a single disease, it almost certainly comprises a number of similar entities, characterized principally by arthritis of the appendicular joints, each of which has distinct modes of presentation and may have the same or different causes. It may also be considered as a closely related series of host-determined specific responses with an immunoinflammatory pathogenesis, possibly activated by contact with an external antigen or antigens. A dauntingly complex immunogenetic predisposition is often present. The relative frequencies of the three principal onset types (oligoarthritis, polyarthritis, and systemic onset) have varied considerably in published series and reflect the biases that confound estimates of incidence and prevalence (Table 9–4).1,2 There are also potential ethnic differences in onset types.3 Clinical aspects of these onset types are discussed in detail in Chapters 10, 11, and 12.

Classification Chronic arthritis in childhood is a complex area of study and investigation, not least because of inconsistencies of definition and terminology. It is genetically heterogeneous, phenotypically diverse in presentation and during the course of the disorder, and substantially without a single pathognomic diagnostic approach. The classification of childhood arthritis has been problematic for decades.4,5 In the 1970s, two sets of criteria were proposed to classify chronic arthritis in childhood: those for JRA, developed and validated by a committee of the American College of Rheumatology (ACR),6 and those for JCA, published by the European League Against Rheumatism (EULAR).7 Later, a third classification (for JIA) was proposed by the Pediatric Task Force of the International League of Associations for Rheumatology (ILAR).8 These three classifications are compared in Table

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9–5 and Table 9–6. Problems in applying these criteria include the necessity to exclude other diseases for which there are no validated diagnostic or classification criteria for children and the fact that all three were based on populations of northern European derivation.

ACR Criteria for Classification of Juvenile Rheumatoid Arthritis The ACR criteria have been widely used, validated, and revised (see Table 9–1),6,9–11 but they are applicable primarily to white American children. They defined the age limit in children, the duration of disease necessary for a diagnosis, and the characteristics of the arthritis (Fig. 9–1). Three types of onset were recognized: oligoarticular (pauciarticular), polyarticular, and systemic. The requirement that age at onset of arthritis be less than 16 years was a criterion based more on practice patterns than on age-related biologic variation in disease. Furthermore, although persistent objective arthritis in one or more joints for 6 weeks was sufficient for diagnosis, as determined by computer-assisted statistical analysis, a duration of at least 6 months was required before the onset type could be certain (unless characteristic systemic features were present). The type of onset is defined by a constellation of clinical signs present during the first 6 months of illness. Oligoarticular onset is defined as arthritis in four or fewer joints. Polyarticular onset is defined as arthritis in five or more joints. In determination of the onset type, each joint is counted separately, except for the joints of the cervical spine, carpus, and tarsus; each of these structures is counted as one joint. Systemic-onset JRA is characterized by a daily (quotidian or intermittent) fever spiking to greater than 39˚ C for at least 2 weeks in association with arthritis of one or more joints. Most children with systemiconset disease also have a characteristic rash, and many have other evidence of extra-articular involvement, such as lymphadenopathy, hepatosplenomegaly, or pericarditis. Nine course subtypes were identified during long-term follow-up.

EULAR Criteria for Classification of Juvenile Chronic Arthritis In 1977, at the EULAR conference on the Care of Rheumatic Children in Oslo, the term juvenile chronic arthritis (JCA) was proposed for the heterogeneous group of disorders that present as chronic arthritis in childhood (see Table 9–2).7 The onset

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TABLE 9–1 Criteria for the Classification of Juvenile

TABLE 9–3 Proposed Classification Criteria for Juvenile

Rheumatoid Arthritis

Idiopathic Arthritis: Durban, 1997

1. Age at onset <16 yr 2. Arthritis (swelling or effusion, or presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, and increased heat) in one or more joints 3. Duration of disease 6 wk or longer 4. Onset type defined by type of disease in first 6 mo: a. Polyarthritis: ≥5 inflamed joints b. Oligoarthritis (pauciarticular disease): <5 inflamed joints c. Systemic-onset: arthritis with characteristic fever 5. Exclusion of other forms of juvenile arthritis Modified from Cassidy JT, Levinson JE, Bass JC, et al.: A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 29: 274–281, 1986.

TABLE 9–2 Criteria for a Diagnosis of Juvenile Chronic Arthritis 1. 2. 3. 4.

9 C H R O N I C A RT H R I T I S

Age at onset <16 yr Arthritis in one or more joints Duration of disease 3 mo or longer Type defined by characteristics at onset: a. Pauciarticular: <5 joints b. Polyarticular: >4 joints, rheumatoid factor negative c. Systemic: arthritis with characteristic fever d. Juvenile rheumatoid arthritis: >4 joints, rheumatoid factor positive e. Juvenile ankylosing spondylitis f. Juvenile psoriatic arthritis

From European League Against Rheumatism (EULAR) Bulletin 4. Nomenclature and Classification of Arthritis in Children. Basel, National Zeitung AG, 1977.

types of JCA and age of onset were defined according to the ACR criteria. The disorder must have been present for at least 3 months, and other rheumatic diseases must have been excluded. Included within the JCA classification, however, are juvenile ankylosing spondylitis (JAS), psoriatic arthropathy, and arthropathies associated with inflammatory bowel disease. The only substantial differences between the ACR and the EULAR criteria are (1) inclusion of JAS, psoriatic arthritis, and the arthritis of inflammatory bowel disease and (2) restriction on use of

1. Systemic 2. Oligoarthritis a. Persistent b. Extended 3. Polyarthritis (rheumatoid factor negative) 4. Polyarthritis (rheumatoid factor positive) 5. Psoriatic arthritis 6. Enthesitis-related arthritis 7. Undifferentiated arthritis a. Fits no other category b. Fits more than one category From Petty RE, Southwood TR, Baum J, et al: Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 25: 1991–1994, 1998.

the term juvenile rheumatoid arthritis to children with arthritis and rheumatoid factor (RF) seropositivity, although no definition of RF seropositivity is provided.

ILAR Criteria for Classification of Juvenile Idiopathic Arthritis In 1993, the Pediatric Standing Committee of ILAR proposed a classification of the idiopathic arthritides of childhood (see Table 9–3). This classification8 and its subsequent revisions (Durban, Edmonton),12–14 were developed with the aim of achieving homogeneity within disease and categories. The designation undifferentiated arthritis includes conditions that, for whatever reason, either do not meet criteria for any other category or meet criteria for more than one category. These JIA criteria still require validation and consensus and will almost certainly be modified further as new evidence for pathogenesis becomes available.15–26 For the student of pediatric rheumatology, differences in nomenclature require care in interpreting the literature, because the terms JRA, JCA, and JIA are often incorrectly used as if they were interchangeable and synonymous. This dilemma has been the subject of several publications.4,16,27–29 Throughout this text, every attempt has been made to ensure that the terms JRA, JCA, and JIA accurately reflect the cited publications. If more than one set of criteria may pertain (e.g., use of the term juvenile

TABLE 9–4 Characteristics of Chronic Arthritis in Children by Type of Onset Characteristic

Polyarthritis

Oligoarthritis (Pauciarticular Disease)

Systemic Disease

Percent of cases Number of joints involved Age at onset

30 ≥5 Throughout childhood; peak at 1–3 yr 3:1 Systemic disease generally mild; possible unremitting articular involvement 5%

60 ≤4 Early childhood; peak at 1–2 yr 5:1 Systemic disease absent; major cause of morbidity is uveitis 5–15%

10 Variable Throughout childhood; no peak 1:1 Systemic disease often self-limited; arthritis chronic and destructive in half Rare

10% (increases with age) 40–50% Guarded to moderately good

Rare 75–85%* Excellent except for eyesight

Rare 10% Moderate to poor

Sex ratio (F:M) Systemic involvement Occurrence of chronic uveitis Frequency of seropositivity Rheumatoid factors Antinuclear antibodies Prognosis *In girls with uveitis.

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TABLE 9–5 Comparison of Classifications of Chronic Arthritis in Children Juvenile Rheumatoid Arthritis (ACR)

Juvenile Chronic Arthritis (EULAR)

Juvenile Idiopathic Arthritis (ILAR)

Systemic Polyarticular Oligoarticular (pauciarticular)

Systemic Polyarticular Juvenile rheumatoid arthritis Pauciarticular Juvenile psoriatic arthritis Juvenile ankylosing spondylitis

Systemic Polyarticular RF-negative Polyarticular RF-positive Oligoarticular Persistent Extended Psoriatic arthritis Enthesitis-related arthritis Other arthritis

ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; ILAR, International League of Associations for Rheumatology; RF, rheumatoid factor.

TABLE 9–6 Characteristics of the ACR, EULAR, and ILAR Classifications of Chronic Arthritis in Children Characteristic

ACR

EULAR

ILAR

Onset types Course subtypes Age at onset of arthritis Duration of arthritis Includes JAS Includes JPsA Includes inflammatory bowel disease Other diseases excluded

3 9 <16 yr ≥6 wk No No No

6 None <16 yr ≥3 mo Yes Yes Yes

6 1 <16 yr ≥6 wk Yes Yes Yes

Yes

Yes

Yes

ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; ILAR, International League of Associations for Rheumatology; JAS, juvenile ankylosing spondylitis; JPsA, juvenile psoriatic arthritis.

arthritis) or a compromise is in order, the designation chronic arthritis is used.

HISTORICAL REVIEW The concept that inflammatory polyarthritis occurred in childhood was first suggested in 1864 by Cornil,30 who described a 29-year-old woman who had had chronic inflammatory arthritis since the age of 12. Diamant-Berger31 reviewed the subject in 1890 and included 35 previously published cases and 3 of his own. He commented on the acute onset of disease, the predominant involvement of large joints, a course characterized by exacerbations and remissions, frequent disturbances of normal growth, and a generally good prognosis. Still32 presented the classic description of chronic childhood arthritis in 1897, while he was a medical registrar at the Hospital for Sick Children, Great Ormond Street, London. He pointed out that the disease almost always began before the second dentition, was more frequent in girls, and was usually of insidious onset. The acute onset of disease in 12 patients who had lymphadenopathy, splenomegaly, and fever was described in detail. Serositis characterized by pleuritis and pericarditis was common, although rash was not noted. Still observed that there was often no articular pain and that children exhibited a marked tendency to early contracture and muscle atrophy. The cervical spine was affected in the majority of cases, often during the early stages of the disease. Still suggested that childhood arthritis might have a different etiology from that of rheumatoid arthritis or might include more than one disease. This classic description is an outstanding example of bedside observation.33 Today, the acute systemic onset of JRA is even now sometimes

■ Figure 9–1 The joints of the wrists and hands of a 21⁄2-year-old boy with systemic-onset disease are swollen, warm, and painful.The proximal and distal interphalangeal joints are erythematous.There are flexion contractures of the fingers. (See color insert.)

called Still’s disease. French authors have often used the term syndrome de Chauffard-Still for chronic arthritis with lymphadenopathy and splenomegaly. In 1901, Hirschsprung34 confirmed Still’s observations that a chronic articular disease was associated with lymphadenopathy and splenomegaly in young children; he also noted the occurrence of hepatomegaly. In 1939, Atkinson35 published a review of 118 cases of Still’s disease, 86 of whom were patients with severe arthritis, lymphadenopathy, and splenomegaly. In the excellent review of Edstrom,36 only 3 of 65 children with chronic arthritis had marked lymphadenopathy and splenomegaly, and Bille37 found no examples of “Still’s disease” among his 65 patients with chronic childhood arthritis. Other large series that are well documented include studies by Colver,38 Holzmuller,39 Coss and Boots,40 Pickard,41 and Lockie and Norcross.42 Monographs on the subject were published by Wissler in 194243 and by Françon in 1946.44 Coss and Boots40 did not view Still’s disease as an independent clinical entity and indicated that the term juvenile rheumatoid arthritis should be used to refer to all cases of idiopathic inflammatory arthritis. Dawson45 supported this view but stressed that children differed from adults by the severity and frequency of the systemic symptoms and by interference with normal growth and development. Many early authors stressed that JRA could begin as a type of monarthritis that most frequently affected the knee and could persist in one joint for the duration of the illness or for several years before other joints were involved.36,37,39,41

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Stoeber46 summarized experience at the Rheumakinderklinik in Garmisch-Partenkirchen from 1952 to 1976 in 1654 children ranging in age from 10 months to adolescence. Until Colver published the first follow-up studies of JRA in 1937,38 the prognosis in this disease was considered to be poor.47,48 Extended periods of observation of patients experiencing onset in childhood led some early authors to conclude that severe destruction of cartilage occurred in many children and that ankylosis would supervene in most.49,50 Subsequent studies indicated that the mortality rate was in the range of 7% to 9%.41,42 However, most children recovered, often without significant disability.36,41,42 In Edstrom’s study,36 87% of patients seen early in the course of their disease experienced good functional recovery; even 65% of those reviewed after the first or second year of disease had a good prognosis. However, only 39% of children seen later than 2 years after onset returned to normal function. A long, uninterrupted period of active disease was significantly associated with a poor prognosis; only 6% of children whose disease became quiescent within the first 4 years experienced severe disability. Sury51 identified 151 patients from 1920 to 1948 who had a chronic form of arthritis with onset before the age of 15 years. Thirty-nine percent of referred patients and 19% of the children from Copenhagen were severely disabled. The peak age at onset in 100 girls was between 2 and 4 years. In 8 of 51 boys, onset was during the first year of life. Of 41 patients whose disease began with monarthritis, 23 had persistent disease in that one joint for at least the first year. At necropsy, 12 children had a verrucous endocarditis.

EPIDEMIOLOGY Chronic arthritis in children is not a rare disease, but the true frequency of its occurrence is not known (see Chapter 1).52 In historical reviews, between 2.7% to 5.2%

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of all patients with “rheumatoid arthritis” (RA) had onset before 15 years of age.53 The disorder has been described in all races and geographic areas, although its incidence and prevalence vary considerably throughout the world,4,54,55 which partly reflects the ethnicity, immunogenetic susceptibility, and environment of the population under study.56,57 The possibility of interaction of environmental triggers is most clearly evident in systemic-onset disease, with studies supporting seasonal variation in incidence.58–61 Oen and Cheang54 published a meticulous review of the epidemiology of childhood arthritis. Considered as confounding variables were the diagnostic criteria employed, disease exclusions, source of the data (population, clinic, practitioner, health survey), geographic origin, race, and years of observation. No significant differences were found for diagnostic criteria or duration of the study. However, prevalence was higher for population-based studies and for data from North America, whereas clinic-based studies were more homogeneous in results. Andersson Gäre reviewed and summarized the epidemiology and outcome of children with JCA in Sweden compared with reports from other centers.62

Incidence The incidence of chronic arthritis has varied from 2 to 20 per 100,000 (Table 9–7).53,54,59,63–84 A clinic survey in Michigan from 1960 to 1970 calculated a minimal incidence of 9.2 per 100,000 children at risk per year.64 Estimates in Finland ranged from 6 to 8 per 100,000 in Laaksonen’s study53 to 18.2 per 100,000 (95% confidence interval [CI], 10.8 to 28.7) in the study of Kunnamo and colleagues67 and others.85 In Norway,80 the incidence was

TABLE 9–7 Studies of Incidence and Prevalence of Chronic Arthritis in Children Authors (ref. no.) Group I Towner et al. (65) Peterson et al. (77) Mielants et al. (70) Andersson Gäre (62) Manners & Diepeveen (74) Kaipiainen-Seppanen & Savolainen (75) Ozen et al. (79) Kiessling et al. (82) Group II Gewanter et al. (66) Kunnamo et al. (67) Prieur et al. (68) Arguedas et al. (81) Group III Laaksonen (53) Bywaters (63) Sullivan et al. (64) Rosenberg (69) Denardo et al. (72) Oen et al. (59) Malleson et al. (73) Symmonds et al. (76) Fujikowa & Okuni (78) Moe & Rygg (80)

Origin

Year

Diagnostic Criteria

Incidence (per 100,000 Children/yr)

Prevalence (per 100,000 Children)

USA USA Belgium Sweden Australia Finland

1983 1996 1993 1994 1996 1996

EULAR, ACR ACR EULAR EULAR EULAR ACR

10.8–13.9 11.7 — 10.9 — 14

83.7–113.4 86.1–94 167 86.3 400 —

Turkey Germany

1998 1998

EULAR EULAR

— 3.5

64 20

USA Finland France Costa Rica

1983 1986 1987 1998

ACR ACR EULAR EULAR

— 18.2 1.3–1.9 6.8

16–43 — 8–10 31.4

Finland UK USA Canada USA Canada Canada UK Japan Norway

1966 1968 1975 1990 1994 1995 1996 1996 1997 1998

English English ACR ACR ACR ACR ACR EULAR ACR EULAR

6–8 — 9.2 5–8 4 5 8 10 0.83 22.6

75–100 60–70 65 39.7 — 32 40 — — 148.1

ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; Group I, predominantly population-based; Group II, surveys of medical practitioners; Group III, clinic-based.

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22.6 per 100,000. However, 42% of these children were positive for the human leukocyte antigen B27 allele (HLA-B27). The incidence of chronic arthritis in children varied depending on the classification criteria employed (EULAR versus ILAR).86 Data from the Mayo Clinic in Olmstead County, Minnesota, reported an incidence of 13.9 per 100,000 (95% CI, 9.9 to 18.8) during the period 1960–1979.65 A more recent study from the same center indicated that the frequency of this disorder decreased from 15 per 100,000 during 1960–1969 to 7.8 per 100,000 for 1980–1993.77 Seasonal variation was also apparent in this investigation, in Sweden,62 in one Canadian study,59 and in Finland.84 This trend, however, was not confirmed in a larger study from Canada.60

Prevalence Prevalence rates for chronic arthritis in childhood have varied from 16 to 150 per 100,000 (see Table 9–7).54,83 Bywaters63 found the prevalence of “Still’s disease” in English school children to be approximately 65 per 100,000. In the Tecumseh Community Health Survey of 2000 children between 6 and 15 years of age,87 10% complained of joint pain, slightly less than 10% related a history of previous joint swelling, and 5% had morning stiffness, although only two children were found to have chronic arthritis on examination, a prevalence close to that estimated by Bywaters. The 10-year weighted cumulative prevalence per 100,000 in Michigan was 46 for girls and 19 for boys.64 The prevalence was 86.3 per 100,000 in the Swedish study62 and 83.7 to 113.4 per 100,000 (95% CI, 69.1 to 196.3) in Minnesota.65 In Norway,80 the point prevalence was 148.1 per 100,000. As a number of studies suggest, these figures undoubtedly represent minima. The survey by Manners and Diepeveen74 in Australia of 12-year-old school children reported a prevalence of 400 per 100,000 based on an examination of each child included in the survey. Clearly, rheumatic symptoms, past or present, are not uncommon in children and far exceed the estimated prevalence when objective criteria are used and an examination is performed by an experienced pediatric rheumatologist.1,88 Published data are difficult to compare because of varying referral patterns,2 the heterogeneity of the disease, its evolution over time, differences in classification criteria, dissimilarity of source populations, and variable case ascertainment.56 Substantial geographic and ethnic differences are present in regard to age at onset, relative frequencies of onset types, and immunologic markers.

Age at Onset Chronic arthritis in children was arbitrarily defined as arthritis beginning before the age of 16 years. Onset before 6 months of age is distinctly unusual; however, the age at onset is often quite early, with the highest frequency occurring between 1 and 3 years of age, although it varies considerably depending on onset type.36,40,42,51,53,64,89–93 The distribution of ages at onset of arthritis for 300 children in whom the definition of JRA conformed to that of the ACR criteria is in Figure 9–2.64 The peak age at onset was between 1 and 3 years for

■ Figure 9–2 Age at onset of JRA in 300 children: total group (-▲-), girls (-●-), and boys (-●-). For the total group and for girls, a large peak is observed at 1 to 2 years. A bimodal distribution with peaks at 2 years and at 8 to 10 years suggests heterogeneity of arthritis in boys. (From Sullivan DB, Cassidy JT, Petty RE: Pathogenic implications of age of onset in juvenile rheumatoid arthritis. Arthritis Rheum 18: 251, 1975.)

the total group and for girls, but for boys this relationship was much less impressive.

Sex Ratio Twice as many girls as boys are affected by chronic arthritis. Marked differences in this ratio are apparent in the various onset types. These observations suggest either that there are three (or more) different diseases included under the classification for arthritis affecting primarily the appendicular skeleton, or that disease expression is modified by sex chromosome–determined factors (see Table 9–4).

Geographic and Racial Distribution The incidence and prevalence data outlined previously were derived primarily from American or northern European white populations. There are few comparable data for other geographic or racial groups.94,95 Nonetheless, suggestions of racial disparity in frequency exist.54,96 Schwartz and colleagues97 concluded that the proportion of African-American children with JRA in a referral clinic population in the United States was consistent with their representation in the population served. However, there was a striking under-representation of this ethnic group in young children with oligoarticular and polyarticular onsets. Some reports suggest that chronic arthritis in children and adults is less frequent in African than in European populations; in Nigeria, however, the proportion of all patients with onset of chronic inflammatory arthritis in childhood may be somewhat higher.98,99 Lower frequencies of JRA have been reported in children of Japanese, Filipino, or Samoan origin than in whites living in Hawaii.100 The incidence of JRA in Japan was reported to be low (0.83/100,000),101 and chronic

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arthritis may be less common in Americans of Chinese ancestry than in American whites,94 but there is a paucity of data describing these children. Studies from Asia are minimal, but reports from India have most often noted a higher frequency of polyarthritis, compared with oligoarthritis or systemic-onset disease.102–104 An analysis of white and Western Canadian Indian children suggests that, although chronic arthritis occurs in aboriginal children, its frequency is not higher than that for the white population, whereas HLA-B27–associated arthritis is appreciably more frequent in the aboriginal group.105 However, Oen and colleagues106 noted an impressive incidence of the disorder (23.6 per 100,000), in addition to a high frequency of seronegative spondyloarthropathies, in Inuit children of northern Canada. The data reported by Boyer and associates107 suggest that the incidence of RFseropositive polyarthritis is increased in southeast Alaskan Yupik Eskimo children. The numbers of patients in these studies are small, however, and conclusions with respect to actual incidence and prevalence of chronic arthritis in these groups are tentative. Similar studies are being conducted in American Indian children.108

ETIOLOGY AND PATHOGENESIS As indicated previously, chronic arthritis in childhood is certainly not a single disease. These children represent a heterogeneity of phenotypes with at least three primary modes of onset. Two observations are paramount in considering pathogenesis and etiology.109,110 First, it is an autoimmune disease. T-cell abnormalities and the pathologic characteristics of the chronic synovitis suggest a possible cell-mediated pathogenesis.111 Multiple autoantibodies, immune complexes, and complement activation indicate potential humoral abnormalities. Second, it is most assuredly a complex genetic trait (oligogenic or polygenic).112,113 The various forms of the disease display nonmendelian inheritance, and interactions of multiple genes are likely to be important in these diseases. Many of the putative genetic predispositions are within the major histocompatibility complex (MHC) region on chromosome 6; however, non-MHC genes undoubtedly play a role in some of the syndromes (see Chapter 4). Although there are undoubtedly genetic predispositions, as well as putative environmental triggers, any theory of pathogenesis must account for a number of factors, including the clinical heterogeneity of the disease; the higher prevalence in girls; the narrow peak ages at onset; the absence of a peak age at onset for systemic disease; and the widespread immunologic perturbations.114 There may be multiple etiologic events, or the disorder may result from a single pathogenic vector with diverse clinical patterns evolving from interactions with the host. It may be postulated that an infectious agent, infecting a child at a point of vulnerability—defined by age, intercurrent illness, prior antigenic experience, immunologic maturity, or immunogenetic predisposition—results in a permanent infection, which emerges as a clinical disorder. It is necessary to consider differing sets of conditions for development of each onset type and course subtype. Possible causes include aberrant

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immunologic regulation, psychologic stress, trauma, hormonal abnormalities, and infection.

Immunopathogenic Mechanisms A number of observations contribute to the hypothesis that the immune system is intimately involved in pathogenesis. First, there is abundant evidence of altered immunity, abnormal immunoregulation, cytokine production, and polymorphisms.109,115–119 Second, there is an association between specific immunodeficiencies and rheumatic diseases, including chronic arthritis (see Chapter 33). Third, there is a close relationship between immune reactivity and inflammation, the hallmark of arthritis (see Chapter 3). Whether it is principally an immunogenetically determined disorder or an antigen-driven immunologic response is uncertain. One study alleged that breast feeding has a protective effect on the development of the disorder,120 especially in oligoarticular disease; however, a strong relationship was not confirmed in another investigation.121

The Innate Immune System: Immune Complexes Complement activation and consumption probably play a role in perpetuation of the inflammatory reaction and in determining specificity of response.122 Levels of circulating immune complexes parallel activity of the arthritis and systemic features.111,123–125 The pro-inflammatory activity of circulating immune complexes appears to be related to their size.126 Complement activation is also reflected in levels of fragment Bb of the alternative pathway and C4d, which correlate with circulating immune complexes and clinical activity of the disease.127,128 The circulating complexes consistently contain immunoglobulin M (IgM) RFs,129–131 even though most of these children are seronegative by conventional RF testing. They may be positive, however, for hidden RFs detected by acid gel filtration of their sera.132 Levels of these tightly bound RFs correlate with activity of the disease, particularly in children with many involved joints.133 The pro-inflammatory potential of such immune complexes may be enhanced because of their resistance to normal complement-mediated degradation due to this interaction with RFs. The immune complexes identified in synovial fluid also vary in size, composition, ability to activate complement, and potential for induction of cytokine secretion.111

T Lymphocytes and Cytokine Profiles Speculations on pathogenesis have centered on the possibility that there is a disordered interaction between type 1 (Th1) and type 2 (Th2) helper T cells (see Chapter 3).134,135 Th1 cells, or inflammatory CD4+ T cells, predominantly secrete interleukin-2 (IL-2), IL-3, interferon-γ (IFN-γ), granulocyte colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α) and TNFβ, and activate macrophages. Th2 cells secrete IL-3, IL-4, IL-5, IL-6, IL-10, GM-CSF, and TNF-α, which effect activation and differentiation of B cells. TNF-α and its soluble receptors and IL-6 occupy a central role in pathogenesis136 and provide a rationale for current therapeutic studies.137 Macrophage migration inhibitory factor (MIF) is increased in concentration in the vascular compartment of children with JIA. This abnormality is directly related to excess transmission of a two-point promotor haplotype (CATT(7)–MIF–173*G/C) that increases susceptibility to chronic inflammation.138 Investigations of the cytokine network in these children are often contradictory and incomplete, making interpretation of pathogenic mechanisms difficult. Differing results are undoubtedly related to the assay methods employed, stage and activity of the disease, treatment, identification of onset type and course

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subtype, and whether plasma, serum, or synovial fluid was analyzed. A number of excellent reviews have been published116,119,137,139,140 (see also Chapter 3). Synovial fluid T cells appeared to be similar in type and responsiveness to those in peripheral blood in some studies,141,142 but in others CD4+ T cells were decreased in synovial fluid but increased in synovial tissue.143,144 Selective recruitment of T cells expressing CCR5 and CXCR3 has been reported.145 In most instances, T cells from the synovial fluid or membrane had increased expression of activation markers.141,142,145–148 Studies of Scola and colleagues149 indicated that cytokine expression patterns were typical of a type I bias. Murray and colleagues150 studied synovial T-cell infiltrates in 17 children and found that the level of T-cell activation (CD3+ IL-2R+) was significantly higher in oligoarthritis (especially for CD8+ cells) and that the CD4/CD8 ratio was lower. A subsequent study of the immunohistologic patterns of expression of synovial Th1 and Th2 cells found increased secretion of IL-4.151 Clonotypic restriction has been reported.152 Patterns of expression of TNF-α and -β and their receptors and other cytokines have also been studied.151,153,154 Ozen and colleagues79 observed a marked Th1 response in synovial fluid mononuclear cells in 4 of 5 children by immunofluorescent identification of intracellular cytokines through flow cytometric analysis (increased IFN-γ in addition to IL-4). The chemokine receptor CCR4 has been linked to a similar increase in the IL-4/IFN ratio.155 Coculture with heatshock protein (HSP) 60 produced only a slight increase in IFN-γ products in the one synovial fluid sample tested. A recent report indicated that synovial dendritic cells express the receptor activator for NF-κB (RANK).156 Gattorno and colleagues157 investigated the pattern of cytokine production in T-cell clones from synovial fluid mononuclear cells in five children with oligoarthritis. Large amounts of IFN-γ were produced with a predominant Th1/Th0 pattern. Razuiddin and coworkers158 found a mixed Th-cell response in stimulated peripheral blood mononuclear cells in systemic-onset disease. Studies of single nucleotide polymorphisms have confirmed different genetic influences in systemiconset disease for IL-6159,160 and MIF.161,162 Similar studies in oligoarthritis have focused on TNF haplotypes.163 Synovial cytokine levels differ in children with JRA compared to adults with RA.164 TNF-α G → A −238 and −308 polymorphisms may define outcomes in subtypes of chronic arthritis in children.165

T-cell Receptor Polymorphism Abnormalities of assembly and interactions of the trimolecular complex consisting of putative antigen and genes controlling selection of T-cell receptor (TCR) peptide chains and HLA specificities are of increasing importance in considering immunopathogenesis.166–168 Oligoclonal selection of the TCR chain has been demonstrated, a finding that is more characteristic of synovial fluid and tissues than peripheral blood.169,170 Maksymowych and associates171 confirmed a high frequency of the TCR allele TCR-Vβ6.1 among HLA-DQA*0101-positive children. A subsequent report identified this TCR null allele as a risk factor for a polyarticular course in children with early-onset oligoarticular disease positive for DQA1*0101.172 This association was not confirmed in a study from Norway,173 nor did Nepom and coworkers174 identify TCR polymorphism in their studies of oligoarticular-onset JRA. In the report of Thompson and colleagues,170 TCR-Vβ8 was clonally expanded in children with polyarticular disease and TCR-Vβ20 was increased in oligoarthritis.

Peripheral Blood Mononuclear Cells The results of studies of T-lymphocyte phenotypes in the peripheral blood have been inconsistent and are difficult to

interpret because of absence or inadequacy of control data. In general, studies of T-cell responses to mitogens such as phytohemagglutinin or concanavalin A indicate that proliferation is normal in children with inactive or oligoarticular disease but diminished in those with active disease.175–177 Multiple inhibitors may be present.178 Aberrations in suppressor T-lymphocyte function may be instrumental in immunopathogenesis and permit overproduction of autoantibodies.143,179–183 Some studies of peripheral blood lymphocytes have demonstrated normal ratios of CD4+ (helper/inducer) to CD8+ (suppressor/cytotoxic) T cells.142,184,185 Morimoto and coworkers175 found decreased CD4+ and increased CD8+ cells, an apparent result of antibody to CD4+ T cells that was present in the sera of patients with active disease. Some have also found increased CD8+ T cells in children with systemic and polyarticular onset,186,187 whereas others noted decreased CD8+ T cells, particularly in systemic-onset disease.188,189 In contrast, B-cell numbers are increased in these children.183,184 Similar discrepancies have been observed in the frequencies of markers of T-cell activation: Tac or IL-2 receptor expression was found to be normal,142,190 HLA-DR antigens normal190,.191 or increased,184 and very-late-activation antigen (VLA-1) increased only in children with active disease.190 Although many of these studies suggest a global T-cell regulatory defect, their results may have been influenced by therapy. Massa and colleagues192 found that treatment with methotrexate led to a decrease in CD4−, CD8−, and γ/δ T-cell numbers.

Autoantibodies B-lymphocyte numbers are normal to increased, depending on onset type, but their mitogen responsiveness may be impaired.184,193 Immunoglobulin levels tend to be high, at least partly reflecting the nonspecific inflammatory response. Antibody responses to new T cell–dependent antigens such as bacteriophage OX 174 may be defective.194 Some autoantibodies may more likely be epiphenomena than integral to pathogenesis, except for complications such as vasculitis, in which immune complexes participate in vascular inflammation. Autoantibodies to nuclear, immunoglobulin, and other antigens are common in sera of children with JRA.195 Among these autoimmune phenomena are antibodies to histones196–203; anti-neutrophile cytoplasmic antibodies204–206; anti-perinuclear, anti-keratin, and anti-RA33 antibodies207–209; anti-cardiolipin antibodies200,210–212; and the DEK oncoprotein (possibly associated with IFN-γ).213 Antibodies to high-mobility group (HMG) proteins214 are increased in JRA to a defined epitope on HMG-17,215,216 and in oligoarticular disease to an HMG-2 protein.217,218 Autoimmunity to types I, II, and IV collagens have been demonstrated in some studies.219–221 Immunity to cartilage link protein has been noted.222 IgA anti-gliadin antibodies have been described223 but are not predictive of celiac disease in JCA.224 Anti-cyclic citrullinated peptide antibodies have been reported, especially in RF-seropositive disease,225 but less frequently than in adults with RA.226

Hormonal Factors The often striking differences in sex ratio, as well as the characteristic preadolescent or postadolescent peaks in incidence of specific categories of childhood arthritis, suggest that reproductive hormones may play important roles in pathogenesis.227,228 In a study by Khalkhali-Ellis and colleagues,229 androgen levels in children with chronic arthritis and in aged-matched controls were similar for progesterone and dehydroepiandrosterone (DHEA). However, in prepubertal patients, 17β-estradiol was undetectable, and the concentration of the sulfated conjugate of DHEA was significantly less than in controls. Testosterone was lower in the synovial fluid than in matched serum; patients with

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the lowest synovial fluid levels were those with disease of the longest duration. Therefore, low androgen levels may contribute to pathogenesis because they exert a protective effect against cartilage degradation.230 A number of studies have identified an interesting association of elevated serum prolactin levels in chronic arthritis and in systemic lupus erythematosus (SLE) (see Chapter 16). Prolactin is produced by cells of the anterior pituitary and other cells, including lymphocytes; in addition to its endocrine effects, prolactin enhances cell proliferation and survival.231 Levels were increased in children with chronic arthritis and antinuclear antibody (ANA) seropositivity.227,232,233 The prolactin concentration correlated with levels of IL-6 and with a chronic course of the disease. Both glucocorticoids and hydroxychloroquine inhibit prolactin secretion.228

Infection That infections can cause arthritis in children is not in doubt. Arthritis after viral infections is probably common, although it is usually self-limited.234 The possible role of infection in causation235 is supported by the finding that chronic arthritis is especially common among children who have impaired defense mechanisms and overt forms of immunodeficiency such as selective IgA deficiency, hypogammaglobulinemia, or deficiency of the C2 complement component (see Chapter 33). Arthritis is also a complication of infection with the human immunodeficiency virus.236 There is considerable evidence that viral infections do not just cause transient arthritis but are associated with human autoimmune disease.237 Persistent rubella virus infection has been demonstrated in children with arthritis in some studies,238,239 but was not confirmed in others.240,241 Postvaccination arthritis has been described after routine vaccinations242 and after measles-mumps-rubella (MMR) vaccine, and a chronic arthropathy was documented in one study (predominantly in females243) but not in another.241 HLA-DR associations with rubella vaccine arthritis have been demonstrated.244 Arthritis in children has also been linked to perinatal infection with the influenza virus A2H2N2.245,246 This unique epidemiologic study demonstrated the possibility of delayed expression of disease resulting from a presumed intrauterine or neonatal viral infection, not unlike the long-term effects that have been documented with intrauterine rubella infection. A somewhat tenuous link between chronic arthritis and parvovirus B19 has also been noted.247–249 IgM antibodies to parvovirus B19 were demonstrated in significantly more children with JRA, compared with those with acute self-limited arthritis or in a healthy control population.250 Remission of arthritis after viral infections has also been described.251,252 Antibody levels to specific viruses are also increased.253 Inflammatory responses may be triggered by molecular mimicry to Epstein-Barr virus proteins.254 In spite of these reports, there is no consistent evidence for an association of any specific viral infection with any form of chronic childhood arthritis. Mycoplasma, β-hemolytic streptococcus, and enteric organisms (Salmonella, Shigella, Campylobacter, and Yersinia) are all known to cause reactive arthritis (see Chapter 30). A possible role of chlamydial infection has been suggested.255 The observation that children with oligoarthritis and uveitis frequently have antibodies to bacterial peptidoglycan supports the possibility of a causative role for bacterial infection in this disease.256 The cyclic pattern of incidence of chronic arthritis documented from 1979 to 1992 in Manitoba by Oen and colleagues59 correlated with the occurrence of infections to Mycoplasma pneumoniae. RA has resulted after hepatitis B vaccination.257,258

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Humoral and cellular immune responses to highly conserved bacterial HSPs are present in children with chronic arthritis.259–262 HSPs have been demonstrated in the serum and synovial fluid.262–264 Van Eden and colleagues265 postulated that reactive T-cells are part of the normal immune repertoire for TCR V-gene products; self-HSPs and bacterial HSPs may trigger this response. In 13 of 15 children with oligoarthritis, T-lymphocyte proliferative responses to HSP 60 were detected an average of 12 weeks before remission of the inflammatory disease.262,266 Spontaneous remission was characterized by CD30+ T-cells directed to HSP 60.267 Albani and associates261,268 demonstrated immune responses to the dnaJ HSP from Escherichia coli, especially in children with polyarticular disease. This protein has five amino acids that are homologous with those in the binding groove of DRB1, which in itself is increased in frequency in these children. Therefore, molecular mimicry may play a role in pathogenesis.269–271 Despite this circumstantial evidence, however, a direct link between infection and chronic childhood arthritis has remained elusive.

Psychologic Factors It is well documented that psychologic stress is particularly common in families of children with arthritis.272,273 It has not been possible, however, to be certain whether the psychosocial disturbances preceded or followed the development of arthritis. Current research indicates that psychologic factors inherent in the family and child affect their adaptation to chronic illness but are unlikely to have played a role in the causation of the disease. Some studies suggest that susceptibility to arthritis is associated with dysregulation of the autonomic nervous system that leads to lack of an appropriate response of the child’s immune system to stimuli274 and may be influenced by neuroendocrine gene polymorphisms.275

Physical Trauma Chronic arthritis has been reported by parents to follow minor physical trauma to an extremity. Such trauma may serve as a localizing factor, or it may simply call attention to an already inflamed and weakened joint. Benign hypermobility and the rare syndrome of congenital insensitivity to pain are both associated with trauma and may predispose to joint inflammation. The fact that certain joints (e.g., the knee) are frequently affected could be interpreted to suggest that trauma associated with weight bearing in the young child is a factor in initiating chronic inflammation.

Additional Studies of Pathogenesis A relatively large number of basic investigations of potential pathogenic mechanisms in chronic arthritis in children have been published recently. Each report of abnormalities in serum or synovial fluid clarifies an area of potential pathogenesis but also of future therapeutic interest. At this time, no sequential cascade of events can be identified. In synovial fluid and tissues, additional data on IFN-δ/IL-4 ratios,149,155 angiogenic factors,276 proinflammatory cytokine secretion,277 vascular endothelial growth factor,278 and Fas-induced apoptosis279,280 are of interest. Studies by DeBenedetti and colleagues118,281 reported increased expression of enzymatic generated P- and E-selectins, upregulated by Th1 cells, and additional investigations282,283 of levels of adhesion molecules and selectins in serum and synovial fluid. Decreased serum fibrinolytic activity,284 abnormalities involving matrix metalloproteinase 3 and its tissue inhibitor,285 and abnormalities of CD2R286 and CD27287 and their interactions with T cells are observed in some children. Expression of the p53 protein has been investigated.288

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Animal Models of Inflammatory Joint Disease The study of animal models of human disease provides clues about etiology, but these models are, at best, approximations of human disease. Fundamental differences in etiology and pathogenesis almost certainly exist and may be difficult to recognize. In spite of these limitations, and because of the obvious difficulties involved in direct study of human rheumatic diseases, various spontaneous and induced models of disease in animals have been the focus of a number of studies289 and may be relevant to human diseases.290

Adjuvant Disease Intradermal injection of complete Freund’s adjuvant (mineral oil, detergent, and Mycobacterium butyricum) into the footpad of susceptible strains of rats results in the development of a chronic polyarthritis, sometimes accompanied by lesions of the skin and auricular cartilages, and an anterior uveitis.291,292 This disease is adoptively transferable by T lymphocytes, and Cohen and associates demonstrated that the model may be manipulated by T-cell clones capable of inducing, preventing, or ameliorating the disease.293–296 Antibody appears to have no significant role in pathogenesis. The course of adjuvant arthritis may be intermittent or chronic; if chronic, it results in tissue destruction with calcification and ankylosis of joints. The arthritogenic component of the adjuvant is a peptidoglycan dimer, muramyl dipeptide.297

Polyarthritis Induced by Type II Collagen Native type II collagen in incomplete Freund’s adjuvant induces chronic polyarthritis in certain strains of rats and mice.298–303 The disease can be passively transferred with specific antibody to type II collagen.304 Recent studies have suggested a role for cellmediated immunity in the pathogenesis of this disease.305–309 The severity of the arthritis in mice has been reduced by a synthetic collagen vaccine310 and by gene therapy with viral IL-10.311,312

Arthritis Induced by Infectious Agents Erysipelothrix rhusiopathiae and Mycoplasma are each capable of inducing arthritis in domestic pigs,313–315 and Mycoplasma species are arthritogenic in many other species, including rabbit, cow, goat, sheep, mouse, chicken, and turkey.316 Spontaneous infection with Chlamydia psittaci causes polyarthritis in lambs.317 Reovirus causes synovitis in chicks.318 Caprine arthritis is caused by infection with a retrovirus.319–321

Spontaneous Rheumatoid-Like Arthritis A disease resembling rheumatoid arthritis spontaneously occurs in dogs322 and MRL/l mice323 but rarely in primates such as monkeys.324 In the canine and mouse models, RFs are demonstrable.323,325

Transgenic Mice The NSE/hIL-6 transgenic mouse overexpresses IL-6 and is characterized by stunted growth.326 Levels of insulin-like growth factor binding protein 3 (IGFBP-3) are decreased and result in a decreased association of IGF-I in the 150-kD ternary complex secondary to increased clearance of the IGF-I. The TNF-α-transgenic mouse has been studied for the development of bone disease327 and arthritis.328

GENETIC BACKGROUND Familial Chronic Arthritis in Children Familial chronic arthritis is rare, and multigeneration cases are seldom recognized. Although disease rarely occurs in affected siblings, data on HLA segregation underscore a hereditary basis to immunopathogenesis.329,330 Within any one family, arthritis tends to have the same type of onset, and even the same complication of uveitis.331 An examination of time of onset of arthritis in families in which two or more children were affected indicated that the interval between onset of arthritis in each pair of siblings varied from 7 months to 11 years. In no instance was disease onset simultaneous, although in most cases the ages at onset were similar. An increase in the frequency of chronic arthritis developing in childhood has been reported in the parents of multiple offspring with this disorder.332 There is no association between birth order and the development of arthritis.333 The development of chronic arthritis in twins has been extensively studied.330,334–336 A concordance rate of 44% was reported in identical twins and one of 4% in dizygotic twins.337 Ansell and colleagues338 indicated that 2 of 5 pairs of identical twins were concordant for arthritis; in one pair of twin boys, however, a diagnosis of JAS was made later. Six nonidentical twins were discordant for disease. Studies by Clemens and associates339 in more than 2000 children with JCA documented a remarkable concordance between siblings for onset of disease, clinical manifestations, and disease course. Ten of 12 sibling pairs who were concordant for type of onset shared two DR antigens; the other two pairs shared one HLA-DR antigen.339 A multicenter study reconfirmed these findings in 71 sibling pairs, both of whom had chronic arthritis (and in 3 siblings in 3 families); 94% of these children were white.330 The mean interval between onset of disease in the siblings was 4.4 years (standard deviation [SD], 4.2 years). More than three quarters were concordant for onset type, and 79% were concordant for disease course. Among seven sets of twins, the interval between disease onset was shorter (3.3 months), and all were concordant for onset type (6 oligoarthritis, 1 polyarthritis) and course subtype. Uveitis was concordant in only 3 of 16 sibling pairs. There is also an increased prevalence of autoimmunity in these families with JRA.340 Chronic inflammatory rheumatic diseases are more common in parents of multiple offspring affected by chronic arthritis.332 One further association bears attention: the occurrence of JRA and adult RA in the same family. Documentation of this event is scant, and it must be concluded that JRA and RA uncommonly occur in the same family, which is consistent with their different HLA associations. However, Rossen and colleagues341 studied four families with multiple cases of JRA and RA and concluded from histocompatibility data that susceptibility to arthritis was influenced by a dominant allele with variable penetrance and expressivity. An increased frequency of autoantibodies has been documented in first-degree relatives of children with chronic arthritis.342

Human Leukocyte Antigen Relationships Although chronic arthritis has rarely been documented in siblings or in children whose first-degree relatives have another rheumatic disease, more than 50 studies of histocompatibility antigens have pointed clearly to the role

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■ Figure 9–3 Proportion of the study population, by disease-onset type (A) and by sex (B), in each age-at-onset category with the HLADR4 allele.The horizontal line represents the frequency of the allele in the control group. Pauci, pauciarticular; Poly, polyarticular. (From Murray KJ, Moroldo MB, Donnelly P, et al: Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles. Arthritis Rhum 42: 1843–1853, 1999, Copyright © 1999. Wiley-Liss, Inc. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

of certain HLA specificities in predisposing to these diseases.112,329,337,343–372 These investigations also have provided evidence of fundamental distinctions between adult RA and arthritis in children.373,374 It was hoped that HLA specificities might aid in the reclassification of children with chronic arthritis, but this remains an unfulfilled aspiration. Only recently has it been noted that risk and protective effects of these immunogenetic profiles are age related for each onset type and for a number of course subtypes. These complex interactions and age- and sex-specific windows of susceptibility and protection were examined in detail in a provocative paper by Murray and colleagues.382 As an illustration, the population distribution for HLA-DR4 in this study for children with polyarticular onset and 254 ethnically matched unrelated controls is depicted in Figure 9–3. In addition, an increased frequency of certain class III MHC genes may contribute to susceptibility in some populations375 but not in others.356,376,377

Associations with Class I Antigens An increased frequency of A2, B27, and B35 alleles has been documented.375,378–381 A2 is associated predominantly with earlyonset oligoarticular disease in girls.382 An increase in the frequency of HLA-B27 in early studies was possibly related to inclusion of children with JAS, and later investigations document inconsistent increases in the frequency of this antigen.380,383 However, HLA-B27 may confer an age-related risk to oligoarthritis in boys (50% risk at 7.3 years; 80% risk at 11.9 years).382

Associations with Class II Antigens Class II genetic associations are more numerous and complex in relation to specific onset types and course subtypes than are the few documented class I specificities.384 These associations are most obvious in early-onset oligoarthritis and in RFseropositive polyarthritis. They are more heterogeneous and inconclusive in RF-seronegative polyarthritis and systemic disease. Terminology has changed over the years for many of these specificities.385

Interactions with Non-HLA Genes A number of non-HLA genes, on chromosome 6 or on other chromosomes, may be important in a predisposition to chronic arthritis or in its pathogenesis.386 A weak association with TAP2B, a polymorphism in a member of the adenosine triphosphate–binding cassette superfamily, is present for early-onset disease.387 TAP1B may function as an additive susceptibility factor.388 Interaction with other non-HLA genes is also possible, such as IL-1A2, a variant of the IL-1α gene, in early-onset oligoarthritis.389 The gene for IL-1α, or a gene for which its polymorphism is a marker, may also contribute risk for early-onset disease and uveitis.389,390 One study suggested that homozygosity of the B allele of the LMP2 proteosome subunit may increase susceptibility to a putative subtype of chronic arthritis that is associated with B27.391 Data have also been reported for the LMP7 gene.392 Polymorphism in the osteoprotegerin gene may correlate with articular erosions and low bone mass (see Chapter 38).393

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Associations with Other Autoimmune Diseases and Chromosomal Abnormalities There may also be an association of the various types of onset with genetic and chromosomal abnormalities394 and with other autoimmune diseases (see Chapters 4 and 32). Most frequently reported is insulin-dependent diabetes mellitus.395,396 In a referral diabetic clinic population of 200 children, 6 had polyarticular disease and 1 had probable early JAS.395 Autoimmune thyroiditis has also been reported.397 A syndrome that includes flexion contractures, short stature, and skin changes, the socalled Rosenbloom syndrome, may complicate diabetes mellitus and should not be confused with inflammatory joint disease (see Chapter 32).398,399 Myasthenia gravis was reported in four children with chronic arthritis.400 Autoimmune neuromyotonia has also been noted. Other non-HLA genetic associations have been suggested that might increase a predisposition to disease. Among these are selective IgA deficiency401 (see Chapter 33) and the velocardiofacial syndrome.402 One child with arthritis and deletion of the short arm of chromosome 18 was IgA deficient.403 The phenotypic profile of the chromosome translocation in the velocardiofacial syndrome—del(22q11.2) (CATCH 22)—includes chronic destructive arthritis, normal numbers of T lymphocytes, and normal or elevated serum immunoglobulins.404,405 No children had the complete DiGeorge syndrome. Sullivan and associates402 suggested that T-cell immunodeficiency in a subgroup of patients with this deletion syndrome permits polyarthritis to develop. The coexistence of IgA deficiency and arthritis in the 22q11 syndrome has been observed.406 Turner’s syndrome has also been identified in a number of patients.407 In a study of this association,408 18 of approximately 500 children with JRA were found to have Turner’s syndrome. Polyarticular disease was present in 7 who had progressive seronegative arthritis and a 45 XO genotype. It is not entirely clear whether the arthropathy of Down syndrome differs from idiopathic chronic arthritis.394 In children with Down syndrome and arthritis, the joint disease has often been indistinguishable from polyarticular disease. In some children, the arthritis is more like psoriasis, and the latter is seemingly increased in frequency in trisomy 21. Polyarthritis was reported in a child with partial trisomy 5q, monosomy 2p.394

CLINICAL MANIFESTATIONS Constitutional Signs and Symptoms Anorexia, weight loss, and growth failure occur in many children. Significant fatigue is rarely a feature of limited articular disease, but it is a common symptom in children with polyarticular or systemic disease, especially at onset and during periods of poor disease control. It may be expressed as an increased sleep requirement, lack of energy, or increased irritability. Night pain may interrupt sleep and contribute to fatigue. Sleep fragmentation may also exacerbate pain as well as fatigue in these children.409,410

Pain A child with chronic arthritis may not complain of pain at rest,411,412 but active or passive motion of a joint elicits pain, particularly at the extremes of the range of motion

(ROM). Pain is usually described as aching or stretching and is of mild-to-moderate severity. In contrast, children with pain-amplification syndromes almost always describe pain as extremely severe (see Chapter 37). Pain elicited by pressure or tenderness is usually maximal at the joint line or over hypertrophied, inflamed synovium. Bone pain or tenderness is not characteristic, and its presence should alert the examiner to the possibility of a malignancy involving bone.413 The manner in which a child communicates discomfort or dysfunction varies cognitively according to developmental age. The child may express increased irritability, or the joints may be tender on examination or painful in motion. In the young child, there may be no complaints of pain, although it is not clear that the child is not experiencing pain. Young children, however, may alter the manner in which the affected joint is used, assume a posture of guarding the joints, or entirely refuse to use a limb in order to avoid pain. Their expression of pain is thereby physical rather than vocal. In such circumstances, parents report that the child does not appear to be in pain but that he or she limps or reverts to more infantile patterns of movement. The relation of cognitive stage to expression of pain is not certain. Some studies detected no age-related differences in reporting of pain.414,415 In others, younger children with limited joint disease complained of the most severe pain,416–418 and in still others, older children reported more pain.411,412,419 This was related, it was suggested, to their concern about the significance and consequences of the disease. Pain may be an important component of functional disability. It may limit school attendance, physical activity, and social interactions.420 Debate continues about pain perception in children with arthritis.412,421 Two studies concluded that children perceived less pain than their adult counterparts did, although the evaluation instruments were not ideal in either case.422,423 One investigation reported that affected children had lower pain thresholds than healthy children did.424 In another study, Sherry and associates425 stated that only 14% of children with arthritis (mostly oligoarticular type) studied in an outpatient setting indicated that they had no pain. In a more recent report, 57 children with chronic arthritis, aged 7 to 17 years, reported the presence of pain, usually described as aching.415 No differences were found with respect to type of onset of arthritis, sex, age, or disease duration. There was often an overall lack of association between the child’s psychosocial functioning and reports of the nature or intensity of the pain.415,426 In some studies, the child’s report of pain intensity correlated with the physician’s estimate of disease activity or severity,426 but in others no correlation was found.415,423,427 In one study,428 pain as assessed by a pediatric pain questionnaire was compared with the results of thermography of affected joints. Correlations between the visual analogue scale scores determined by parents and those measured by physicians were significant (P < .01 and < .05, respectively). However, correlation between the children’s scores and thermography was not significant. The authors interpreted these findings to indicate that relationships among the multifactorial aspects of the subjective pain response in joint inflammation were far from direct. Severity of disease accounted for only a relatively small percentage of the variance among factors that influenced the subjective pain response.416 Both acute and chronic pain in children are often underappreciated and therefore undertreated.415,426 Children may not complain of pain per se because of their level of cognitive

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development, and pain might better be evaluated by a child’s responses to physical examination of the joints than simply by inquiring about the presence of pain. Measurement of pain in children is facilitated by the use of instruments such as the Pediatric Pain Questionnaire.429 Using a visual analogue scale, Varni and colleagues429 confirmed that reports of pain by children as young as 5 years correlated well with reports made by parents and physicians. It therefore seems reasonable to conclude that children with arthritis experience as much pain as adults when that pain is accurately evaluated in relation to developmental stage. In a study of children with chronic arthritis,411 many reported pain as a major symptom that affected their daily activities. The pain was modestly correlated with long disease duration, older age, and variables related to demographic scales. Disease status and measurable psychologic variables accounted for a modest amount of variance in pain scores. The results suggested that factors that were contributing to pain in children were quite different from those that had been identified in adults with RA. Another study430 examined three psychologic measures in children and their families that significantly affected functioning. Greater emotional distress in the child and in the mother, as well as the level of family harmony, correlated with a higher degree of reported pain in the child.431

Characteristics of Joint Inflammation Morning stiffness and gelling after inactivity are common manifestations of inflammatory joint disease. They are infrequently vocalized by the young child but frequently reported by parents as morning slowness or stiffness. The arthritic joint exhibits the cardinal signs of inflammation: swelling, erythema, heat, pain, and loss of function (see Fig. 9−1). Swelling of a joint may result from periarticular soft tissue edema, from intra-articular effusion, or from hypertrophy of the synovial membrane. Effusion and hypertrophy of the synovial membrane are common, whereas in arthritis accompanying diseases such as Henoch-Schönlein purpura, periarticular swelling is more prominent. Involved joints are often warm but usually not erythematous. In contrast, the joint may be erythematous in septic arthritis or acute rheumatic fever and in some of the other reactive arthritides.

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The characteristic initial complaints are stiffness and pain at the back of the neck; rapid loss of extension and rotation may result. Unilateral apophyseal joint disease may result in asymmetry of neck extension. Subluxation of the atlantoaxial joints may occur early, rendering the child at risk for injury in an accident or with attempted intubation before general anesthesia. Cervical spine ankylosis carries much the same risks. It may be a major problem for the anesthetist because of difficulty in obtaining adequate neck extension and the necessity to use nasotracheal rather than orotracheal intubation or a laryngeal mask. Involvement of the thoracolumbar apophyseal joints is generally not appreciated clinically. However, scoliosis, possibly reflecting asymmetrical apophyseal joint inflammation, was up to 30 times more frequent in early studies.435,436 Scoliosis apparently is now much less frequent. Minimal reactive sclerosis of the sacroiliac joints may occur in a few children (less than 5%) and should be distinguished from the more pronounced disease observed in JAS.437,438 The sacroiliac joints may eventually fuse, particularly in children who have been bedridden. Small outpouchings of synovium are not uncommon and are particularly evident at the extensor hood of the proximal interphalangeal (PIP) joints and around the wrist or ankle. Less commonly, synovial cysts occur in the antecubital area or anterior to the shoulder.439 They may be the initial or sole manifestation of chronic arthritis and, if unilateral, may be misinterpreted as a tumor or as deep venous thrombosis (Fig. 9–4). Ultrasound imaging, magnetic resonance imaging (MRI), or arthrography aids in correct diagnosis. Large synovial cysts are an unusual complication. These may occur in the popliteal space (Baker’s cyst) (Fig. 9–5), rupture into adjacent muscles, and dissect into the calf.440 This event is characterized by sudden sharp pain and swelling in the calf, followed by crescentic ecchymoses about the malleoli. A normal child may occasionally develop a transient popliteal cyst.441

Distribution of Affected Joints Any joint may be affected, but large joints are most frequently involved. Small joints of the hands and feet may also be affected, particularly in polyarticular-onset disease. Attention must also be directed to the temporomandibular joint (TMJ) and to the cervical, thoracic, and lumbosacral spine. The sternoclavicular, acromioclavicular, and sternomanubrial joints are infrequently affected. Cricoarytenoid arthritis is unusual but may be responsible for acute airway obstruction.432 Inflammation of the synovial joints of the middle ear, the incudomalleal and incudostapedial articulations, is rarely appreciated clinically. Tympanometric studies, however, have indicated that subclinical disease may be present in almost two thirds of children with JRA.433 Disease in the apophyseal joints of the cervical spine occurs at onset in approximately 2% of children and may present as a torticollis.434 Approximately 60% eventually develop involvement of this area of the axial skeleton.

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■ Figure 9–4 Brachial synovial cyst. A 6-year-old girl developed this dissecting cyst of her right arm as the first manifestation of chronic arthritis. Later, bilateral effusions developed in both knees. (See color insert.)

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CHILDHOOD ■ Figure 9–5 A, Popliteal cyst or Baker’s cyst.The cyst was associated with pain at the back of the knee, was somewhat tender, and transilluminated. Aspiration yielded clear yellow fluid of low inflammatory activity. B, Arthrogram of a popliteal cyst, with contrast medium outlining the communication (arrow) between the synovial space and this dissecting cyst in an 18-year-old boy who had arthritis since the age of 9 years.

Tenosynovitis Tenosynovitis is more common than is usually appreciated, but it is generally not a striking or isolated clinical complaint.442 The most common sites are the extensor tendon sheaths on the dorsum of the hand, the extensor sheaths over the dorsum of the foot, and those of the posterior tibial tendon and the peroneus longus and brevis tendons around the ankle. Loss of extension of the fingers may result from a stenosing synovitis of the flexor tendon sheaths and may be responsible, in part, for a claw-hand deformity. Clinically recognized carpal tunnel syndrome is uncommon in children with involvement of the wrists. Tenosynovitis of the superior oblique tendon of the eye may cause pain on upward gaze, sometimes with diplopia, the so-called Brown’s syndrome.443,444

Extra-articular Manifestations The frequency with which extra-articular complications occur during the course of chronic arthritis emphasizes the systemic nature of this disease. It should also serve as a reminder that, on occasion, therapy induces systemic complications that may in themselves contribute significantly to morbidity. Chronic uveitis, a unique complication, is discussed in Chapter 11; episcleritis445 and keratoconjunctivitis sicca can also occur.446

Generalized Abnormalities of Growth and Development Abnormalities of growth and development are frequent complications of chronic arthritis or its treatment. Linear growth is retarded during periods of active systemic disease.447 Accelerated growth may occur with suppression of the active disease by therapy or during a remission. It is unusual, however, for a child who has suffered prolonged arrest or slowing of growth to return to the previous growth channel. Puberty and secondary sexual characteristics are often delayed.448 Levels of growth hormone and IGF-I and -II are often normal in children with chronic arthritis but may be impaired.449 IGF-I was low in the children studied by Davies and colleagues,449 and in the investigation of DeBenedetti and coworkers, it was inversely correlated with IL-6 levels in children with systemic disease.450 Many early studies commented on the general arrest of development, retardation of linear growth, asymmetry of develop-

ment, or persistence of infantile proportions.32,40 In a study of 119 children, Ansell and Bywaters451 found that long duration of active disease was associated with reduction of linear growth even in children who had not received glucocorticoid drugs. During remission, height returned to normal in 2 to 3 years if premature epiphyseal fusion had not occurred. Stunting was severe only in children with long-standing, active disease. Similar findings were reported in the extensive prognostic investigation by Laaksonen53 of 544 children. In a sequential study of height in 31 children,452 about half were below the 3rd percentile for age and sex at the 5- to 7.5-year follow-up interval. However, 3 of 9 children were below the 3rd percentile at onset of disease. Undetected disease of some duration might have accounted for this finding. In a study of 56 children between the ages of 4 and 18 years who had disease for more than 1 year, Bacon and White453 found that mean height for age was below the 35th percentile for children with polyarticular or systemic-onset disease. Mean weight for age and weight per height were significantly diminished in those with polyarticular disease. In a study of adults who had had arthritis as children, Lovell and colleagues454 documented growth retardation (height less than 5th percentile) in 50% of children with systemic onset, 11% of those with oligoarticular onset, and 16% of those with polyarticular onset. Glucocorticoid therapy could only partly explain these observations. A marked decrease in height velocity (−2 SD) was observed in 56% of children with systemic arthritis by GarciaConsuegra and associates.455 In their study, growth retardation was associated with glucocorticoid administration, nutritional status, bone mineral density, and early disease onset. Glucocorticoid medications also result in measurable growth retardation or may intensify that initiated by the disease.456 Growth retardation was evident in children treated with prednisone in a dose estimated to be equal to or greater than 5 mg/m2/day for 6 months or longer.457 Laaksonen and colleagues,458 however, found that glucocorticoids in this dose range did not produce growth retardation if used for short periods.

Localized Growth Disturbances Localized growth disturbances result from destruction of a growth center, accelerated development of ossification centers of the long bones of an inflamed joint, or premature fusion of the physis. Brachydactyly of the digits develops from premature closure of the epiphyseal growth plates. During early active disease, development of the ossification centers is accelerated, apparently related to the hyperemia of inflammation and local production of growth factors. The ultimate result may be

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■ Figure 9–6 Arthritis of the second and fourth proximal interphalangeal joints on the left hand associated with brachydactyly of those fingers.

either overgrowth of the affected limb or premature fusion of the involved epiphyses, resulting in diminished length. This latter phenomenon may be widespread and symmetric, resulting in small hands and feet, or it may be isolated, as in the example of brachydactyly illustrated in Figure 9–6. Arthritis of the lower limb, especially of the knee, frequently causes accelerated growth and epiphyseal maturation. If this occurs in one knee only, a discrepancy of leg lengths results. Only rarely does premature epiphyseal fusion cause shortening of the affected leg. Although accurate clinical measurement of leg length is difficult, a good estimate can be obtained by (1) measuring the distance from the superior anterior iliac spine to the medial malleolus in the supine position, (2) estimating leg lengths with the child in a supine position by comparison of malleolar symmetry, or (3) using a set of boards of calibrated thickness to determine which is required to level the iliac crests when the child is standing. A difference of greater than 0.5 cm is probably significant, and differences of 5 cm or more occasionally occur. Inability to extend both knees makes these measurements invalid, however; under these circumstances, visual comparison of the heights of the equally flexed knees in a supine position gives some indication of the presence of a leg-length inequality. Apparent leg-length inequality may also result from pelvic rotation and scoliosis. As the child grows, inequalities of minimal-to-moderate degree may disappear, but they persist in up to two thirds of these children. Whether the long-term result is shortening or lengthening of the affected limb appears to depend considerably on the age of the child— or, more precisely, on the degree of maturation of the skeleton—at the time of the inflammatory insult. If the child is very young and the potential for growth is considerable, the affected limb tends to grow longer. If the disease occurs shortly before the physis would be expected to fuse, shortening of the affected limb is more likely. Micrognathia is a striking example of localized growth retardation (Fig. 9–7). Marked alterations of facial morphology (birdface deformity) may result. In a Swedish survey of 70 children, 56% had symptoms (crepitus, pain, difficulty opening the mouth) and 41% had radiographic evidence of TMJ pathology attributable to arthritis.459 In one patient, the disease began in a TMJ. Another study corroborated the frequency (50%) of TMJ abnormalities and alterations in mandibular growth.460 Extreme

■ Figure 9–7 Arthritis began in this young man at the age of 2 years and pursued an unremitting polyarticular course. Disease of both temporomandibular joints has caused micrognathia and retrognathia with an anterior open underbite.

micrognathia is most likely to occur if arthritis begins before 4 years of age. The mandible ossifies by intramembranous bone production. Its growth is affected by a number of factors that contribute to mandibular growth abnormalities. Pain in a TMJ may inhibit normal masseter muscle development, which in turn retards mandibular bone development, resulting in a shortened mandibular ramus and body. Destruction of the condyle of the mandible causes further diminution of overall mandibular height. In some children, overgrowth of the condyle may contribute to TMJ dysfunction.461 An association of micrognathia and arthritis of the apophyseal joints of the cervical spine per se has been asserted in a number of studies,462–464 but this observation may not be valid. Although the stereotypical abnormality is bilateral micrognathia with an anterior open overbite, unilateral TMJ disease is much more common than bilateral disease. It is characterized by mandibular asymmetry; deviation to the affected side on opening of the jaw; difficulty in palpating the affected mandibular condyle; and pain, tenderness, or crepitus of one or both TMJs. In many instances, TMJ arthritis appears to be asymptomatic, although some children report a preference to chew on the unaffected side, experience pain with maximal opening of the mouth, or are aware of clicking or other sounds accompanying movement of the joint. Little is understood about the effect of chronic arthritis on dental caries or periodontal disease.465

Osteopenia Osteopenia has emerged as a potentially major determinant of functional outcome in young adults who have had chronic arthritis as children.466–474 Children with chronic arthritis develop a diminished bone mass compared with normal children and thereby are at increased risk for fractures in adulthood and for an earlier onset of osteoporosis.475–477 An important determinant of future fracture risk is the peak bone mass achieved at the end of skeletal maturation, which is almost complete by the

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late years of adolescence.478 Genetic polymorphisms of the vitamin D and calcitonin receptors479 and the osteoprotegerin gene393 may play a role in the development of low bone mass. These interrelationships are discussed in Chapter 38.

ORGAN-SPECIFIC MANIFESTATIONS OF CHRONIC ARTHRITIS Skin and Subcutaneous Tissue The classic rash of systemic-onset disease has already been mentioned and is discussed in Chapter 12. A second cutaneous change, occurring particularly in children with involvement of the hands, is a dark discoloration of the skin over the PIP joints.480 The presence of this finding may reflect disease chronicity. In children with tender joints, retention keratosis may simulate a pigmented lesion.

may improve over several years. Treatment includes the use of pressure “stockings” or “gloves.”

Vasculitis Rheumatoid vasculitis is rare and occurs most often in the older child with RF-positive polyarthritis. This type of vessel involvement must be distinguished from benign digital vasculitis (Fig. 9–8), which is more frequent, and may occasionally be associated with vascular calcification on radiographs along the course of the digital arteries. The occurrence of Raynaud’s phenomenon is generally indicative of another connective tissue disease and not of chronic arthritis per se. Pityriasis lichenoides et varioliformis acuta (PLEVA or MuchaHabermann disease) has been recorded in a few children with JRA,484,485 scleroderma,484 Takayasu’s arteritis,486 polyarteritis nodosa,485 Wegener’s granulomatosis,487 and other vasculitides.485,488 These are rare occurrences, however, and may be entirely coincidental.

Muscle Disease Nodules Nodules occur in a variety of rheumatic diseases in children. Rheumatoid nodules occur in 5% to 10% of children with chronic arthritis, almost always confined to those with polyarthritis. Nodules are most frequent below the olecranon, but they also occur at other pressure points, on the digital flexor tendon sheaths, Achilles tendons, and occiput, as well as on the bridge of the nose in a child who wears glasses.

Atrophy and weakness of muscles around inflamed joints is characteristic and is often accompanied by a shortening of the muscles and tendons that results in flexion contractures. A nonspecific myositis may account for some of the associated fatigue and muscle weakness. It does not have a characteristic distribution, and

Typical rheumatoid nodules are firm or hard, usually mobile, and nontender. The overlying skin may be erythematous. They may be solitary or multiple, may change in size over time, and may persist for months to years. They are almost always associated with RF seropositivity and in this respect are generally regarded as a poor prognostic sign. Benign rheumatoid nodules or pseudorheumatoid nodules occur as isolated abnormalities in otherwise healthy children. They are painless, may be single or multiple, and sometimes become quite large (greater than 5 cm). They occur especially over bony prominences such as the anterior tibia or scalp and are characterized by spontaneous regression and recurrence. They frequently recur after surgical excision. Subcutaneous granuloma annulare, a relatively common disease in children, may be histologically indistinguishable from either rheumatoid or pseudorheumatoid nodules. Its clinical appearance and location (shins, dorsum of the foot), umbilicated appearance, and the absence of other disease confirm the diagnosis. Other disorders, such as multicentric reticulohistiocytosis and acute rheumatic fever, are associated with subcutaneous nodules (see Chapter 31).

Lymphedema Asymmetrical lymphedema of the subcutaneous tissues of one or more extremities has been documented in several children with arthritis.481–483 The swelling is usually painless and may be somewhat pitting. The cause is unknown except for its unclarified relationship to inflammation, but does not seem to be related to local obstruction caused by joint swelling. The course is chronic but

■ Figure 9–8 Punctate erythema of the palms and finger pads was the sole manifestation of benign perivasculitis in this 5-year-old girl with chronic arthritis. The lesions were not raised or tender and disappeared after treatment with nonsteroidal anti-inflammatory drugs. (See color insert.)

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histopathologic studies are sparse. Data from adults with RA suggest that it is characterized by a perivasculitis and lymphocytic infiltrates (lymphorrhages). Serum levels of muscle enzymes are not increased. A few children with widespread, prolonged, active arthritis develop progressive muscle atrophy that is most severe and persistent if it occurs before 3 years of age.489

Cardiac Disease Pericarditis The overall prevalence of pericardial involvement is estimated at 3% to 9%.490 Pericarditis tends to occur in the older child with systemic disease, but it is not related to age at onset or severity of joint disease.491 It may occasionally precede development of arthritis, or it may occur at any time during the course of the disease, usually accompanied by a systemic exacerbation. Episodes typically persist for 1 to 8 weeks. Most pericardial effusions are asymptomatic, although some children have dyspnea or precordial pain that may be referred to the back, shoulder, or neck. Examination may document diminished heart sounds, tachycardia, cardiomegaly, and a pericardial friction rub, usually at the left lower sternal border. In many cases, pericardial effusions develop insidiously, are not accompanied by obvious cardiomegaly or electrocardiographic changes, and escape recognition except by echocardiography. Tamponade is rare and is characterized by pulsus paradoxus, venous distention, hepatomegaly, and peripheral edema. Chronic constrictive pericarditis is very rare and is characterized by pulsus paradoxus, a small heart, venous distention, ascites, and peripheral edema. In general, children with pericarditis do not fare worse than others in outcome, and this complication should not necessarily be regarded as a poor prognostic sign.

Myocarditis Myocarditis is much less common than pericarditis and may result in cardiomegaly and congestive heart failure.492 In 3 children reported by Miller and French,493 failure occurred in the absence of overt pericardial effusions in children with severe active disease. At necropsy, diffuse myocardial changes typical of congestive cardiomyopathy were present in one child. Goldenberg and colleagues490 reported that 4 children had perimyocarditis and 2 had myocarditis in a retrospective study of 172 children with JRA. Children with JRA may also demonstrate abnormal diastolic relaxation, similar to that which occurs in ischemic heart disease, and therefore may have an additional risk factor for coronary artery disease.492

Endocarditis Valvular disease, seemingly unrelated to other causes, has been documented in more than 10 children: 8 had aortic insufficiency, and 2 had mitral insufficiency. Sudden deterioration in cardiac function may occur. Valve replacement was necessary in some of these patients.494

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Pleuropulmonary Disease Parenchymal pulmonary disease is rare, but diffuse interstitial fibrosis occurs in a small number of children495,496 and may precede other evidence of arthritis.497 Athreya and colleagues495 noted interstitial disease in 8 of 191 children, all of whom had a systemic onset. Another report detailed pathologic findings in a child who died of pulmonary fibrosis.498 One child was described with primary pulmonary hypertension,499 and another with pulmonary hemosiderosis.500 Pulmonary function studies documented abnormalities in 10 of 16 children.501 In some children, these abnormalities may be the result of respiratory muscle weakness.502 Pleural effusions may occur with carditis, or they may be asymptomatic and detected only as incidental findings on chest radiographs. Pulmonary rheumatoid nodules as described in adult RA are rare in childhood.

Gastrointestinal Tract Except for symptoms induced by medications, gastrointestinal (GI) tract disease is rarely described in children with chronic arthritis. Intestinal pseudo-obstruction503 has been reported. Peritonitis was documented in two children.504 In children with major GI tract disease, the possibilities of inflammatory bowel disease, celiac disease, or cystic fibrosis—all of which may be associated with arthritis—should be considered. Sjögren’s syndrome is uncommonly identified in children but occasionally complicates RF-positive polyarthritis (see Chapter 21).

Lymphadenopathy and Splenomegaly Enlargement of lymph nodes and spleen may occur alone or together and are especially characteristic of systemiconset disease. Marked symmetrical lymphadenopathy is particularly common in the anterior cervical, axillary, and inguinal areas and may suggest the diagnosis of lymphoma. Mesenteric lymphadenopathy may cause abdominal pain or distention and may lead to the erroneous diagnosis of an acute surgical abdomen. Splenomegaly is usually most prominent within the first years after onset. The degree of splenomegaly may be extreme, but it is uncommonly associated with Felty’s syndrome (splenic neutropenia).505,506 Functional hyposplenia (as in SLE) has not been reported.

Hepatic Disease Hepatomegaly is less common than splenomegaly and occurs almost exclusively in children with systemic-onset disease. Moderate to marked enlargement of the liver is often associated with only mild derangement of functional studies and relatively nonspecific histopathologic changes. This type of liver disease is most evident at onset and typically diminishes with time. Chronic liver disease does not occur. Massive enlargement of the liver is usually accompanied by abdominal distention and pain. Progressive hepatomegaly is characteristic of secondary amyloidosis. Occasionally, a fatty liver is associated with glucocorticoid administration. Hepatitis (transaminasemia) related to therapy with nonsteroidal

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anti-inflammatory drugs (NSAIDs) may occur (see Chapter 5). A rare, and apparently benign, transient elevation of serum alkaline phosphatase has been reported in several children.507,508 This abnormality presumably does not result from hepatotoxicity, although it may be confused with it. Reye’s syndrome had been associated with aspirin therapy509 (see Chapter 5). The macrophage activation syndrome is discussed in Chapter 12.

Neurologic Disease Involvement of the central nervous system is usually related to complicating factors such as metabolic derangement, salicylate toxicity, high fever, embolism, and other systemic diseases. In some children, central nervous system disease has been so overwhelming as to suggest a primary relationship with the arthritis or its treatment.510 Some reports may have represented unrecognized instances of Reye’s syndrome. Cerebral and cutaneous vasculitis was described in one child with RF-seropositive disease.511 Entrapment syndromes (peroneal, tibial, tarsal) are not as common in children as in adults with RA but should be considered in the differential diagnosis of tenosynovitis or vasculitis involving peripheral nerves.

Renal Disease Urinary tract abnormalities may occur as a complication of chronic arthritis or as toxic effects secondary to treatment. Intermittent hematuria or proteinuria is an occasional finding in some children, but it should be noted that low-grade proteinuria and hematuria occasionally occur in normal children. Microscopic hematuria and lowgrade proteinuria may reflect the effects of medications, including NSAIDs, gold compounds, or D-penicillamine. Abnormal urinary findings also raise the possibility that the child has vasculitis or intravascular coagulation, a disease such as SLE, or (rarely) amyloidosis. Renal papillary necrosis has been described in a number of children and is thought to be partly related to NSAID use (see Chapter 5). Hypercalciuria has been identified as an additional rare cause of hematuria in some children.512 In Anttila’s study of 165 children, transient microscopic hematuria was observed in 23%, leukocyturia in 25%, and low-grade proteinuria in 42%.513,514 Recurrent or persistent hematuria (4%), leukocyturia (6%), and proteinuria (2%) were uncommon. Hematuria and leukocyturia were more frequent during the initial observation period. Proteinuria was associated with the presence of extra-articular disease, prolonged duration of active disease, and amyloidosis (40% of the children who died). Renal biopsy was performed in 35% of the children and documented minimal glomerular changes in 22% and tubular atrophy in 13%. Chronic pyelonephritis was a common finding at necropsy. Interstitial nephritis and gold-induced nephrotic syndrome were rare. More recent studies of renal dysfunction suggest that abnormalities of tubular function are common.515 Although the frequency of proteinuria (2.3%), hemoglobinuria (3.5%), erythrocyturia (4.1%), and leukocyturia (5.3%) were low in a study of 176 children with chronic arthritis, urinary β2-microglobulin or N-acetyl-β-glucosaminidase levels were elevated in 38.5%. Increased excretion of these proteins was associated with active

polyarticular disease and was most frequent in children receiving slow-acting antirheumatic drugs or two or more NSAIDs. It is not clear whether these changes represent the effects of the disease or drug-related toxicity.

PATHOLOGY The histopathologic features of chronic arthritis in children are similar to those described in RA. There is villous hypertrophy and hyperplasia of the synovial lining layer (Fig. 9–9). The subsynovial tissues are hyperemic, edematous, and infiltrated with lymphocytes and plasma cells. Vascular endothelial hyperplasia is often prominent. There is a selective accumulation in the synovium of activated T cells, which are clustered around antigen-presenting dendritic cells. Fibrin may be layered onto the superficial surface of the synovium or incorporated within it. An exuberant synovitis and pannus formation eventually results in progressive erosion and destruction of articular cartilage and, later, of contiguous bone with pannus formation. Rheumatoid nodules and necrotizing vasculitis are rarely, if ever, present in synovial tissue from children with chronic arthritis. Onset types cannot be distinguished on the basis of synovial histopathology.516,517 In RA, the primary infiltrating cell is the T lymphocyte, which may be distributed diffusely throughout the synovium or form nodules or germinal centers. CD4+ helper-inducer T cells and CD8+ suppressor-cytotoxic T cells may be visible. In addition, macrophages and dendritic cells abound in mature synovitis. In late disease, B lymphocytes and plasma cells producing RF can be demonstrated. Multinucleated giant cells and mast cells are also present. Hypertrophy of synovial lining cells, fibroblasts, and blood vessels leads to the development of papillary fronds. Extension of the inflammatory granulation tissue or pannus that spreads from the synovium and invades the cartilage and bone results in osteolysis, which is visible radiographically as erosion and subchondral cyst formation.

■ Figure 9–9 Photomicrograph of synovial tissue from the knee of a young boy with arthritis.Villous hyperplasia and hypertrophy, edema, proliferation of new blood vessels, and infiltration by mononuclear cells are prominent.

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Erosions occur preferentially in the “bare” areas of the joint, where bone is not covered by articular cartilage (see Chapter 2). They are irregular but sharply defined. Dissolution of the cartilage (chondrolysis) results from enzymatic digestion by neutral proteases, cathepsin, and collagenase from cells of the pannus. Immune complexes may also contribute to chondrolysis. Metaplasia of the granulation tissue may result in the formation of new cartilage, bone, or fibrous tissue, leading to ankylosis. End-stage disease is characterized by deformity, subluxation, and fibrous or bony ankylosis. Joint destruction usually occurs later in the disease course of childhood than in adulthood, and permanent joint damage is absent in many children even after years of chronic inflammation. (Newer studies with MRI are likely to revise the impression of the extent of joint damage in early disease). The greater thickness of juvenile cartilage may offer some protection in this regard. The hyaline cartilage of the hip is destroyed in progressive stages during the course of severe disease, and during healing it may be replaced by a fibrocartilaginous layer. Rice bodies may be present and consist primarily of amorphous fibrous material, fibrin, and small amounts of collagen. Viable cells are incorporated within this matrix and appear more normal than the synovial cells of the inflammatory foci. The majority of these cells resemble type B synovial lining cells, although a few type A cells are also visible. Residual blood vessels in some of these bodies attest to their former attachment to the synovial membrane. The rash is one of the most characteristic hallmarks of the disease (see Chapter 12). It is characterized by minimal perivascular infiltration of mononuclear cells around capillaries and venules in the subdermal tissues. A neutrophilic perivasculitis resembling that of the rash of rheumatic fever may accompany the more flagrant lesions. Subcutaneous nodules may be histopathologically typical of rheumatoid nodules, or they may have a looser connective tissue framework resembling that of the nodules of rheumatic fever (see Chapter 10). Classic rheumatoid nodules consist of three distinct zones: a central area of necrosis and granulation tissue, surrounded by a radially arranged palisade of connective tissue cells that, in turn, is enveloped by chronic inflammatory cells. In children, the central area of fibrinoid necrosis and the epithelioid palisades may be absent or less structured. The serosal lining surfaces of the pleural, pericardial, and peritoneal cavities of the body may exhibit a nonspecific fibrous serositis that is characterized clinically by effusion and pain. Enlargement of the lymph nodes is related to a nonspecific follicular hyperplasia that in rare instances may closely resemble lymphoma. Hepatic abnormalities are characterized by a nonspecific collection of periportal inflammatory cells and hyperplasia of Kupffer’s cells.

LABORATORY EXAMINATION Although the laboratory may provide support for a diagnosis of chronic arthritis, no laboratory test or combination of studies can confirm the diagnosis. The laboratory can be used to provide evidence of inflammation, to support the clinical diagnosis, to monitor toxicity of therapy, and as a research tool to understand more completely the pathogenesis of the disease.

Blood Indices Hematologic abnormalities reflect, in a general way, the extent of the inflammatory disease. Children with limited

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joint disease seldom exhibit any hematologic aberrations beyond that of mild anemia. Those with moderately extensive arthritis usually have a normocytic hypochromic anemia. The anemia may be moderately severe, with a hemoglobin in the range of 7 to 10 g/dL (70 to 100 g/L) in children with severe, uncontrolled disease. Although the anemia is attributable to chronic disease (low serum iron, low total iron-binding capacity, adequate hemosiderin stores),518 iron deficiency may also play a role. Plasma iron transport and iron available for erythropoiesis are reduced in systemic disease. More severe anemia may respond to recombinant erythropoietin in combination with intravenous iron therapy.519,520 Serum ferritin is elevated in children with active arthritis and correlates closely with systemic activity521; in that sense, such elevations do not reflect iron stores but represent a response as an acute phase reactant. Erythroid aplasia has been reported522; hypoplastic crises in some instances may represent a virusassociated reactive hemophagocytic syndrome523 or the macrophage activation syndrome (MAS).524 Leukocytosis is common in children with active disease, and leukocyte counts are strikingly high, 30,000 to 50,000 cells/mm3 (30 to 50 × 109/L), in children with systemiconset disease. Polymorphonuclear leukocytes predominate. The platelet count may rise dramatically in severe involvement; in disease of long standing, thrombocytosis may signal an exacerbation. Thrombocytopenia is rare and may signal an evolution of the disease into SLE.525,526

Erythrocyte Sedimentation Rate and C-Reactive Protein The Westergren erythrocyte sedimentation rate (ESR) is a useful but not totally reliable measure of active disease at onset and during follow-up of a child with arthritis. It is occasionally helpful in monitoring the therapeutic efficacy of a medication program, although the ESR does not necessarily correlate with the articular response to medications.527 The C-reactive protein (CRP) level may be a more reliable monitor of the inflammatory response; at least it is less often increased in a child in whom no clinical inflammatory disease can be found.

Serum Immunoglobulins Increases in serum levels of the immunoglobulins are correlated with activity of the disease and reflect the acute-phase response. Extreme hypergammaglobulinemia is present in the sickest children and returns toward normal with clinical improvement. Viral antibody titers may also be increased, but levels of antibodies to rubella and rubeola viruses are usually similar to those of appropriate control groups or are associated with a polyclonal increase in immunoglobulin concentrations. In one study, 37% of 200 children with JRA had hypergammaglobulinemia, defined as a level of 1.96 SD or higher from normal, in at least one immunoglobulin class.528 In general, persistent hypergammaglobulinemia was an important hallmark of a deteriorating clinical course and poor therapeutic response. Selective IgA deficiency occurred in 4% of the children. In addition, abnormally low levels of IgA were more

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frequent than in normal controls. No relation of immunoglobulin concentrations to age at onset or duration of disease was found. In contrast, another study found normal levels of immunoglobulins in 86% to 94% of children with chronic arthritis.529 Significantly increased concentrations of IgG, IgA, and complement factor C4 were present in children with active disease, whereas elevated IgM levels were characteristic of the disease itself. Studies by the same authors indicated that serum antibody levels to enteric bacteria (Escherichia coli O55 and O86, common antigen, Shigella polyvalent antigen) were normal.530 No abnormalities of immunoglobulin allotypes have been reported.531 Marked increases in low-molecular-weight IgM have been described, presumably reflecting a perturbation of intracellular assembly of subunits.532

Rheumatoid Factors Classic IgM RFs were first detected by assays relying on the agglutination of IgG-coated latex particles or human or sheep erythrocytes. Most laboratories now use a nephelometric method; an enzyme-linked immunosorbent assay (ELISA) has also been employed.133 RFs of other immunoglobulin isotypes have been reported, but their significance is uncertain. The latex fixation and sensitized sheep cell agglutination tests for the detection of classic IgM anti-IgG RFs are positive in a variable percentage of children with chronic arthritis, depending on the age of the population under study and the onset type. RFs are unusual in a child younger than 7 years of age and are seldom helpful diagnostically at onset of disease. In the U.S. Pediatric Rheumatic Disease Registry,533 20 (3%) of 686 children with polyarticular onset were RF positive. In a study by Oen and colleagues534 in Canadian First Nation children, the high frequency of RF-positive polyarticular disease (42%) was probably related to the high prevalence of HLA-DRB1 antigens bearing the RA shared epitope. The diagnostic importance of RF seropositivity in a child with possible chronic arthritis is mitigated by the frequent occurrence of abnormal titers in the other connective tissue diseases of childhood, especially in SLE. In a study of the diagnostic utility of RF serology in children,535 RF tests were as likely to be positive in children with diseases other than chronic arthritis as in that disorder (specificity, 326/332 [98%]; sensitivity, 5/105 [4.8%]). As a diagnostic aid, therefore, tests for RFs are of little utility.

Children with high titers of RFs likely represent a subgroup distinct from the larger number of children with seronegative disease and are identified in separate groups in the EULAR and ILAR classifications. RFs are common in children with later age of onset and polyarticular disease, and in those who are older, have subcutaneous rheumatoid nodules or articular erosions, or are in a poorer functional class. The percentage of children with RF seropositivity also rises progressively as the age at onset or the duration of disease of the cohort group under study increases. They are especially common in the presence of HLA-Dw4 (DRB1*0401) and Dw14 (DRB1*404) specificities. These observations suggest that RFs might be a result rather than a determining event in children who go on to experience unremitting, disabling disease during the early adult years. Anti-cyclic citrullinated peptide antibodies are also found in children with RF-positive polyarthritis.225

There is a general increase in IgM synthesis by peripheral blood B cells.536 Many studies have demonstrated other types of antiglobulins in the sera of children with chronic arthritis or have reported more sensitive and specific tests for RFs.122,130,537–551 The majority of children with seronegative disease have IgG antiIgG antibodies demonstrated by immunosorbent techniques.537,539–541,546 Pepsin agglutinators of the IgG class are found more often in children with disease than are classic RFs.538 Miller and colleagues541 employed five different immunosorbents to search for occult antiglobulins. Antiglobulins detected by binding to sepharose-linked globulin followed by acid elution were found in 8 normal children and 52 children with chronic arthritis. Only 4 children with arthritis had significantly elevated levels; antiglobulins per se were not diagnostically helpful. In the studies of Moore and associates,122,130,351,542–545,547 68% to 75% of children had “hidden RFs,” defined as IgM 19S antiglobulins detected by acid elution of IgM-containing fractions of serum from a gel filtration column. Hidden RFs were found in 59% of children who lacked classic RFs by using a complementdependent hemolytic assay, and their presence correlated well with disease activity. Not only were hidden RFs more frequent, but they were also of higher titer than in healthy children or other disease control groups. Titers correlated with activity of the disease and did not differ significantly between those with polyarticular and oligoarticular disease. Hidden RFs could be inhibited more readily by the use of human IgG than by IgG of animal origin, although the detection system continued to be a hemolytic assay employing rabbit IgG. These studies have focused on North American and European patients. In a survey of 43 children from Turkey,552 19S IgM hidden RFs were present in 56% of patients (46% with oligoarthritis, 64% with polyarthritis, 80% with systemic onset). The latex fixation test was positive in only one patient, who had polyarticular disease. Hidden RFs were present in lower percentages in India102,553–555 and Greece.556

Antinuclear Antibodies Tests for ANAs are more useful than those for RF in diagnosis and classification. Standardized serum dilution titers are usually low to moderate. Most ANAs are of the IgG class, although antibodies of the IgM and IgA classes are found. ANAs of unknown specificities are commonly demonstrable. The frequency of ANAs is highest in girls of younger age at onset, especially in those with oligoarticular disease, and lowest in older boys and in those with systemic-onset disease. ANAs reach their highest prevalence (65% to 85%) in children who have oligoarthritis and uveitis.557,558 Therefore, determination of ANA seropositivity is supportive of the diagnosis and important in identification of children most at risk for chronic uveitis. Studies have demonstrated persistent ANA seropositivity in a small but significant group of children with musculoskeletal complaints in whom no autoimmune or rheumatic disease was found.559–561 Care must therefore be exercised in interpreting the significance of ANA seropositivity in children who do not have objective evidence of arthritis. At the present, tests for ANAs are most often performed on HEp-2 cells. The frequency of ANA seropositivity is increased with the use of this substrate compared with mouse liver, as is background positivity in normal children. The most common patterns are homogeneous and speckled. The antigenic specificities of ANAs have not been identified. Evaluation of specificities by Western blot with HEp-2 cell

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nuclei demonstrated extensive heterogeneity of reactivity.197 The appearance of antibody to double-stranded DNA (dsDNA) during the course of chronic arthritis should be recognized as a warning of a transition to SLE. In a study of 77 children, the frequency of antibodies to defined nuclear antigens (Sm, RNP, DNA, RNA, RAP, SS-A, and SS-B) was only 13%.562 However, the authors noted a small group of girls with polyarthritis and late onset of disease who had an increased frequency of RFs or antibodies to the RAP antigen. They suggested that these patients might be infected with the Epstein-Barr virus (which is associated with anti-RAP) and that this virus might play a role in pathogenesis. In another study, granulocyte-specific ANAs of the IgG class were found in all children with uveitis but in none of those with acute systemic-onset, and they tended to correlate with the number of affected joints.563 Half of the granulocyte-specific ANAs were capable of fixing complement and correlated with active disease.564

Serum Complement and Immune Complexes The third component of complement (C3) is often elevated in the sera of children with active disease, acting as an acute phase protein. The activated form of the molecule (C3d) may be increased as well. This observation indicates that the pathogenesis of arthritis in children may include complement-mediated tissue damage.126,565–569 Immune complexes are present in the sera of some children with systemic-onset disease and polyarthritis122 and in children who are RF seropositive.123,554 It has been suggested that children with systemic disease might have a defect in antibody-forming capacity or in macrophage function that results in decreased clearance of circulating immune complexes.

Plasma Lipids Dyslipoproteinemia occurs de novo in children with chronic arthritis, separate from the effects of glucocorti-

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coids.570,571 Tselepis and colleagues572 reported that 14 patients with active arthritis had lower plasma cholesterol and high-density lipoprotein cholesterol levels and higher triglycerides than comparable children with another disease or controls. Plasma platelet-activating factor (PAF) acetylhydrolase activity was also decreased in parallel with the activity of the disease. These low levels of PAF acetylhydrolase activity may have resulted in a loss of anti-inflammatory activity, because PAF is a lipid mediator of inflammation.

Synovial Fluid Analysis Synovial fluid is usually a group II or inflammatory fluid (Table 9–8); however, the level of the leukocyte count does not always correlate with the degree of clinical activity. Very low counts, such as 600 cells/mm3 (0.6 × 109/L), have been observed in fluid from joints clinically involved by intensely active and symptomatic disease. Conversely, counts in the range of septic arthritis, such as 100,000 cells/mm3 (100 × 109/L), have been described in children with otherwise classic disease. The principal cellular constituents are polymorphonuclear neutrophils and mononuclear cells, including lymphoid dendritic cells. Synovial fluid levels of glucose may be low, as in adult RA. Synovial fluid complement levels are not as uniformly depressed as in adult disease.573 Rynes and colleagues574 found intra-articular activation of the classic complement pathway in some children, but not of the alternative pathway. Complement activation products, however, were not detected in the joint fluid of children with oligoarticular disease in the study by Miller and associates.575 Complexes of IgG, IgG RF, and complement components along with hidden RFs have been described in both synovial tissue and eluates.573,576 The concentration of glycosaminoglycans in synovial fluid (hyaluronic

TABLE 9–8 Characteristics of Synovial Fluid in the Rheumatic Diseases Group and Condition

Synovial Complement

Color and Clarity

Viscosity

Mucin Clot

WBC Count

PMN (%)

Miscellaneous Findings

Very high High

Good Fair to good

<200 <2,000

<25 <25

Debris

High

Fair to good

1,000

<25

Noninflammatory Normal Traumatic arthritis

Normal Normal

Osteoarthritis

Normal

Yellow and clear Xanthochromic and turbid Yellow and clear

Systemic lupus erythematosus

↓

Yellow and clear

Normal

Normal

5,000

10

Rheumatic fever Chronic arthritis Reactive arthritis

Normal to ↑ Normal to ↓ ↑

Yellow and cloudy Yellow and cloudy Yellow and opaque

↓ ↓ ↓

Fair Poor Poor

5,000 15,000–20,000 20,000

10–50 75 80

Tuberculous arthritis

Normal to ↑

↓

Poor

25,000

50–60

Septic arthritis

↑

Yellow-white and cloudy Serosanguineous and turbid

↓

Poor

50,000–300,000

>75

Inflammatory Lupus erythematosus cells

Pyogenic

PMN, polymorphonuclear leukocyte; WBC, white blood cell; ↓, decreased; ↑, increased.

Acid-fast bacteria Low glucose, bacteria

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acid and chondroitin sulfates) is decreased compared with normal controls, accounting for the low viscosity of inflamed synovial fluid.

tion with MRI to differentiate actively inflamed synovium from synovial fluid.590 MRI may prove especially valuable in permitting an early, accurate diagnosis of many of the rare and unusual causes of monarthritis.591

RADIOLOGIC EXAMINATION

Overview

Imaging Techniques Imaging is an important tool for diagnosing arthritis and monitoring its progression. A systematic approach to the evaluation of radiographs577–581 ensures that maximal information is obtained. Technical advances in imaging techniques since about 1990 have contributed considerably to the radiologic investigation of chronic arthritis. Radiologic abnormalities have been reviewed by Reed and Wilmot582 and mimics of the disorder by Wihlborg and colleagues.583 Although plain film radiography is still the mainstay of imaging techniques, computed tomography, high-resolution ultrasonography, radionuclide imaging, and MRI have begun to contribute considerably to the knowledge of early articular changes. Radiography is the best initial investigation in most situations. The only exception to this rule is radiography of the lumbosacral spine and the sacroiliac joints: Unless the indications are very specific, the information gained may not justify the amount of radiation required. Ultrasonography584–586 is often the best way of identifying intra-articular fluid, particularly in joints such as the hip and shoulder, where fluid may be difficult to demonstrate clinically.584,587 Ultrasound studies of the wrist may help delineate joint effusion from tenosynovitis or a ganglion cyst.588 Computed tomography can demonstrate otherwise poorly defined lesions in the sacroiliac joints, TMJs, or feet. Thermography is not widely available, although it can document the extent and degree of joint inflammation by registering heat output. The role of arthrography in the investigation of arthritis in a child has been largely supplanted by MRI, but arthrography can be helpful in demonstrating popliteal cysts and loose bodies. Radionuclide imaging with technetium 99m (99mTc) is a sensitive but less specific investigative tool. The blood-flow phase illustrates vascular integrity; the blood-pool phase evaluates the homeostasis of inflow versus outflow; the bone-uptake phase demonstrates lesions characterized by a decrease or increase in retention of isotope. Unlike other imaging techniques, radionuclide scans demonstrate hemodynamics and metabolic activity in bone or joint at the time the study is being performed. Radionuclide scans therefore provide early evidence of joint inflammation with increased uptake of the isotope on both sides of the joint. They do not necessarily differentiate inflammatory arthritis from septic arthritis or other joint diseases. MRI has the potential to illuminate understanding of intra-articular pathology in a way that no other imaging technique can (see Fig. 11–8).584 It is now possible to identify abnormalities of noncalcified tissues before they evolve into lesions that result in bony changes detectable by plain radiography.589,590 Intravenous gadolinium is taken up by synovial tissue and can be used in conjunc-

Sequential radiologic changes have been examined in relation to the type of onset of the disease and will be summarized in the following paragraphs.592 Early radiographic changes reflect inflammation; they include periarticular soft tissue swelling and widening of the joint space caused by increased intra-articular fluid or synovial hypertrophy. Juxta-articular osteoporosis and growth-arrest lines are common early abnormalities.582 Generalized osteoporosis may also be significant, especially in the postpubertal girl with polyarticular disease.469 Periosteal new-bone apposition occurs most commonly in the short tubular bones of the phalanges, metacarpals, and metatarsals (Fig. 9–10) but occasionally involves the long bones as well. Widening of the midportions of the phalanges from periosteal new-bone apposition is a characteristic feature of polyarthritis. Later radiologic changes include joint-space narrowing, marginal erosions, subluxation, and ankylosis. Thinning of cartilage is difficult to assess radiographically and is often called jointspace narrowing. In fact, it is the layer of noncalcified cartilage overlying bone, not the joint space, that is narrowed. Such a change is best evaluated in joints of the lower extremity if the radiograph is taken with the patient standing. Erosions are often not generally demonstrable by plain radiographs before 2 years of active disease, even in a child with polyarthritis. Indeed, in some children with limited joint disease, erosions may not be visible even after 1 or 2 decades of constant effusion and swelling of a joint. However, in one long-term study,593

■ Figure 9–10 Severe chronic arthritis in an 8-year-old girl. Demineralization is widespread, and there is damage to the proximal epiphyses of the middle phalanges and soft tissue swelling around the proximal interphalangeal joints. Periosteal new-bone apposition (arrow) is present on the metacarpals.

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erosive changes of the small joints of the hands and feet were present at 5 years in 67 of 70 children with RF-seropositive disease. Subluxation involves large as well as small joints. Of the large joints, subluxation is most common in the wrist, hip, and shoulder. Subluxation of the tibiotalar, hip, shoulder, elbow, and other joints may also occur. Bony ankylosis occurs earlier in children than in adults and is particularly pronounced in the carpal and tarsal joints and in the cervical spine. Ankylosis can be confirmed by computed tomography. Aseptic necrosis of the femoral head, humeral epiphysis, or tibial plateau is not common, even in children treated with high-dose glucocorticoids for long periods,594 although early series reported osteonecrosis more frequently.595 Some studies reported frequent fractures related to chronic disease or severe generalized osteoporosis,592,596,597 but this is an unusual event in clinical practice today. These abnormalities are particularly common in children who have had severe disease and undergone long periods of immobilization or steroid therapy. The supracondylar area of the femur is a characteristic site of a fracture that occurs after manipulation for contracture of the knee. Microfractures of the growth plates may be related to abnormal mechanical stress. The normally balanced muscle forces about joints are altered by severe joint deformities, erosion, and subluxation as well as by inflammation of the periarticular connective tissues. Abnormal compression forces on the growth plates result.

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Localized growth disturbances are among the most remarkable skeletal changes. Epiphyseal ossification centers are advanced in development within weeks after onset of the disease. This finding is most obvious when the disease is asymmetrical (Fig. 9–11). Radial atrophy (overtubulation) often accompanies linear overgrowth of the long bones. Even if arthritis is confined to the knee, growth of the pelvis on the same side may be stunted, and coxa valga may be present. Growth abnormalities were particularly evident in children with monarticular or oligoarticular disease. Longitudinal overgrowth was the rule, although affected bones were generally smaller in diameter than normal. Brachydactyly and micrognathia occurred predominantly in children with systemic disease and in those with early age at onset; it occurred to a lesser extent in those with polyarthritis. Accelerated epiphyseal maturation during active disease was sometimes associated with future stunting of full growth of the affected bones. Spondylitis typical of chronic arthritis was noted in all regions of the axial skeleton. Abnormalities of the upper segments of the cervical spine were the most characteristic change, and a few children had arthritis of the cervical spine at onset of disease. Atlantoaxial subluxation and disease of the thoracolumbar spine did not develop in children with monarthritis, even of long duration. Dwarfing or remodeling of the dorsolumbar vertebral bodies, probably attributable to arthritis of the apophyseal joints of that region, occurred in a few patients. Sacroiliac arthritis, both with and

■ Figure 9–11 These radiographs illustrate localized growth disturbances in children with chronic arthritis. A, Arthritis persisted for 7 years in the left wrist of this 9-year-old girl, resulting in osteoporosis and acceleration of maturation of growth centers and a small hand. B, Monarthritis of the left knee has persisted for 8 years in this 14-yearold girl, causing osteoporosis, epiphyseal advancement and enlargement, discrepancy in leg length (left leg longer than right leg), and radial atrophy of the long bones. C, Pelvis of the patient described in B. Arthritis has not been present in the hip, and the regional demineralization and miniaturization of the left side of the pelvis are secondary to the effects of inflammatory disease of the left knee.

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without coincident cervical disease, was present in four children but was distinguishable from that of JAS. Early findings of soft tissue swelling or osteoporosis were present in 45% of children with polyarthritis or systemic-onset disease and in 75% of those with oligoarthritis. Periosteal newbone formation and striking metaphyseal rarefaction were found only in children with polyarthritis and systemic-onset disease. Metaphyseal bands related to focal osteoporosis and hyperemia of the zone of ossification of the epiphyseal plate were common and similar to those that accompany acute leukemia (Fig. 9–12). Periosteal new-bone apposition occurred adjacent to involved joints but not in children with monarthritis or oligoarthritis, despite a subsequent polyarticular course in some of these patients. Advanced radiologic changes were also related to the type of onset of disease (Fig. 9–13). Destruction of cartilage and bone was marked in children with polyarticular or systemiconset disease and was less frequent and usually less severe even in those with oligoarthritis who subsequently developed polyarthritis. Bony ankylosis was a late change. Large joint subluxation, especially at the hip, was particularly characteristic. Fractures of the epiphyses and vertebral compression fractures occurred only in children with severe, long-standing disease. The increased frequency of these findings in children with systemic disease was probably related to extended use of glucocorticoid drugs in this group, because fractures were rare in children in whom these agents had not been used. Fractures were not observed in children who had oligoarthritis.

Changes in Specific Joints Elbow, Wrist, and Hand Evaluation of arthritis affecting the hands is challenging because of the necessity to differentiate changes caused by arthritis from those reflecting bony maturation. Poznanski and colleagues598 proposed a scoring system to quantify the relative amounts of wrist cartilage. This measurement, the relative carpal length (RCL), compares the distance from the base of the third metacarpal to the midpoint of the distal radial growth plate with the length of the second metacarpal bone. The lower this ratio, the greater the severity of wrist and intercarpal joint cartilage loss. Mason

■ Figure 9–13 Severe symmetrical erosions of the heads of the second through fifth metatarsals.The poorly corticated lesions are prominent on the inferomedial aspects of the bones.

and colleagues599 found that one third of patients with polyarticular JRA had an RCL greater than 2 SDs below the mean for age, usually accompanied by periarticular osteopenia, joint space narrowing, or erosion at the time of diagnosis. Erosions, subluxations, and enlargement of the radial head may occur. Subluxation at the radiocarpal joint is a characteristic radiologic abnormality, particularly in the child with long-standing wrist disease. Reduced carpal length is a consistent finding.598 Bony ankylosis of the carpal bones is another characteristic change (see Figure 10–13), and similar changes may occur in the metacarpophalangeal (MCP) joints. In the wrist, there may be disproportionate shortening of the ulna, with the result that the radius compensates by becoming bowed. Pronounced ulnar subluxation of the wrist is characteristic. A recent study evaluated radiographic progression and disability in children with JIA.600 Marked bony overgrowth and enlargement of the epiphyses may also occur at the interphalangeal joints. Failure of growth of small tubular bones results in brachydactyly. This condition is occasionally but not always related to premature epiphyseal fusion, especially if selective stunting of one or two bones occurs. A common site for this finding is the fourth metacarpal bone. Asymmetrical fusion may occur if only a portion of the epiphyseal plate is affected, resulting in abnormal angulation of the joint. Radial deviation at the MCP joints is more characteristic than ulnar drift. In severe, late, uncontrolled disease, bony destruction in the hand may be extensive.

Shoulder

■ Figure 9–12 Zones of metaphyseal rarefaction in both tibias (arrow). These abnormalities are not specific for chronic arthritis and are later replaced by growth arrest lines.

The shoulder is involved in fewer than 10% of children at onset of disease, although perhaps one third eventually develop involvement of this joint.601 Children with oligoarthritis rarely have shoulder disease, but in those with polyarticular or systemic-onset disease, the frequency of involvement rises to 50% or 80%, respectively, and involve-

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■ Figure 9–14 In A, the left mandibular condyle is eroded and flattened. In B, the ramus of the mandible is shortened. (A and B, courtesy of Dr. B. Blasberg.)

ment is almost always bilateral.601 Loss of ROM is most marked in internal rotation and is accompanied by marked atrophy and weakness of the rotator cuff. Superior subluxation of the shoulder and avascular necrosis may result. Disease of the acromioclavicular joint is uncommon.

Temporomandibular Joint The TMJ is usually evaluated by Panorex views and, if necessary, by tomography or MRI.602 Flattening or even complete dissolution of the mandibular condyle may occur (Fig. 9–14).592,603–606 Mandibular asymmetry with undergrowth on the affected side may be present if the disease predominantly affects one TMJ.607,608

rowing and fusion occur but are more characteristic of seronegative spondyloarthritis (tarsitis).613 Erosive disease (see Fig. 9−13) and localized growth disturbances (Fig. 9–15) are typical of severe polyarticular disease. MRI is particularly useful for identification of the extent of inflammation of the ankle joint and may confirm the presence of synovitis at a multiplicity of sites: tibial-talar, subtalar, and talonavicular joints, and peroneal and posterior tibial tendon sheaths.614

Knee Rosberg and Laine609 noted that the medial femoral condyle tended to enlarge more than the lateral condyle in children with arthritis of the knee. Overgrowth of the patella may be marked in long-standing disease. Erosion and enlargement of the intercondylar notch of the femur occur. These changes have also been reported as characteristic of hemophilia and tuberculosis. Cysts in the popliteal fossa are best demonstrated by ultrasound imaging.610 Children with monarthritis in whom the diagnosis is uncertain should undergo MRI to evaluate for other causes of persistent joint swelling.591,611

Ankle, Subtalar Joints, and Foot Loss of “joint space” is frequent in long-standing arthritis of the ankle or subtalar joints.612 Aseptic necrosis of the dome of the talus may also occur. Intertarsal joint nar-

■ Figure 9–15 Brachydactyly of the fourth metatarsal bones and juxtaarticular osteoporosis of the fourth metatarsophalangeal joint in a child with chronic arthritis affecting those joints.

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Hip Articular inflammation and muscular imbalance influence growth and architecture of the hip joint.615,616 Subluxation of the hip is best evaluated on a weight-bearing anteroposterior radiograph to confirm upward and lateral displacement of the femoral head (Fig. 9–16). Ultrasonography may demonstrate increased intra-articular fluid or synovial hypertrophy, particularly between the femoral head and the medial margin of the acetabulum. Protrusio acetabuli may also develop and is sometimes rapidly progressive. Osteonecrosis of the femoral head is not as frequent as in SLE, but if suspected from the plain films, it should be evaluated by a radionuclide scan or MRI.617,618 Kobayakawa and coworkers595 reported a high frequency of necrosis of the femoral head. Of 206 children hospitalized for treatment, 36 (17.5%) had pain or restricted hip motion. Definite radiographic evidence of avascular necrosis of the femoral head (condensation, fragmentation, resorption, and flattening of the epiphysis) was found in 10 hips in 6 children, and signs suggestive of this diagnosis were found in a further 20 hips in 13 children. A sclerotic rim at the base of the femoral neck (suggesting earlier ischemia) was also observed. A more recent study demonstrated a low frequency of osteonecrosis.594

■ Figure 9–17 A, Fusion of the spinous processes of the second and third cervical vertebrae in a teenage girl with early-onset disease. B, More extensive fusion of spinous processes resulting in a severe pseudoarticulation and accompanied by destructive changes at the C5–C6 junction.There were no neurologic signs.

Spine Characteristic radiologic abnormalities of the axial skeleton occur in children with chronic arthritis, depending on onset type.437,619 The predominant changes are in the apophyseal joints of the upper cervical segments. Bony fusion is frequent and often is observed first at the C2–C3 level (Fig. 9–17). Fusion of adjacent spinous processes may also be present. A single lateral film of the cervical spine may not be sufficient to determine the presence of ankylosis in this location. The distances between spinous processes in flexion and in extension should be compared to confirm that fusion has occurred. Atlantoaxial subluxation is also common. The upper limit of the

■ Figure 9–16 Marked subluxation of the left hip of a 5-year-old boy with onset of severe, unremitting arthritis at the age of 11⁄2 years.The femoral neck is osteoporotic, and there is aseptic necrosis of the femoral head, which is subluxed laterally and superiorly out of a shallow, poorly formed acetabulum.

atlanto-odontoid distance in children is approximately 4 mm, measured at the bottom of the arch of C1 on a lateral film taken in flexion with a 40-inch tube-to-film distance. There is normally a small amount of displacement between the bodies of C2 and C3 in the young child (2 to 12 years of age); this change should not be misinterpreted as early subluxation. Instability of the atlantoaxial joint may lead to impingement on the cord and brainstem (Fig. 9–18). There may also be cephalad encroachment of the odontoid into the foramen magnum. Locke and colleagues620 studied the atlanto-odontoid distance in 200 normal children aged 3 to 15 years. If the measurement was greater than 4 mm in the neutral position, an atlantoaxial subluxation was usually confirmed. Age and sex were not significant factors in evaluating these measurements. Other signs of atlantoaxial subluxation were increased tissue density anterior to the cervical spine, flexion greater than 10 degrees between the atlas and the axis, compensatory curve of the lower cervical spine, and narrowing of the atlantovertebral foramen. Narrowing of an intervertebral disk associated with atrophy or maldevelopment of adjacent vertebral bodies probably reflects fusion of the adjacent apophyseal joint or joints, even if it is not well delineated radiologically. Vertebral bodies at areas of fusion fail to grow normally and are smaller and narrower than contiguous vertebral bodies (an altered ratio of height to width). The corresponding intervertebral spaces are reduced, and the disk is sometimes calcified. Vertebral compression fractures are sometimes apparent, especially in children who have been treated with glucocorticoids (Fig. 9–19), and commonly occur in the thoracolumbar vertebrae. Scoliosis of the thoracolumbar spine was previously more common in children with chronic arthritis than in healthy children.436 Sacroiliac arthritis is not characterized by the degree of reactive sclerosis that occurs in JAS.437,621 In long-standing disease, however, there may be subchondral sclerosis and secondary cartilaginous space narrowing. Late fusion may occur in chil-

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■ Figure 9–18 A, Lateral spine of a 12-year-old girl with systemiconset disease at the age of 11 years, showing atlantoaxial subluxation (arrow) and fusion of C3–C4. B, Magnetic resonance image of the cervical spine at age 26 years. Note the impingement of the odontoid on the upper cervical cord (arrow). (B, Courtesy of Dr. J. W. McCune.)

dren with severe disease who have been in a wheelchair or at bed rest for long periods. Patient characteristics and disease variables have been evaluated for influence on the development of sacroiliac arthritis in children with chronic arthritis.23

TREATMENT Approach to Management Although chronic arthritis cannot yet be cured, spontaneous remissions fortunately occur in many children,

and, in the interim, disease control is hopefully achievable. The aims of treatment are, therefore, to control pain and preserve ROM, muscle strength, and function; to manage systemic complications; and to facilitate normal nutrition, growth, and physical and psychological development (see Chapter 8) (Table 9–9). Along with advances in therapeutics has come a raised expectation for disease control. An “adequate” response is no longer considered to be acceptable under most circumstances. The possibility of absolute control of inflammation is a goal that should be pursued within the constraints of safety and cost. Increasingly, the aim of treatment is remission rather than improvement. Although the major focus of medical therapy is on the arthritis, other extra-articular complications (e.g., uveitis, serositis, growth retardation, osteopenia) require consideration. The treatment program should be family centered, community based, and well coordinated.622,623 An ideal approach involves a multidisciplinary team that consists of a pediatric rheumatologist, nurse clinician, social worker, physical therapist, occupational therapist, and psychologist. Consultation with a physiatrist, psychiatrist, orthopedic surgeon, dentist, or nutritionist is often indi-

TABLE 9–9 Objectives of the Treatment of Chronic Arthritis in Children Immediate Relieve discomfort Preserve function Prevent deformities Control inflammation Long-term

■ Figure 9–19 Radiograph of the lumbar vertebrae of a 12-year-old girl with severe debilitating disease requiring glucocorticoid therapy, showing numerous areas of vertebral compression.

Minimize side effects of disease and treatment Promote normal growth and development Rehabilitate Educate

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TABLE 9–10 Psychosocial and Educational Management of Chronic Arthritis in Children Understand the patient’s and parents’ goals Understand the psychologic effect of fluctuations in disease activity Undertake early realistic career planning Emphasize the benefit of regular school participation Facilitate normal peer group interaction

cated. Regular ophthalmologic consultation is mandatory. Because this rheumatic disorder is characterized by chronic or recurrent inflammation of the joints and varying systemic manifestations, the child and family must accept the need for long-term treatment and surveillance. Patient and family education and incorporation of the family’s needs into the management program are essential to facilitate optimal compliance and therapeutic benefit.624–626 Most children with chronic arthritis require a combination of pharmacologic, physical, and psychosocial approaches (Table 9–10). A priority in management is to foster normal psychological and social development and participation in peer-group activities. Attendance at school is strongly encouraged; only rarely is home instruction justified.627 The child should also remain in the physical education program at school (if at all possible), if not as a participant then as an involved member of the class assigned to alternative activities; otherwise, the child should be enrolled in adaptive physical education. Children should largely determine their own level of activity. Inappropriate restriction of recess time or peergroup association can be harmful both physically and psychologically. Participation in recreational activities and camps with other children with arthritis is frequently of benefit. Children who attend camps realize that they are not the only ones with arthritis, profit from group educational experiences, and have the opportunity to test their limits in a safe, supportive, and understanding environment. Vocational evaluation and advice is appropriate in the adolescent with arthritis.

Basic Medical Program The systematic approach to pharmacologic treatment is to begin with the safest, simplest, and most conservative measures.628–631 If this approach proves inadequate, other therapeutic modalities are promptly selected in an orderly progression. It is now realized that the more rapidly inflammation can be controlled, the less likely it is that there will be permanent sequelae. NSAIDs are the mainstay of initial treatment in approximately 75% of patients. Three developments, however, have fundamentally altered the current therapeutic approach beyond that point: Intra-articular glucocorticoids have proved effective in treating joint disease; low-dose methotrexate has substantially changed the choice of treatment options; and new therapeutic modalities such as etanercept and infliximab promise even further improvements in the risk/benefit ratio.632 Although combination pharmacotherapy is attractive in a child with severe disease for whom more limited regimens have failed, adequate clinical studies of effectiveness and safety are generally

lacking.633,634 Specific recommendations for therapy are presented in Chapters 10 through 12. It is not usually possible at onset of the disease to predict which children will recover and which will go on to have unremitting disease with lingering disability or enter adulthood with serious functional impairment.635–637 Therefore, the initial therapeutic approach must be vigorous in all children. Furthermore, therapeutic strategies must recognize differences in approaching the three types of onset: oligoarthritis, polyarthritis, and systemic disease. Evolution of the nine course subtypes in the ACR classification, and recognition of prognostic indicators, will lead to ongoing modifications of the program in keeping with the response of the child. Evidence of improvement is based on a review of the clinical course, repeated physical examinations, charting of the articular severity index and global responses, and laboratory estimates of inflammation.638,639 These evaluations have been systematized in the so-called core set variables.640 A clinically significant response is an improvement of at least 30% in at least three of the variables, with worsening by no more than 30% in not more than one variable. More demanding criteria require 50% or 70% improvement.641 It is undoubtedly true that a number of these evaluations are redundant.642,643 A preliminary definition of a disease flare in JRA has also been studied.644 It is almost impossible to be confident of the risk/benefit ratio for many of the therapeutic regimens for children with chronic arthritis.645 The possibility that there may be important differences in the therapeutic efficacy of antirheumatic drugs depending on ethnicity and genetic background has been largely unexplored.646 Experimental data and clinical observations confirm the efficacy of NSAIDs, gold compounds, methotrexate, glucocorticoids, and etanercept. It is not as certain that other medications, such as hydroxychloroquine, sulfasalazine, D-penicillamine, intravenous immunoglobulin (IVIG), or cyclosporine, confer a statistically and clinically significant benefit. Experience with the biologic agents is still limited, in terms of both number of children treated and duration of follow-up. Toxicity is often a foremost concern in the longterm use of steroids or immunosuppressive agents such as azathioprine or cyclophosphamide. Because of the relative lack of scientific guidance by appropriately designed studies, undertaken in adequate numbers of children with appropriate control of confounding factors such as type of onset and course of the disease, the experience and judgment of the pediatric rheumatologist often become the most important principles of guidance. Alternative or complementary therapies, although of no proven benefit, are widely used by children with chronic arthritis. Their use is often fostered by information or misinformation available through the World Wide Web. Parents should be directed to more objective sources of information, such as the Arthritis Foundation’s Guide to Alternative Therapies.

Consideration should be given to continuation of an NSAID for at least 3 to 6 months after all evidence of active disease has disappeared. Methotrexate therapy should probably be continued for 1 year or longer after a remission has been achieved. One might also consider a different mode of withdrawal, such as decreasing administration to every 2 weeks for a period of time before discontinuation.628,647 In combination therapy, a consensus has not developed on withdrawal of medica-

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tions. Perhaps NSAIDs can be discontinued first along with steroids, methotrexate tapered next, and then, finally, etanercept stopped. In children, potentially toxic regimens such as prolonged use of steroid and immunosuppressive drugs should be employed only in uncontrolled or life-threatening disease.

Nonsteroidal Anti-inflammatory Drugs In most children, one of the NSAIDs is used in the initial approach to therapy (see Chapter 5). All of these drugs have antipyretic, analgesic, and anti-inflammatory actions, as well as—for those that have been approved for use in children—a record of long-term safety. Most currently used NSAIDs inhibit the activity of cyclooxygenases 1 and 2 and therefore have the potential to induce GI irritation.648,649 Although this side effect is unusual in children, ranitidine and misoprostol may ameliorate it.650 The new selective cyclooxygenase 2 (COX-2) inhibitors have not generally been evaluated in children.651 Basic immunizations should be continued, consistent with guidelines appropriate for the geographic area.652 Recent observations in clinical trials in older adults have suggested an increased risk of cardiovascular events secondary to NSAIDs. There are no comparable studies in children. Of particular concern is the allegation that this risk was increased with the administration of naproxen. The possibility exists that this toxicity (if confirmed) may be a “class effect” extending beyond the Cox-2 drugs. Therefore administration of any NSAID should likely be accompanied by an explicit dicussion of the risk/benefit ratio and the requirement of additional clinical data before a firm judgment can be made on its role in the treatment of inflammatory and rheumatic diseases. There is no convincing evidence that one NSAID is superior to another. The choice among many possibilities should be based on the documented experience with the drug in children, its tolerability, toxicity, convenience of use, and cost. Only a few of the NSAIDs have been approved in the United States for use in children (i.e., naproxen, tolmetin, and ibuprofen). Results of evaluations of several other NSAIDs indicate that they are as effective, but no more so, than salicylates, naproxen, or tolmetin. The clinical trials of NSAIDs by the Pediatric Rheumatology Collaborative Study Group (PRCSG) led to the conclusion that approximately 65% of children who were going to respond did so by 4 weeks of therapy, although some children were late responders: A 100% level of response in patients who were deemed to be responders was not obtained before 12 weeks in 72 of the 127 children who progressed to a favorable outcome.653 Clinical response to an NSAID is variable and relatively unpredictable. A child may not respond to one drug, or may eventually lose an initial response, and yet may respond to another. In such cases, it is logical to select an NSAID from a different chemical class than that first used (salicylic, propionic, indoleacetic, pyrrolealkaonic, or N-phenylanthranilic acids or oxicams; see Chapter 5). However, except for issues of toxicity, it is not often useful to try one NSAID after another in an attempt to find one to which the patient will respond; the effect of this approach may be to delay institution of more effective second-line therapy. Naproxen is effective in the management of joint inflammation in a dose of 15 to 20 mg/kg/day given with food. It needs to be given only twice daily, and it is available as a suspension

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(125 mg/5 mL), a definite advantage in the treatment of young children. Naproxen is usually well tolerated, although mild epigastric discomfort is occasionally encountered. Cutaneous pseudoporphyria, a side effect of this drug and occasionally of other NSAIDs, is characterized by a bullous eruption on the face, hands, and other sun-exposed areas, which often leaves an irregular, shallow scar (see Chapter 5).654–658 Ibuprofen is a relatively mild anti-inflammatory agent and is usually well tolerated in a dosage of approximately 35 mg/kg/day, divided into 3 or 4 doses given with food. The suspension (100 mg/5 mL) consists of both S and R enantiomers and is not absorbed as well as the tablets.659 It should therefore be given in a dosage of approximately 45 mg/kg/day divided into 3 or 4 doses a day. Tolmetin, given with food in 3 divided doses totaling 25 to 30 mg/kg/day, is equally effective as an anti-inflammatory drug. Diclofenac may be useful in children who are unable to tolerate other NSAIDs because of gastric side effects. It is prescribed in 3 doses per day; a slow-acting preparation is also available. Sulindac is an inactive prodrug that is converted in vivo to the active sulfide and therefore offers little theoretical exposure to the GI mucosa. It has also been suggested that it is less nephrotoxic than other NSAIDs. Celecoxib, rofecoxib, and more recent analogues of the COX-2 inhibitors have been introduced for treatment of arthritis in adults. These drugs are reputedly less likely than traditional NSAIDs to cause gastric irritation and peptic ulcer disease.649 Other NSAIDs may have specific benefits, although their use in childhood has often not been officially approved. Indomethacin, in a dose of 1 to 3 mg/kg/day to a maximum of 125 mg/day, is useful in treating the fever and pericarditis of systemic-onset disease. In many children, intermittent fever responds only to prednisone or, alternatively, to indomethacin. Indomethacin is a potent anti-inflammatory drug. It has been of particular value in older children, but its overall use has been limited, perhaps inappropriately, by headache or epigastric pain, and occasionally by serious side effects of masked infection and sudden death.660 Piroxicam needs to be given only once a day, and it may be particularly useful in the older child or adolescent in whom compliance with taking prescribed medication is a problem.

Aspirin The role of aspirin as the drug of choice in initial management has been supplanted by the NSAIDs. The reasons for this are related more to convenience of administration and relative freedom from side effects than to superior efficacy. Aspirin probably resulted in more frequent instances of transaminasemia than the newer NSAIDs. Nonetheless, considering its long and extensive use, aspirin has a remarkable record of effectiveness in suppressing fever and other aspects of inflammation and a proven record of long-term safety. Its epitaph has not yet been carved in stone, and aspirin will probably continue to be a part of the pediatric rheumatologist’s anti-inflammatory armamentarium because of its low cost. Aspirin is started at 75 to 90 mg/kg/day in 4 doses given with food to minimize gastric irritation and to ensure therapeutic blood levels. Lower doses per kilogram may be indicated in children who weigh more than 25 kg. The therapeutic serum salicylate level is 20 to 25 mg/dL (1.45 to 1.8 mmol/L), usually measured 2 hours after the morning dose. It may be difficult to reach therapeutic levels in children with acute systemic disease, but increasing the dose beyond 130 mg/kg often results in salicylism. If high doses are required initially, they should be reduced gradually to maintenance levels as the

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systemic manifestations of the disease subside. Awakening the child at night to administer aspirin is not necessary, because the serum half-life of salicylate is prolonged once therapeutic levels have been achieved. Aspirin should not be chewed, because it can cause gingival inflammation and erosions of the biting surfaces of the teeth. An adequate trial of aspirin should last at least 6 weeks. Choline magnesium trisalicylate (liquid) may offer an alternative therapeutic agent to use of the NSAIDs until questions on cardiovascular risk are addressed in children. Aspirin and other NSAIDs are associated with interstitial nephritis and renal papillary necrosis. A few children may develop analgesic nephropathy when taking aspirin alone.661,662 Azotemia and hypertension do not occur in children with NSAID nephropathy per se, but the NSAID should be discontinued or the dose reduced if renal involvement is suspected. It is estimated that this complication occurs in approximately 1% of children who receive NSAID therapy.

Analgesics Although it is not an anti-inflammatory drug, acetaminophen given 2 to 3 times a day may be useful for control of pain or fever in the systemically ill child. This drug should not be used for long-term basic management of the disease because, when used with an NSAID, it may contribute to interstitial nephritis. Ketorolac has profound analgesic effects but less prominent anti-inflammatory effects. Its principal use is in the short-term management of pain. The therapeutic role for the glucosamine compounds, if any, awaits clarification.

Methotrexate Methotrexate, because of its relatively rapid onset of action, efficacy, and acceptable toxicity, is considered the initial second-line agent for treatment for most children with chronic arthritis.663–670 The advantages of this medication are efficacy at relatively low doses, oral administration, once-a-week dosing, and apparent lack of oncogenicity or production of sterility.667,671–673 Although most patients who respond do so by 3 months, occasionally a child may require a longer period of treatment. Principal toxicities are directed at the bone marrow, liver, and, very rarely, the lung (see Chapter 5). Cirrhosis of the liver is not an expected toxic effect in children on weekly therapy.674–677 Malnutrition, viral hepatitis, diabetes mellitus, obesity, and alcohol consumption increase the risk. In this respect, the guidelines recommended by the ACR should be observed.645,678–680 Routine liver biopsies are not indicated. Methotrexate-induced pneumonitis and effects on pulmonary function have been reported rarely in children (Fig. 9–20).681–684 Accelerated nodulosis is uncommon.672,681,685 There is no consistent effect on bone mass.686 Because some NSAIDs may interfere with the protein-binding and excretion of methotrexate, their dosage should be kept constant during treatment. Folic acid, 1 mg/day (or folinic acid687,688) is given during treatment with methotrexate to reduce GI and mucosal toxicity with no diminution in therapeutic effectiveness.

■ Figure 9–20 Posteroanterior (A) and lateral (B) radiographs of the chest of a 131⁄2-year-old girl who developed polyarticular disease in the summer of 1997. In December of that year, low-dose methotrexate was started at 7.5 mg once a week.These films were obtained in May 1998.They demonstrate a diffuse, fine, fibronodular, interstitial infiltrate throughout the lower two thirds of the parenchyma. At that time, she was asymptomatic and there were no abnormalities on examination of the chest. Pulmonary function tests confirmed a mild restrictive pattern with an initial diffusing capacity for carbon monoxide 79% of predicted. High-resolution computed tomographic examination confirmed the presence of bilateral, linear, and reticular nodular interstitial infiltrates. The methotrexate was stopped and, over the course of the next year, the radiographic appearance gradually returned toward normal, as did pulmonary function.

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Monitoring for toxicity includes a complete blood cell count, white blood cell differential and platelet counts, and measurement of serum levels of liver enzymes and albumin. The drug is given as a single weekly dose on an empty stomach with clear liquids 45 minutes before breakfast or, alternatively, at bed time at least 2 hours after dinner, especially on a Friday or Saturday, to avoid missing school if ill. The injectable preparation (25 mg/mL) can be used orally in children in order to prescribe the correct amount. The minimum oral starting dose is 10 mg/m2 weekly (equal to or greater than 0.3 mg/kg). If clinical response is inadequate, or if oral administration is associated with nausea, vomiting, a trial of subcutaneous administration should be attempted, or a higher dose range (0.65 to 1.0 mg/kg, with a maximum dose of approximately 30 to 50 mg/week) should be chosen for a trial of effectiveness.689–691 GI absorption of oral methotrexate in older children is 50% to 80% at less than 20 mg/week, but unreliable at 20 mg or greater per week. Determinations of plasma levels were previously recommended but are not generally necessary.692,693 Intramuscular administration, as an alternative to the subcutaneous route, is effective but not necessary.691,694 Methotrexate is discontinued if no objective response is documented or if toxicity develops despite a reduction in dose. Clinical improvement of arthritis and relatively low toxicity have been reported in a number of studies.663–666,673,689,692,695–701 Assessments included number of swollen joints, morning stiffness, systemic features of the disease, mean daily dose of glucocorticoid, ESR, and CRP concentration. Reviews by Wallace and colleagues698 and others667,695,702,703 have suggested that virtually all children respond to methotrexate and approximately one half achieve a remission. Ruperto and colleagues704 reported a 66% response rate. The poorest response is associated with systemiconset disease and the best with oligoarthritis.705 The double-blind random trial of methotrexate by the PRCSG included two treatment groups, one receiving 5 mg/m2/week and one 10 mg/m2/week, along with a placebo control group.666 Statistical improvement in articular severity was observed, with a mean of 26 for the placebo group and 63 for the 10-mg group. Recalculating these data by the newer core set of criteria for response640,641,704 (3 or more of any 6 core variables improved by at least 30%, with up to 1 variable worse) indicated that 72% of children improved with methotrexate, compared with 44% of the placebo group.697,706 The drug was discontinued in 2 of 45 patients (hematuria, persistent transaminasemia). One placebo patient developed severe GI irritation. A report of Wallace and coworkers692 included 23 children with seropositive polyarthritis who were treated with doses of methotrexate that ranged from 0.1 to 0.6 mg/kg/week. Twenty-one children improved significantly, and remission occurred in 2 children. It was possible to reduce the dose of glucocorticoids in 6 of 9 children. The average time to clinical response was approximately 3.3 months (range, 1 to 8 months). It was not possible to identify clinical involvement that would predict improvement. A study by Harel and associates707 found that carpal length as a measure of cartilage loss was significantly improved or slowed in 11 of the 17 children who responded to 2.5 years of therapy, during which all of the nonresponders had a deterioration of carpal length. Ravelli and colleagues708 provided further evidence of the effectiveness of methotrexate in that there was radiologic

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improvement or a slowing of deterioration of carpal length in children who had responded during a 2-year period of administration; carpal length was significantly worse in nonresponders as a measure of joint destruction. A younger age at onset and being a male correlated with a higher risk of poorer radiologic outcome. The extended oligoarticular course subtype was the best predictor of efficacy.600,709 It is somewhat difficult to categorize methotrexate as an antiinflammatory drug or a remittent drug. Administration is associated with immunologic changes, such as a decrease of double negative (CD4−CD8−) and γ/δ T-cell levels.192 Methotrexate therapy should be continued even after a sustained clinical remission of the disease is achieved.705,710 Early withdrawal has resulted in an exacerbation of the arthritis, and reinstitution of the drug did not always result in a satisfactory clinical response. However, in children who have gone into remission, it is necessary to discontinue methotrexate at some time—the question is when.706 A study by Ravelli and coworkers710 indicated that one third of children relapsed after discontinuation of the drug. It has been reported that clinical response to the drug can be evaluated by a functional index.700 The child most at risk was the one who had an oligoarticular onset with a subsequent polyarticular course.709 A report by Gottlieb and colleagues705 strengthened the conclusion that methotrexate is a remittive agent. Approximately 50% of children in all onset groups who achieved a remission developed a relapse approximately 11 months after withdrawal of the drug. Only 50% regained control of the disease an average of 15 months after reinstitution of therapy. The most convincing evidence of the disease-modifying nature of methotrexate was the long period of time after withdrawal before relapse (range, 1.5 to 36 months). The authors identified younger age at onset (less than 5 years) as indicating a more likely chance of relapse.

Glucocorticoid Drugs Glucocorticoid medications are indicated for uncontrolled or life-threatening systemic disease, in the treatment of chronic uveitis as local ophthalmic drops or injections, and as intra-articular agents.

Systemic Glucocorticoids Systemic glucocorticoids should be instituted only with a well-considered therapeutic plan and a clear set of clinical objectives. Disease control may not be possible in some patients except at a cost of unacceptable glucocorticoid toxicity, and some inflammatory activity may have to be accepted in exchange for less drug toxicity. Systemic glucocorticoid therapy, even in high doses, probably does not limit the duration of active disease, prevent extra-articular complications, or alter the eventual outcome of the disease. Given orally or intravenously, these agents are more suited to management of systemic rather than articular disease. Although the use of glucocorticoid drugs alone to suppress joint inflammation is to be discouraged, lowdose or alternate-day prednisone is of benefit in children with severe polyarthritis unresponsive to other therapeutic programs. Low-dose prednisone711 (i.e., 0.1 to 0.2 mg/kg) can be used as a “bridging” agent in the initial treatment of the moderately to severely affected child who is started at the same time on other, slower-acting

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anti-inflammatory drugs. For severe uncontrolled systemic manifestations with marked disability, prednisone is often prescribed as a single daily morning dose of 0.25 to 1.0 mg/kg/day (maximum 40 mg) or in divided doses in more severe disease. After satisfactory control of the systemic manifestations is achieved, or after it is obvious that acceptable control is not attainable, prednisone should be gradually decreased, if at all possible, as advanced therapy is introduced. Prolonged use of systemic glucocorticoids leads to iatrogenic Cushing’s syndrome, growth suppression, fractures, cataracts, and increased susceptibility to overwhelming infection (see Chapter 5). In spite of these unavoidable toxicities, systemic glucocorticoids are important and effective agents for treatment of some of the most serious manifestations of chronic arthritis.712 Growth retardation commonly develops in children who receive long-term steroids,713,714 even in doses comparable to physiologic replacement levels (i.e., prednisone 3 to 5 mg/m2/day or 0.075 to 0.125 mg/kg/day).457 This effect (among others) is related to blunting of growth hormone release, interference with collagen synthesis, delayed skeletal maturation, and negative effects on IGF reactivity. Effects of glucocorticoids on growth and bone mineralization may be ameliorated by the use of deflazacort, if it is available.715,716 It is important that the child and family be aware of the signs and symptoms of glucocorticoid deficiency and understand that the drug must not be discontinued abruptly under any circumstance because of the risk of precipitating an adrenal crisis. Vomiting or diarrhea in a child who is receiving steroids requires a parenteral glucocorticoid in an equivalent dose (see Chapter 5). Children taking systemic glucocorticoids should wear an identification bracelet or necklace indicating their name, diagnosis, and the fact that they are taking a steroid. This precaution facilitates emergency intravenous steroid administration in the presence of serious trauma or stress. Supplemental steroid is also necessary before and during surgical anesthesia. Although a number of choices exist for the specific drug to be used in these circumstances, one preference is dexamethasone for intramuscular administration before the operation and intravenous hydrocortisone during the procedure. It often becomes difficult to reduce the dose of a glucocorticoid because of a child’s adaptation to chronic steroid excess. Steroid pseudorheumatism may complicate even slow withdrawal of the drug, particularly at lower dose levels. This syndrome is characterized by increased stiffness, joint pain, fever, irritability, and malaise with each reduction of dose. It can be minimized if reductions are 1 mg or less in the lower dosage ranges and are instituted not more often than every 1 to 2 weeks.

time thereafter, with careful attention to electrolyte and fluid balance, and to the potential for cardiac arrhythmia or acute hypertension.

Intra-articular Glucocorticoids The role of intra-articular administration of depot glucocorticoids is changing, but at the present time it is clearly indicated (1) in the management of oligoarthritis that has not responded to an appropriate program of NSAIDs or (2) as an aid to physical therapy of an inflamed, contracted joint.719–721 Intra-articular glucocorticoid therapy should be considered in the management of polyarticular disease in which one or several target joints have not responded to NSAIDs and anti-inflammatory drugs. However, intra-articular injections should be given only a limited number of times (e.g., three times in a single joint during 1 year). Triamcinolone hexacetonide, if available, has been the drug of choice at a dose of 20 to 40 mg for large joints. With the use of topical anesthesia and then local infiltration with buffered lidocaine, most children older than 7 years of age can cooperate with the procedure. Although EMLA cream (lidocaine 2.5%/prilocaine 2.5%) has been recommended, Uziel and colleagues722 did not find it better than placebo. Younger children, and those in whom a hip joint or several joints are being injected, require conscious sedation or light general anesthesia. As in any such procedure, aseptic technique must be followed. The efficacy and safety of intra-articular steroid administration has been studied by a number of authors.719–721,723–728 Almost all patients have a beneficial response; in 60% the response persists for at least 6 months, and in 45% there is no evidence of inflammation in the injected joint for at least 1 year.719,721 Side effects are uncommon, although two deserve special mention. The risk of subcutaneous atrophy and cutaneous depigmentation at the site of injection (Fig. 9–21) can be avoided or minimized by carefully preventing leakage of the depot preparation around the needle track. Intra-articular or periarticular calcification occurs in approximately 15% of treated patients, as evidenced

Steroid Pulse Therapy Intravenous pulse glucocorticoid therapy offers an alternative approach to serious, unresponsive disease. The effect is immediate, and it is hoped that long-term toxicity is decreased.717,718 Methylprednisolone is the drug of choice, in a dose of 10 to 30/mg/kg per pulse. Protocols consist of single pulses spaced 1 month apart, three pulses given sequentially on 3 days each month, or three pulses administered on alternate days each month. Pulse therapy is not without potentially serious toxicities; it should always be given in a short-stay clinic with cardiovascular monitoring during the infusion and for a

■ Figure 9–21 Subcutaneous atrophy (arrow), 10 months after intra-articular injection of triamcinolone acetonide tertiary-butylacetate.

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on radiographs.721 Systemic side effects are rare, although a beneficial “overflow” effect may occur in uninjected joints, or there may be transient improvement in manifestations of the disease.729 Intra-articular septa, demonstrable by ultrasonography, may impede free distribution of injected glucocorticoid within the joint and prevent a complete therapeutic response. In a retrospective series by Sherry and colleagues,730 repeated intra-articular steroid injections were compared with traditional therapy as management for unilateral knee arthritis. Fewer leg-length and thigh-circumference discrepancies were associated with the steroids. In a study from Israel by Padeh and Passwell,731 the efficacy and safety of intra-articular triamcinolone hexacetonide was examined in 70 children who had received a total of 300 injections. Excellent benefit was achieved in 246 (82%) of 300 joints for longer than 6 months. Discontinuation of other medications was possible in 61% of these patients. A complete remission or correction of joint contracture occurred in 115 (82%) of 141 children with oligoarthritis. Eleven patients with popliteal cysts and 12 patients with tenosynovitis experienced satisfactory resolution of the abnormality. Three patients developed subcutaneous atrophy that eventually cleared. Two had a transient postinjection flare of joint pain and increased swelling. None of 20 patients examined by radiography had periarticular calcifications.

Biologic Response Modifiers Tumor Necrosis Factor Inhibition Recent therapeutic approaches for children with unremitting disease include soluble TNF-α receptor (TNFR) p75 fusion protein (etanercept)732–739 and recombinant monoclonal human IgG antibody to TNF-α (infliximab and, more recently, adalimumab).739,740–743 The safety of longterm use of these agents in children was recently reviewed.744 Etanercept has become standard therapy for arthritis that has not responded adequately to methotrexate. It is administered in a minimum dose of 0.4 mg/kg subcutaneously twice a week (maximum, 25 mg per injection), with continuation of previous medications, such as methotrexate and an NSAID.745,746 Before starting therapy, base-line laboratory determinations should be reviewed (complete blood cell count, comprehensive metabolic panel, ESR, CRP, urinalysis) and a negative skin reaction to the purified protein derivative (PPD) tuberculosis skin test must be documented. Thereafter, clinical and laboratory monitoring should be continued as with methotrexate therapy (if methotrexate is not continued, laboratory monitoring is subject to reevaluation). Singledose administration each week is an option for doses of 25 mg or less in newly diagnosed patients and in older children (4 to 17 years). If the weekly dose is greater than 25 mg, two subcutaneous injection sites should be used. Higher doses (0.8 to 1.8 mg/kg) have been recommended for an inadequate initial clinical response, but efficacy was limited in one study to 2 of 8 children.747 It may be possible to evaluate the blood level of pharmacologically active etanercept to guide dosage in patients with an incomplete response.748 The drug should not be started in any child with an infection or a history of recurrent infections. It has been emphasized that even subtle signs or symptoms of infection need to be investigated promptly, especially in

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younger children (6 years of age or younger). Therapy must be discontinued in the presence of infection or in the perioperative period. The risk of reactivation of tuberculosis or the development of granulomatous or fungal disease must be recognized.749 The status of prior bacillus Calmette-Guérin (BCG) vaccination as a risk factor is undetermined, but, considering the lack of published data, it is apparently not a serious consideration in starting therapy. In an extensive clinical trial,734 etanercept in a dose of 0.4 mg/kg subcutaneously twice a week was given to 69 children with an active polyarticular course whose disease had been refractory or intolerant to methotrexate (40 polyarticular, 22 systemic, and 7 oligoarticular onsets). Ages ranged from 5 to 17 years, with a median disease duration of 5.5 years. At 3 months, 51 patients (74%) met standardized clinical response criteria (30% or greater improvement in 3 of 6 core set criteria with worsening of 30% or more in not more than 1 of 6 criteria and a minimum of 2 active joints). The responders were then randomized to continued administration of TNFR Fc or placebo (in addition to baseline NSAID or low-dose prednisone) for an additional 4 months. There was a clinically and statistically impressive improvement in 19 of 25 children who had been continued on etanercept, and a disease flare in 20 (89%) of 26 children in the placebo group (P = .007). The median time to disease flare in the children taking etanercept was at least 116 days, compared with 28 days in the placebo group. Each component of the core set criteria worsened in the placebo treatment arm and remained stable or improved in children continued on etanercept. The data suggested the possibility of an increased risk of a flare among those patients with a higher baseline ESR. Among patients who demonstrated a clinical response at 90 days, those who remained on etanercept continued to improve from month 3 through month 7, whereas those who received placebo did not. The drug was well tolerated with only mild to moderate upper respiratory infections or injection-site reactions. Long-term efficacy and safety in these studies has recently been summarized.750 The percentages of patients after randomization who maintained definition of improvement were 81% for JRA 30, 79% for JRA 50, and 67% for JRA 70. Studies have not been performed to assess the effects of continued etanercept therapy in patients who do not respond within 3 months after initiation of therapy or who develop a relapse while taking the drug. Its effectiveness if used without concomitant methotrexate is problematic. There are children who are only partially responsive or not responsive to TNF-α blockade, especially those with systemic-onset disease.747,751,752 A wide spectrum of toxicities has also been encountered on long-term administration.752–754 Demyelinating disease755 and pancytopenia were described in a drug warning from the company, and a number of other severe side effects have been reported.752,756

Other biologic agents that interfere with TNF-α (i.e., infliximab, adalimumab) are being evaluated and may prove useful in selected children.739,757–762 Infliximab has not been approved for use in children; a double-blind, randomized placebo-controlled trial in polyarticular disease was completed in 2004 by the PRCSG with doses of 3 and 6 mg/kg.763 One hundred and twenty children, aged 4–17 yrs, with active polyarticular JRA despite receiving methotrexate, were enrolled in a randomized, double-blind study with placebo control for 14 weeks followed by a treatment extension of 38 weeks.

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Infliximab was administered in a dose of 3 mg/kg for a 3-dose induction at weeks 0, 2, and 6. The placebo group then received a 3-dose induction of infliximab of 6 mg/kg at weeks 14, 16, and 20, and then every 8 weeks through week 44. Infliximab, administered in combination with methotrexate, resulted in a trend towards improvement (ACR-JRA 30). It was well tolerated in the 6 mg/kg group. The 3 mg/kg group was associated with more infusion reactions (35% vs. 17.5%). Antibodies to infliximab were also higher in the lower-dose children (37.7% vs. 12.2%). Adverse events were comparable among groups except for infusion reactions; one death from sepsis occurred in the placebo group at 3 weeks.

The drug in adults is given concomitantly with weekly methotrexate, as intravenous infusions of 3 mg/kg at weeks 0, 2, and 6, and thereafter every 8 weeks for maintenance. Dosage and intervals of infusion may or may not differ in children compared with adults. Data on the occurrence of occult sepsis and the risk, if any, of previous BCG vaccination or of malignancy, have not been clarified. A strict stepwise infusion protocol to minimize reactions should be followed, with no infusion time shorter than 2 hours.764 Additional precautions are the same as for etanercept, including a negative skin reaction to PPD.765

receptor antagonist (IL-1Ra). Anti-IL-6 receptor monoclonal antibody is currently in clinical trials based on previous investigations.775 Thalidomide has been recommended for treatment of systemic onset arthritis.776

Intravenous Immunoglobulin IVIG for the treatment of polyarticular or systemic-onset disease, and other rheumatic diseases, has received considerable attention, but results of clinical trials are inconsistent.777,778 A controlled randomized trial of IVIG by the PRCSG in children with systemic-onset disease indicated that the drug had little benefit compared with placebo.779 In an additional trial of IVIG in children with polyarticular disease,780 1.5 to 2.0 g/kg was given twice a month for the first 2 months and then monthly for up to 6 months thereafter, with a maximum dose of 100 g. There were no adverse effects. The authors concluded that approximately 75% of children with polyarticular disease would benefit from IVIG.

Cytotoxic and Immunosuppressive Drugs

Lahdenne and cowokers739 compared therapy with etanercept (10 patients, 0.4 mg/kg subcutaneously twice weekly) and infliximab (14 patients, 3 to 4 mg/kg intravenously at weeks 0, 2, and 6, then every 4 to 8 weeks thereafter) in children with severe polyarthritis refractory to standard therapy, including 2 with psoriatic disease (mean age, 10.2 years; range, 3.3 to 16.3 years). During the trial, 23 patients were taking methotrexate. After 12 months, 89% of the patients taking etanercept achieved an ACR 50% response, compared with 75% of those taking infliximab (P > .05). One patient was withdrawn from etanercept because of lack of compliance, and 5 patients withdrew from infliximab because of adverse events or lack of efficacy. There were no serious infections encountered during this open-label, prospective trial.

Clinical experience with cytotoxic drugs is largely anecdotal or uncontrolled. Use of the immunosuppressive and cytotoxic drugs should be reserved for children with life-threatening complications, major steroid toxicity, or severe progressive erosive arthritis.781 A number of medications have been studied for this purpose, including the purine analogues 6-mercaptopurine and azathioprine and the alkylating agents cyclophosphamide and chlorambucil. Complications of chlorambucil therapy include sterility and an increased risk of malignancies. Successful therapy for amyloidosis in children with JRA usually required the use of chlorambucil.782–786 In one study at 15 years’ follow-up,787 68% of children with chronic arthritis complicated by amyloidosis who had been treated with chlorambucil (0.08 to 0.15 mg/kg/day) were alive; the mortality rate in the untreated group was 100%. Leflunomide, an inhibitor of pyrimidine synthesis, is being tested in children788 and has had encouraging results in adults with RA.789

Other Biologic Agents

Cyclosporine

A number of immune modulators have been tried therapeutically (see Chapter 5). Transfer factor, after an initial encouraging report, did not prove effective.766 Other immunoregulatory drugs, such as levamisole, were too toxic.767 Thymopentin, the active pentapeptide of thymopoietin, had no effect on joint disease, but fever was controlled and the size of lymph nodes, liver, and spleen was decreased.768 The ratio of CD4+ to CD8+ T cells returned toward normal, and there did not appear to be any toxicity. Recombinant IFN-γ has been used experimentally.769 In one study,770 it was given to children (6 systemic onset, 3 polyarthritis, 1 oligoarthritis) for whom other therapies had failed after a long duration of disease (5 to 11 years). Eight patients had significant improvement, and 7 entered remission. Two patients with systemic onset had no response, and 4 relapsed. One child developed a severe infection. Plasmapheresis has been recommended for severe disease771 and may be particularly indicated if high levels of circulating immune complexes are demonstrated. Lymphapheresis and total lymphoid radiation have not been adequately studied in controlled series of patients. Tolerance induction by oral administration of type II collagen has been considered as a therapeutic modality.772,773 Induction of tolerance to epitopes of HSP 60 as potential therapy for childhood arthritis is reviewed in Chapter 11. Anakinra is undergoing therapeutic trials for treatment of chronic arthritis in children.774 It is a recombinant human IL-1

A number of studies of cyclosporine for the treatment of chronic arthritis in children have been reported.790–793 It is given in an oral dose of 3 to 5 mg/kg/day in two divided doses exactly 12 hours apart. Blood pressure should be determined at home for 2 weeks and then evaluated periodically along with urinalyses and estimates of renal function. There may be a small long-term risk of lymphoma. Ostensen and coworkers791 administered the drug to 14 children in a dose of 4 to 15 mg/kg/day for 6 to 20 months. Three were able to undergo glucocorticoid dose reduction; 4 had acute exacerbations of disease while taking the drug; serum creatinine concentration increased in 11, hypertrichosis occurred in 14, and hypertension developed in 1 child. Anemia occurred in 9, and the drug was discontinued in 3. The role of this drug in the treatment of arthritis in children is uncertain, but it is probably critically important in treating the MAS (reactive hemophagocytosis).524,794–797 Combined therapy with methotrexate has been recommended in selected children.798

Other Modes of Advanced Therapy The slow-acting antirheumatic drugs (SAARDs), or diseasemodifying antirheumatic drugs, consist of the antimalarials, sulfasalazine, injectable and oral gold compounds, and

C H A P T E R D-penicillamine. Much of the data regarding therapeutic efficacy of these drugs has been inferred from uncontrolled studies.799–801 The fact that their beneficial effects are not observed for several weeks to months, coupled with the unpredictable, relapsing, remitting course of arthritis, makes evaluation of this group of medications difficult. When the toxicity of many of the members of this group is considered, enthusiasm for their use must be somewhat restrained. Until recently, however, these agents were the mainstay of second-line therapy in children with polyarticular disease in whom NSAIDs had produced no response. Methotrexate has generally replaced the SAARDs in this capacity.703 On the other hand, SAARDs can be considered for children who have an incomplete response to a combination of an NSAID, methotrexate, and a TNF-α blocker.

Hydroxychloroquine Hydroxychloroquine is a useful adjunctive agent for treatment of chronic arthritis in older children.799 The therapeutic effect of hydroxychloroquine is usually subtle and is rarely evident before 2 to 3 months of therapy. If no improvement is demonstrated after treatment for 6 months, it should be discontinued. Hydroxychloroquine is never used alone but is added to an NSAID regimen in a dose of 5 to 6 mg/kg/day. The medication is available only in 200-mg tablets, and often it is not possible to achieve an exact dose per day. An alternative schedule involves calculating the weekly dose and then distributing the correct number of tablets during the week. The drug should be taken with food, because it can be a GI irritant. An ophthalmologic examination, including testing of color vision and visual fields, is usually performed before therapy is started and traditionally every 6 months thereafter.802 With current doses, ocular toxicity is uncommon and recommendations regarding the frequency of reexaminations are being reconsidered.802–804 In general, the drug has not been recommended in children younger than 4 years of age, and sometimes in those younger than 7 years of age, because of the inability of young children to discern colors adequately for testing on grids or visual fields. Although retinal toxicity is very rare, hydroxychloroquine should be discontinued at the first suspicion of retinopathy, because the effects of this drug are cumulative. Corneal deposition of drug may also occur and is usually accepted as an indication for lowering the dose of the drug rather than discontinuing it. Chloroquine is less frequently used than hydroxychloroquine and probably has greater ocular toxicity. The therapeutic effect of hydroxychloroquine has not been conclusively proven in randomized, double-blind studies. In a number of therapeutic trials involving approximately 240 children,799 clinical improvement occurred in 15% to 75% and remission in 45% of patients. Toxicity occurred in up to 60% of the children and required discontinuation of the medication in 10%. An extensive double-blind trial by the PRCSG compared hydroxychloroquine with D-penicillamine or an NSAID.805 A total of 162 children with severe, poorly controlled arthritis were observed over 12 months; 88% of the children completed 6 months of the trial, and 76% completed 12 months. The authors reported that 60% of the hydroxychloroquine group (n = 43), 46% of those taking D-penicillamine (n = 46), and 39% of those taking placebo n = 34) demonstrated clinical improvement at 12 months of therapy.806 Although no unequivocal therapeutic advantages could be attributed to hydroxychloroquine or D-penicillamine compared with placebo, it was difficult to understand why the children given placebo did so well, because failure of a therapeutic trial with an NSAID was an entry criterion. However, improvement of pain on motion was noted in the hydroxychloroquine group more often than the placebo-treated group. Late benefit was unlikely to be documented if a favorable response had not occurred by 6 months.

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No subgroup of children could be identified who were likely to respond to either drug. Hydroxychloroquine may also be beneficial in amelioration of the dyslipoproteinemia that occurs in chronic disease and secondary to glucocorticoid treatment.807

Sulfasalazine Sulfasalazine has been reported to have modest efficacy in some children with chronic arthritis, and it has the advantage of a more rapid onset of anti-inflammatory action than occurs with the other SAARDs. This drug should not be used in children with known hypersensitivity to sulfa drugs or salicylate, impaired renal or hepatic function, or specific contraindications such as porphyria or glucose-6-phosphate dehydrogenase deficiency. Severe side effects (fever, rash, elevation of serum levels of liver enzymes, and the MAS) have been reported in children with systemic-onset disease. Sulfasalazine is started in a dose of 500 mg/day given with food or, for small children, 12.5 mg/kg. This dose is gradually increased until a dose of 50 mg/kg/day (maximum, 2000 mg) is reached. Enteric-coated sulfasalazine may be preferable to reduce dyspepsia. Monitoring for toxicity includes measurement of hemoglobin, differential leukocyte count, platelet count, immunoglobulins, and serum levels of liver enzymes every 4 weeks initially and then every 3 to 6 months (see Chapter 5). Benefit is usually apparent within 4 to 8 weeks after initiation of therapy.

Parenteral Gold Compounds Parenteral gold compounds (sodium aurothiomalate and aurothioglucose) had been indicated in children with polyarthritis if a program of NSAIDs had failed and the disease was extensive or progressing. Before gold therapy is started, it should be determined that the child’s hematologic, renal, and hepatic functions are normal (complete blood cell count, urinalysis, blood urea nitrogen and creatinine concentrations, and serum levels of liver enzymes). A 5-mg intramuscular test dose is given initially, and weekly doses thereafter are gradually increased to a level of approximately 0.75 mg to 1 mg/kg/week (maximum, 50 mg/week). If objective, satisfactory improvement or a remission is achieved in 6 months, therapy is maintained at the same dose with injections every 2 weeks for approximately 3 months, then every 3 weeks for 3 months. If signs of improvement continue during this interval, the gold injections are decreased to every 4 weeks thereafter, with periodic adjustments based on growth and body weight. Before each administration, the child should be assessed for any associated toxicity, such as stomatitis, dermatitis, pruritus, depression of any of the cellular elements of the blood, hematuria, or proteinuria. A decrease in the leukocyte count to fewer than 3500 cells/mm3 (3.5 × 109/L), a fall in the absolute neutrophil count of 50% or more, and development of thrombocytopenia or eosinophilia, hematuria, or clinical symptoms or signs of gold toxicity are indications for at least a temporary interruption of therapy. Therapy may be cautiously resumed at a lower dose after the symptoms or signs of toxicity disappear. Contraindications to reinstitution of gold therapy are severe leukopenia or neutropenia, proteinuria, exfoliative dermatitis, significant oral ulcerations, and consumptive coagulopathy. In the authors’ experience, the most common toxicities are hematuria and dermatitis. The oral gold compound auranofin, or triethylphosphine gold, has been evaluated in a number of studies,808–811 including a 6-month, double-blind, parallel, randomized, placebo-controlled trial in more than 200 children.811 Most investigations suggested, and this controlled study conclusively demonstrated, that the effect of auranofin was modest at best and was probably not significantly better than placebo. The safety of this oral

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gold compound at a starting dose of 0.1 to 0.2 mg/kg/day (maximum, 9 mg/day) was documented in the initial study.812 Toxicity was relatively mild. D-Penicillamine D-Penicillamine has rarely been used in the treatment of children with chronic arthritis since recognition of the superior effectiveness of methotrexate and publication of the PRCSG study in which neither D-penicillamine nor hydroxychloroquine was superior to placebo.805 The dose is approximately 10 mg/kg/day (maximum, 750 mg/day). This level is achieved in three increments at intervals of 8 to 12 weeks each. The drug must be taken on an empty stomach to prevent heavy metals in food from chelating with it and rendering it ineffective. A complete blood cell count and urinalysis are performed once a week until the maximum dose is achieved, after which monitoring at monthly intervals is sufficient. Of particular concern is the possible induction of a lupus-like syndrome, dermatitis, thrombocytopenia, and proteinuria. D-Penicillamine toxicity is not necessarily dose-dependent and may be related to the presence of HLA-Dw33 (HLA-DR3)813 and the C4 null allele.814

Autologous Stem Cell Transplantation Bone marrow transplantation has been initiated as experimental treatment for severe autoimmune diseases including rheumatic diseases unresponsive to conventional therapy. Autologous stem cell transplantation (ASCT) is being evaluated currently in a small number of children.637,815–826 This approach to treatment is indicated only in children in whom control of severe active disease has not been achieved by conventional therapy, including anti-TNF therapy. In one clinical protocol,819 bone marrow harvest was followed by T-cell depletion and a conditioning regimen (antithymocyte globulin, cyclophosphamide, total body irradiation). ASCT was undertaken in children with polyarticular and systemic-onset arthritis (1 and 4 patients, respectively) who had progressive, unremitting disease. At final evaluation, 3 patients were in drugfree remission and 1 had mild oligoarthritis. Deaths from posttransplant viral infections and the MAS have occurred in more than 30 children. Although follow-up has been short and patient numbers limited, the authors of this report judged the results to be encouraging. The results of ASCT in 31 children with refractory systemic JIA treated in eight European centers were summarized by Wulffraat and colleagues.827 Eighteen patients were in complete remission and taking no medication 12 to 60 months after transplantation. A partial response was observed in 6 patients (18%) and no improvement in 7 (21%). Three patients died from transplantation-related causes and 2 others from their disease. Survival and post-transplantation morbidity are likely to be better with improved techniques for harvesting and manipulating stem cells, prevention of viral infections, genetic tests to identify the potential for relapses, tailoring of medications specifically for each recipient, and experience with preventing complications such as the MAS. Serum concentrations of myeloid-related proteins 8 and 14 are markers of disease activity in children who have undergone ASCT828 and may predict flares in JIA.829

Growth Hormone The best approach to the treatment of growth failure and short stature is uncertain.830,831 Most, but not all, children with

chronic arthritis have normal baseline and stimulated blood levels of growth hormone, IGF-I, and IGF-II. Growth hormone has been used with varying success, although early studies may not have used sufficient doses. Davies and colleagues449 treated 28 children who were growth impaired with one of two regimens of growth hormone (12 or 24 IU/m2/week). All patients demonstrated adequate baseline secretion of growth hormone. Although almost all children had an increase in height during 1 year of treatment, those receiving the higher dose of growth hormone grew better. Investigations indicate that daily growth hormone in a weekly dose of 0.3 mg/kg initiates a return to normal growth rates for 1 to 2 years.832 However, glucocorticoid in a prednisone-equivalent dose of greater than 0.35 mg/kg/day interferes with growth hormone responsiveness.832,833 In the study by Touati and associates,834 recombinant growth hormone in a dose of 1.4 IU/kg/week partially counteracted the adverse effects of glucocorticoids on linear growth velocity and lean body mass. In children with rheumatic diseases, the immunostimulatory effects of growth hormone lead to the theoretical possibility of interference with immunosuppression.835 In one study,836,837 growth hormone slightly increased allograft rejection rates. Growth hormone may also increase cytochrome P-450 activity838 and thereby alter clearance of specific drugs (glucocorticoids, sex steroids, anticonvulsants, cyclosporine).

Nutrition The child’s overall nutrition, development, and growth are important aspects of long-term management. Growth retardation and impaired bone mineralization almost invariably occur during periods of active disease and are exacerbated by glucocorticoid administration, anorexia, or inanition. Nutrition and vitamin supplementation (vitamin D and folic acid) are often indicated. Assessment of nutritional status should be a component of every patient’s evaluation.839,840 Management of malnutrition is often difficult in the systemically ill, anorectic child. Nocturnal nasogastric feeding occasionally is necessary to maintain adequate nutrition in such a child.454 Specific measures to address osteopenia and osteoporosis are reviewed in Chapter 38. Marked microcytic, hypochromic anemia is usually not improved by oral iron supplementation which often adversely affects appetite. Occasionally, a child benefits from intravenous iron administration followed by recombinant erythropoetin.520,841 Henderson and Lovell842 suggested the use of a four-parameter test to screen for protein–energy malnutrition. The presence of any two of the following abnormalities indicates the need for a detailed nutritional assessment: weight below 5th percentile, weight-for-height index below 80th percentile, arm circumference below 5th percentile, and serum albumin less than 2.8 mg/dL (28 g/L).

Physical and Occupational Therapy The objectives of physical and occupational therapy are to minimize pain, maintain and restore function, and prevent deformity and disability (Table 9–11). These aspects of treatment are critically important in the child’s total management program.843 In children with active arthritis, a rest period after returning from school in the afternoon and increased time for sleep at night are advisable. Most children, however, determine their own levels of activity.

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TABLE 9–11 Treatment of Chronic Arthritis: Physical Measures Relief of pain Heat/cold Maintenance of joint function Splints Range-of-motion exercises (active/passive) Posture/prone-lying exercises Adequate rest/adequate exercise Balanced physical activity Selected peer sports (tricycle, swimming)

Only rarely is it warranted to push them beyond their present capabilities or to unduly restrict daily activities. Normal play must be encouraged, and the family must realize how vital this is to the growing child in terms of peer group interactions and physical fitness, including achieving and maintaining a desirable level of exercise and musculoskeletal and cardiopulmonary conditioning.844,845 It is important, however, to avoid specific activities that cause overtiring or increased joint pain. Undesirable play is that which places excessive stress on affected joints. Tricycle or bicycle riding and swimming are almost always helpful and do not add undue loading to the joints. Swimming has the added advantage of providing active ROM and muscle strengthening without weight bearing. Although activities such as bicycling and swimming are excellent ways of maintaining muscle strength and ROM, they are not a substitute for a well-designed active and passive therapy program: The child with limited ROM tends to function within the current range rather than regaining lost ROM. Skilled physical and occupational therapists are able to assess the time and intensity of a therapy program that the child can tolerate. Daily physical therapy performed at home should seldom exceed 30 minutes twice a day (and often should be much shorter). The child’s age and temperament, the duration of morning stiffness, and the presence of systemic disease must all be considered in planning a physical therapy program. If possible, adaptive play and games are designed to achieve the desired results.845 The child and parents should agree on realistic goals. It is sometimes difficult for the parent to carry out home therapy and maintain a healthy parent–child relationship. In such circumstances, twice-weekly visits to a physical therapist may be a better plan than daily home therapy by the parent. In some children, it is necessary to institute intensive physical and occupational therapy for 1 to 3 weeks once or twice a year to prevent loss of function. During periods of active inflammation, joint pain and stiffness are reduced by heat. A hot bath in the morning and application of heat before physical therapy reduce stiffness and pain and maximize function. In children with a great deal of muscle spasm, ice may be more beneficial than heat, but this often is not preferred. Passive stretching is usually needed to regain lost ROM. Active exercise is required to rebuild muscle strength. Atrophy of the extensor muscles begins early, and active exercise must be instituted during the initial phases of the disease to maintain the strength of these muscle groups. Cock-up splints for the wrists, ring splints for the fingers, and Orthoplast posterior resting splints for the knees may be used to prevent malpositioning or for the long-term correction

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of deformity. The maintenance of normal ROM or reduction of minimal contractures often requires gentle stretching and the use of resting splints. A cervical collar with a plastic insert should be worn by children with cervical spine disease during automobile travel. Malpositioning and neck discomfort may be minimized by the use of a soft collar while studying and a desk with a tilt top on which the child can do homework. At night, a small pillow under the neck, rather than under the head, is an effective way to reduce neck discomfort. Dynamic splints are helpful for certain joint contractures (elbow and knee). For severe contractures—especially contractures of the wrist, elbow, or knee—serial casting with active exercises every 2 days when the cast is removed may be more effective. If stretching or casting is too forceful or is improperly performed, subluxation of the knee or wrist or even fracture of osteoporotic bone can occur. Appropriate footwear is essential in the child with arthritis of the joints of the ankle and foot.612 Shoes should be lightweight but provide firm lateral support. In children with a leg-length discrepancy, a heel lift or an addition to the bottom of the shoe of the shorter leg should be used, depending on the depth needed. In general, the total compensation should be somewhat less than the leg-length discrepancy. One study has analyzed gait alterations in children with chronic arthritis.846 In children with pain or inflammation of the metatarsophalangeal joints or excessive pronation or supination, a custom-fitted hard insole that slips into the shoe provides considerable comfort and improvement of the gait. Hip flexion contractures can be difficult to treat. Prone lying for a significant period (at least 1 hour/day) helps to reduce the degree of contracture. Several studies416,847,848 have examined psychologic approaches to treatment for children with higher levels of associated pain. The treatment protocol included relaxation training, guided imagery, and biofeedback for the child and training in the use of behavioral techniques for management of daily physical therapy and school attendance for the mothers. The results provided modest support for the use of psychologic interventions in children whose pain significantly affects their activities of daily living.

Orthopedic Surgery At present, orthopedic surgery has a limited but important role in management of chronic arthritis in young children.849–852 In the older child, however, surgical approaches to joint contractures, dislocations, or joint replacement become important components of therapy, and the orthopedic surgeon plays an important role at this stage.852–854 Approaches to some problems, such as limb overgrowth, have not been completely clarified.855 In some reports, surgical epiphyseal arrest was judged to be necessary in approximately one third of the patients.856,857

Synovectomy The long-term outcome of children with joint disease is not altered by prophylactic synovectomy. However, synovectomy may be useful in some children for relief of mechanical impairment of joint motion related to joint pain or synovial hypertrophy.850,858–862 Care must be taken to prevent a postsurgical contracture, and the use of a continuous-motion apparatus has been recommended for this purpose, especially in the young child. Arthroscopic surgery greatly reduces the morbidity associated with synovectomy.863

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Soft Tissue Surgery Soft tissue releases, posterior capsulotomy, and tendon lengthening occasionally are useful in a child with a severe contracture of the knee or hip. In other instances, balanced traction is necessary to expedite the treatment of a knee contracture, although this is often difficult to maintain in the young child. Tenosynovectomy may be indicated to reduce the risk of tendon rupture over the dorsum of the wrist or for adhesive flexor tenosynovitis and trigger finger, which sometimes occurs in children who are RF seropositive.

Reconstructive Surgery Reconstructive surgery has become important in the older patient with marked disability. Total joint prostheses, particularly for the hip or knee, have proved to be of great benefit.627,864 Usually, surgery is postponed until bone growth has ceased. Other special considerations include the status of the other lower-extremity joints, activity of the rheumatic disease in general, currently unresolved questions concerning wear and longevity of prostheses, and possible lack of adequate motivation for rehabilitation in some patients. Many children with polyarthritis are further incapacitated either before or after lower-extremity surgery because of difficulty with crutch walking due to increased use of the hands or wrists, flexion contractures of the elbows, or involvement of the shoulder joints. Preservation of muscle function in anticipation of surgical intervention requires a rehabilitation program over many years devoted to maintaining muscle strength as near normal as possible.

Counseling the Family It is of signal importance that the child and the parents be educated about the present state of knowledge of JRA, its outcome, and therapy. The family must share in the coordination of disease management, which should be community based.865,866 An optimistic attitude must be maintained. Counseling should be initiated by the physician at the time of the first visit and reinforced and continued at follow-up by the team. Educational efforts are repeated as needed during the subsequent clinical course, especially in an effort to increase compliance.867,868 In management, the first priority, concomitant with initial efforts to control the activity of the disease, is to foster normal psychologic and social development. Attendance at school is an integral part of this program. Home instruction is rarely indicated; most pediatricians sense that physically disabled students do better in regular schools. Some families have had psychologically important disruptions such as divorce, separation, death, or adoption, and they often display severe emotional disturbances. More recent studies from North America indicated that families of children with chronic illnesses are much more functional.869,870 It is important to emphasize that coordinated care of the child with a chronic disease requires a team effort.71 This concept presents problems for newly established clinical services because of the number of personnel who need to be involved in an ideal program in addition to the child, the family, the school, and the community agencies. One study found that, for most children with chronic arthritis, basic care was either divided or dupli-

cated, and many aspects of a total supportive program were neglected.871 These authors and others found that a pattern of division, duplication, and neglect was typical of the fragmented care of most children with a chronic disease.

COURSE OF THE DISEASE AND PROGNOSIS The course of chronic arthritis is especially unpredictable early in the disease. Nonetheless, certain generalizations can be made, because the type of onset is associated to some extent with the future unfolding of the disease and its manifestations (Table 9–12).10,872 After the pattern of the disease is well established, the course tends to be more predictable and repetitive. After this initial period of observation of variable duration, it is usually possible to begin to estimate prognosis and therapeutic response on which changes in the management program can be based. It is impossible to predict the eventual disease outcome in any individual child. Furthermore, “outcome” is a complex concept that can be measured in a number of ways873,874 (see Chapter 7).

Functional Disability and Psychosocial Outcome It had been estimated historically that 70% to 90% of children with chronic arthritis have a satisfactory outcome without serious disability.875–877 A small percentage (perhaps 5%) develop a recurrence of arthritis as adults878–880 Approximately 10% to 20% of children enter adulthood with moderate-to-severe functional disabilities.2,671,881 Delay in referral and initiation of an acceptable therapeutic program are associated with a poorer functional outcome. Recent data have been presented on outcome for specific onset types872,882–884 and for long-term follow-up from specific referral centers.844,877,885–893 The data of Wallace and Levinson671 documented poorer long-term results than previously recorded (Table 9–13). At 15 to 20 years, 17% of the patients were in Steinbrocher functional capacity III to IV, and 45% still had active disease (activity of disease was approximately equal for each onset type). A review of previous studies of outcome has been published.894 A study by Ruperto and colleagues636 evaluated long-term outcome in a group of 227 patients from Cincinnati and Pavia. This study examined the effect of specific demographic, clinical, and immunologic variables that were present during the first 6 months of the illness. The mean duration of disease at assessment was 15 years (range, 15.3 to 36.1 years). The best predictor of long-term disability was the initial articular severity score. Early hand involvement was also a strong predictor of future disability, pain, and impaired wellbeing. ANA seropositivity was associated with less disability. This study confirmed that quality-of-life scores are much more difficult to forecast because of the multiple domains that are functioning in this type of outcome. Extensions of this study635 indicated that long-term outcome, based on quality-of-life scales and health assessment questionnaires, was favorable in most patients 5 years or more after onset of symptoms.895,896 The Childhood Health Assessment Questionaire (CHAQ) has been evaluated for measurement of health status in early and late disease.897 Oen and colleagues898 surveyed early predictors of long-term outcome on the CHAQ in 392 patients with JRA

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TABLE 9–12 Clinical Outcome by Onset Type and Course Subtypes Onset Type (N)

Course Subtype (n)

Profile

Outcome

Polyarthritis (78)

RF seropositive (16)

Female Older age Hand-wrist involvement Erosions Nodules Unremitting Female Young age Variable

Poor

ANA seropositive (38) Seronegative (24) Oligoarthritis (121)

ANA seropositive (66)

Good

Seronegative (35)

Female Young age Chronic uveitis Polyarthritis Erosions Unremitting Male Older age Variable

Excellent

Oligoarthritis (30) Polyarthritis (21)

Variable Erosions

Good Poor

RF seropositive (8) HLA-B27 positive (12)

Systemic disease (51)

Good

Excellent (except eyes) Poor Good

ANA, antinuclear antibodies; RF, rheumatoid factors. Cassidy JT, Levinson JE, Bass JC, et al: A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 29: 274–278, 1986.

(of 652 eligible), including 327 white patients, who were 8 years of age or older and had a minimum of 5 years of followup. The most significant early predictors were age at onset and being male. In addition to the results in Table 9–14, worse disability was observed for systemic onset in males, less disability in patients with RF-negative disease, and a shorter duration of activity in RF-positive polyarthritis. ANA seropositivity in oligoarthritis was associated with a longer duration of activity, as was a younger age at onset. The RA shared epitope was associated with less disability in systemic disease. A subsequent report examined radiologic outcome in children from the same clinics.899 More recently, investigators have attempted to avoid the confounding factors of referral-based and clinic follow-up by

TABLE 9–13 Functional Outcome of Chronic Arthritis

Author and year (ref. no.) Laaksonen, 1966 (53) Jeremy et al., 1968 (939) Ansell & Wood, 1976 (940) Hill et al., 1976 (879) Hanson et al., 1977 (941) Stoeber, 1981 (942) Wallace & Levinson, 1991 (671) Zak & Pedersen, 2000 (881) Bowyer et al., 2003 (895) Oligoarthritis Polyarthritis Systemic disease

Years of follow-up (mean) ≥16 5–20 (18) ≥15 (14.5) 5–25 (10) 10–22 (15) 15–20 26 5

Classes III and IV (% of cases) 48 24 23 33 28 41 17 11 0 12 30

Modified from Wallace CA, Levinson JE: Juvenile rheumatoid arthritis: outcome and treatment for the 1990s. Rheum Dis Clin North Am 17: 891–905, 1991.

primarily basing their outcome studies on population surveys. Data from the U.S. Pediatric Rheumatology Disease Registry895 in 703 patients observed between 1992 and 1997, before the era of biologic therapy, indicated that more than 25% of those with polyarthritis, and almost one half of those with systemic onset, had functional limitations affecting school activities. Joint space damage on radiographs was evident at 5 years in two thirds of the polyarticular and systemic-onset groups. Some investigators have also taken the approach recommended by the World Health Organization in 1980 to examine functional adaptation in relation to impairment (based on organ disease), disability (related to personal quality of life),900 and handicap (related to society’s perception of the functioning ability of the individual).901 A study by Peterson and colleagues902 from the Mayo Clinic evaluated the physical and psychosocial impacts of disease in a population-based cohort of 44 adults who had experienced onset of the disease during childhood. Controls (102)

TABLE 9–14 Functional Outcome of Juvenile Rheumatoid Arthritis by the Childhood Health Assessment Questionnaire (CHAQ)

Type of Onset (n) Systemic (40) Pauciarticular (224) Polyarticular (RF−) (80) Polyarticular (RF+) (40)

CHAQ score

Follow-up (mean yr)

Mean

Range

11.6 12.5 12.6 13.9

0.25 0 0.19 0.62

0–2.75 0–2.13 0–2.75 0–3.0

RF, rheumatoid factor. Oen K, Malleson PN, Cabral DA, et al.: Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J Rheumatol 30: 585–593, 2003.

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were age- and sex-matched. Average follow-up was 24.7 years, and mean age was 34 years. The patients had greater disability, more bodily pain, increased fatigue, poorer health perception, and decreased physical functioning along with lower rates of employment and lower levels of exercise compared with the control group. On the other hand, educational achievement, annual income, health insurance status, and rates of pregnancy and childbirth were similar to those of the controls. Active disease was present in 66%, and 16% were under regular medical care for their arthritis. This study concluded that adults who had had chronic arthritis developed long-term physical and psychosocial impairments that have been often ignored in the evaluation of functional outcome. Many of the same outcomes and prognostic factors were identified in a study by Flato and colleagues of 268 patients with JRA who were monitored for a median of 14.9 years (range, 11.7 to 25.1 years).903 Another study from Norway904 included 53 patients with arthritis and 19 with juvenile spondyloarthropathy. Forty-three (60%) of the 72 patients were in a remission at the time of the study, and 60% reported no disability. This study and subsequent reports903,905 supported the conclusion that long-term outcome was more favorable than previously reported, perhaps related to less bias of admission to the study and the early use of more aggressive therapeutic regimens. This group of investigators had previously indicated that poor psychosocial functioning in 22% of the patients on follow-up was associated with premorbid psychosocial dysfunction, chronic family difficulties, and major life events.905 They also confirmed that approximately 19% of the patients were still suffering from chronic pain without evidence of active arthritis.904 It is also the impression of the authors, and of others,943 that a chronic pain syndrome may persist in these patients well after their arthritis has remitted. A number of investigations of adaptation to chronic illnesses in children have been completed recently.869,870,906–909 Studies of adaptation have been limited by assumptions that disease groups of chronic illnesses are homogeneous and that comprehensive adaptation models involve both risk factors and resistance factors within the child and family. In one study, 107 children with JRA,869 114 with insulin-dependent diabetes mellitus, and 88 healthy controls were evaluated every 6 months for 2 years. Differences were observed between mothers and fathers with regard to dependent variables of depression, anxiety, somatization, strain at work, days of work loss due to child’s illness, and extent to which the illness interfered with leisure time in the family. Married mothers missed more work than fathers but demonstrated less overall functional impairment. Single mothers did not differ from married mothers or fathers. The dependent variables—particularly those related to depression, anxiety, and strain at work—decreased for all parents during the 2 years of observation. Premorbid diagnostic groups were associated with maternal depression and paternal distress in passive coping. Parental depression and distress were associated with the child’s behavior in the illness, complaints of pain, and ability to deal with anger and disappointment. Anger level and anger expression styles were highly associated with depression.910 Children who turned their anger inward were most likely to report depression. The child’s functioning did not appear to be related to the clinical diagnostic group. Trajectories within the child’s and family’s adaptations could be identified independent of the diagnostic groups.870 This and other studies911 have concluded that interventions to ameliorate parental distress certainly have beneficial effects on child behavior and on parental reactions to that behavior and the chronic illness.431,912–915 The unreimbursed cost to the family of a child with a chronic rheumatic disease per year is considerable.916 Transition of the child to young-adult identification, vocational planning, and eventually a place in adult life has been

the subject of a number of studies. Excellent summaries are contained in publications by Spencer and colleagues,917 Chamberlain and Rooney,918 and White.919–921

Death In early studies of chronic arthritis in children, the overall death rate was 1% to 4%.922,923 The disease-associated death rate is now perhaps less than 1% in Europe and less than 0.3% in North America. This mortality represents, however, a 4- to 14-fold increase compared with standardized rates. In a study from England,924 the standardized mortality ratio was 3.4 for males (95% CI, 2.0 to 5.5) and 5.1 for females (95% CI, 3.2 to 7.8). The majority of the deaths in Europe were previously related to the development of amyloidosis 925; in the United States, deaths occurred predominantly in children with systemiconset disease and in many cases were related to infection. Infections were associated in the early studies with glucocorticoid therapy and are currently less often fatal. The major causes of death in 46 children observed by Bywaters at Taplow926,927 were renal failure (which in half of the children was associated with amyloidosis) and infections. At the 15-year evaluation, excess mortality was identified in girls who developed arthritis early in life and the frequency of amyloidosis had risen to 7.4%. It was rarely observed as early as 1 year after onset but could develop as late as 23 years, most commonly in children with systemic disease. Spontaneous remissions occurred. Even in Europe, amyloidosis as a complication of chronic arthritis appears to be on the decline, with a decreasing number of deaths784,928,929; however, a recent series from Turkey reported a frequency of 10%.930 Amyloidosis refers to the tissue deposition of the fibrillar protein amyloid.931 Secondary amyloidosis occurs as a complication of chronic inflammatory conditions such as arthritis or infection and in diseases such as familial Mediterranean fever. It is characterized clinically by proteinuria and the nephrotic syndrome, diarrhea, hepatosplenomegaly, or unexplained anemia in a child with profound hypergammaglobulinemia. Amyloidosis may be preceded by marked elevations of CRP, an acute phase reactant that is similar in structure to serum amyloid A (SAA) protein.932 SAA protein responds as an acute phase reactant and is increased in concentration in children with active disease. Although no HLA associations have been confirmed in children who develop amyloidosis,933 a genetic marker for the amyloid P component was identified in one study by restriction fragment length polymorphism.934 Secondary amyloidosis as a complication of chronic arthritis is exceedingly rare in North America but occurs in approximately 5 to 7% of children in certain areas of the world, particularly England, Scandinavia, Poland, and Germany.935 Diagnosis is confirmed by examination of tissue sections stained by Congo red dye. Under the polarizing microscope, amyloid deposits assume a green color that is virtually pathognomonic.936 Rectal submucosa is the most frequently recommended biopsy site; renal biopsy may be hazardous because of an increased tendency toward bleeding. Radionuclide imaging using radioiodinated autologous serum amyloid P is a noninvasive technique for diagnosis and monitoring.937,938

PERSPECTIVE In spite of new insights into causation and considerable advances in treatment, chronic arthritis remains an important cause of chronic pain and disability in child-

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hood. Particularly when considering heroic pharmacologic therapy, one should remember that the disease is often self-limited, albeit after years of activity, and is seldom fatal. On the other hand, undue delay in instituting advanced treatment that may be effective can result in irretrievable damage to joints and other visceral organs and impaired skeletal maturation. The art of medicine is at least as important as its science in guiding the pediatric rheumatologist’s planning of a therapeutic approach. An important factor working in favor of the program of management is the child’s unceasing potential for growth. To a large extent, it is this intrinsic endowment for future physical and psychologic development that enables so much to be accomplished in most children. Even so, much work remains in clarifying the nature and management of these diseases and their complications.

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814. Clarkson RW, Sanders PA, Grennan DM: Complement C4 null alleles as a marker of gold or D-penicillamine toxicity in the treatment of rheumatoid arthritis. Br J Rheumatol 31: 53–54, 1992. 815. Wulffraat NM, Vlieger A, Brinkman JP, et al: Autologus stem cell transplantation (ASCT) in retractory polyarticular and systemic JCA. Arthritis Rheum 41: S129, 1998. 816. Quartier P, Prieur AM, Fischer A: Haemopoietic stem-cell transplantation for juvenile chronic arthritis. Lancet 353: 1885–1886, 1999. 817. Kuis W, Wulffraat NM, Petty RE: Autologous stem cell transplantation: an alternative for refractory juvenile chronic arthritis. Rheumatology (Oxf) 38: 737–738, 1999. 818. Wulffraat NM, Kuis W: Autologous stem cell transplantation: a possible treatment for refractory juvenile chronic arthritis? Rheumatology (Oxf) 38: 764–766, 1999. 819. Wulffraat NM, Kuis W, Petty R: Addendum: Proposed guidelines for autologous stem cell transplantation in juvenile chronic arthritis. Paediatric Rheumatology Workshop. Rheumatology (Oxf) 38: 777–778, 1999. 820. Vossen JM, Brinkman DM, Bakker B, et al: Rationale for high-dose cyclophosphamide and medium-dose total body irradiation in the conditioning of children with progressive systemic and polyarticular juvenile chronic arthritis before autologous stem cell transplantation. Rheumatology (Oxf) 38: 762–763, 1999. 821. Tyndall A, Millikan S: Bone marrow transplantation. Baillieres Best Pract Res Clin Rheumatol 13: 719–735, 1999. 822. Lepore L, Kiren V: Autologous bone marrow transplantation versus alternative drugs in pediatric rheumatic diseases. Haematologica 85: 89–92, 2000. 823. Frosch M, Strey A, Vogl T, et al: Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum 43: 628–637, 2000. 824. Wulffraat M, de K, I, Brinkman D, et al: Autologous stem cell transplantation for refractory juvenile idiopathic artrhitis: current results and perspectives. Transplant Proc 34: 2925–2926, 2002. 825. Wedderburn LR, Abinun M, Palmer P, et al: Autologous haematopoietic stem cell transplantation in juvenile idiopathic arthritis. Arch Dis Child 88: 201–205, 2003. 826. DeKleer IM, Brinkman DM, Ferster A, et al: Autologous stem cell transplantation for refractory Juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity. Ann Rheum Dis 63: 1318–1326, 2004. 827. Wulffraat NM, Brinkman D, Ferster A, et al: Long-term follow-up of autologous stem cell transplantation for refractory juvenile idiopathic arthritis. Bone Marrow Transplant 32 Suppl 1: S61–S64, 2003. 828 Wulffraat NM, Haas PJ, Frosch M, et al: Myeloid related protein 8 and 14 secretion reflects phagocyte activation and correlates with disease activity in juvenile idiopathic arthritis treated with autologous stem cell transplantation. Ann Rheum Dis 62: 236–241, 2003. 829. Schulze zur Wiesch A, Foell D, Frosch M, et al: Myeloid related proteins MRP8/MRP14 may predict disease flares in juvenile idiopathic arthritis. Clin Exp Rheumatol 22: 368–373, 2004. 830. Hopp RJ, Degan J, Corley K, et al: Evaluation of growth hormone secretion in children with juvenile rheumatoid arthritis and short stature. Nebr Med J 80: 52–57, 1995. 831. Bechtold S, Ripperger P, Hafner R, et al: Growth hormone improves height in patients with juvenile idiopathic arthritis: 4-year data of a controlled study. J Pediatr 143: 512–519, 2003. 832. Allen DB, Goldberg BD: Stimulation of collagen synthesis and linear growth by growth hormone in glucocorticoid-treated children. Pediatrics 89: 416–421, 1992. 833. Simon D, Touati G, Prieur AM, et al: Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl 88: 100–105, 1999. 834. Touati G, Prieur AM, Ruiz JC, et al: Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition [published erratum appears in J Clin Endocrinol Metab 83: 1547, 1998]. J Clin Endocrinol Metab 83: 403–409, 1998. 835. Manfredi R, Tumietto F, Azzaroli L, et al: Growth hormone (GH) and the immune system: impaired phagocytic function in children with idiopathic GH deficiency is corrected by treatment with biosynthetic GH. J Pediatr Endocrinol 7: 245–251, 1994. 836. Broyer M, Guest G, Crosnier H, et al: Recombinant growth hormone in children after renal transplantation. Societe Francaise de Nephrologie Pediatrique. Lancet 343: 539–540, 1994. 837. Crosnier H, Guest G, Souberbielle JC, et al: Treatment with recombinant human growth hormone (rhGH) in children with chronic kidney failure or renal transplantation. Arch Pediatr 1: 716–722, 1994. 838. Cheung NW, Liddle C, Coverdale S, et al: Growth hormone treatment increases cytochrome P450-mediated antipyrine clearance in man. J Clin Endocrinol Metab 81: 1999–2001, 1996. 839. Henderson CJ, Lovell DJ, Specker BL, et al: Physical activity in children with juvenile rheumatoid arthritis: quantification and evaluation. Arthritis Care Res 8: 114–119, 1995.

840. Knops N, Wulffraat N, Lodder S, et al: Resting energy expenditure and nutritional status in children with juvenile rheumatoid arthritis. J Rheumatol 26: 2039–2043, 1999. 841. Martini A, Ravelli A, Di Fuccia G, et al: Intravenous iron therapy for severe anaemia in systemic-onset juvenile chronic arthritis. Lancet 344: 1052–1054, 1994. 842. Henderson CJ, Lovell DJ: Nutritional aspects of juvenile rheumatoid arthritis. Rheum Dis Clin North Am 17: 403–413, 1991. 843. Hafner R, Truckenbrodt H, Spamer M: Rehabilitation in children with juvenile chronic arthritis. Baillieres Clin Rheumatol 12: 329–361, 1998. 844. Takken T, van der NJ, Kuis W, et al: Physical activity and health related physical fitness in children with juvenile idiopathic arthritis. Ann Rheum Dis 62: 885–889, 2003. 845. Klepper SE: Exercise and fitness in children with arthritis: evidence of benefits for exercise and physical activity. Arthritis Rheum 49: 435–443, 2003. 846. Frigo C, Bardare M, Corona F, et al: Gait alterations in patients with juvenile chronic arthritis: a computerized analysis. J Orthop Rheumatol 9: 82–90, 1996. 847. Lovell DJ, Walco GA: Pain associated with juvenile rheumatoid arthritis. Pediatr Clin North Am 36: 1015–1027, 1989. 848. Schanberg LE, Sandstrom MJ: Causes of pain in children with arthritis. Rheum Dis Clin North Am 25: 31–53, 1999. 849. Arden GP, Ansell BM: Surgical Management of Juvenile Chronic Polyarthritis. London, Academic Press, 1978. 850. Arden GP: Surgical treatment of juvenile rheumatoid arthritis. Ann Chir Gynaecol Suppl 198: 103–109, 1985. 851. Greene WB: Surgical alternatives for adolescents with severe arthritis. Bull Rheum Dis 43: 3–5, 1994. 852. Pahle JA: Orthopaedic management of juvenile chronic arthritis (JCA). Z Rheumatol 55: 376–387, 1996. 853. Swann M: The surgery of juvenile chronic arthritis. An overview. Clin Orthop 70–75, 1990. 854. Hamalainen M: Surgical treatment of juvenile rheumatoid arthritis. Clin Exp Rheumatol 12 (Suppl 10): S107–S112, 1994. 855. Price CT: Are we there yet? Management of limb-length inequality. J Pediatr Orthop 16: 141–143, 1996. 856. Simon S, Whiffen J, Shapiro F: Leg-length discrepancies in monoarticular and pauciarticular juvenile rheumatoid arthritis. J Bone Joint Surg Am 63: 209–215, 1981. 857. Rydholm U, Brattstrom H, Bylander B, et al: Stapling of the knee in juvenile chronic arthritis. J Pediatr Orthop 7: 63–68, 1987. 858. Granberry WM: Synovectomy in juvenile rheumatoid arthritis. Arthritis Rheum 20: 561–564, 1977. 859. Jacobsen ST, Levinson JE, Crawford AH: Late results of synovectomy in juvenile rheumatoid arthritis. J Bone Joint Surg Am 67: 8–15, 1985. 860. Rydholm U, Elborgh R, Ranstam J, et al: Synovectomy of the knee in juvenile chronic arthritis. A retrospective, consecutive follow-up study. J Bone Joint Surg Br 68: 223–228, 1986. 861. Swann M, Ansell BM: Soft-tissue release of the hips in children with juvenile chronic arthritis. J Bone Joint Surg Br 68: 404–408, 1986. 862. Kvien TK, Pahle JA, Hoyeraal HM, et al: Comparison of synovectomy and no synovectomy in patients with juvenile rheumatoid arthritis. A 24-month controlled study. Scand J Rheumatol 16: 81–91, 1987. 863. Hafner R, Pieper M: Arthroscopic synovectomy of the knee joint in chronic juvenile arthritis. Z Rheumatol 54: 165–170, 1995. 864. Parvizi J, Lajam CM, Trousdale RT, et al: Total knee arthroplasty in young patients with juvenile rheumatoid arthritis. J Bone Joint Surg Am 85: 1090–1094, 2003. 865. Surgeon General’s Report: Children with Special Health Care Needs. Commitment to Family-Centered, Community-Based, Coordinated Care. Bethesda, MD: U.S. Department of Health and Human Services, 1987. 866. Athreya BH, McCormick MC: Impact of chronic illness on families. Rheum Dis Clin North Am 13: 123–131, 1987. 867. Rapoff MA, Lindsley CB, Christophersen ER: Parent perceptions of problems experienced by their children in complying with treatments for juvenile rheumatoid arthritis. Arch Phys Med Rehabil 66: 427–429, 1985. 868. Kroll T, Barlow JH, Shaw K: Treatment adherence in juvenile rheumatoid arthritis—a review. Scand J Rheumatol 28: 10–18, 1999. 869. Frank RG, Hagglund KJ, Schopp LH, et al: Disease and family contributors to adaptation in juvenile rheumatoid arthritis and juvenile diabetes. Arthritis Care Res 11: 166–176, 1998. 870. Frank RG, Thayer JF, Hagglund KJ, et al: Trajectories of adaptation in pediatric chronic illness: the importance of the individual. J Consult Clin Psychol 66: 521–532, 1998. 871. Pless IB, Satterwhite B, Van Vechten D: Division, duplication and neglect: patterns of care for children with chronic disorders. Child Care Health Dev 4: 9–19, 1978. 872. Oen K, Malleson PN, Cabral DA, et al: Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J Rheumatol 30: 585–593, 2003. 873. Dempster H, Porepa M, Young N, et al: The clinical meaning of functional outcome scores in children with juvenile arthritis. Arthritis Rheum 44: 1768–1774, 2001. 874. Michels H: The chronically ill child with rheumatoid arthritis. Z Arztl Fortbild Qualitatssich 91: 219–226, 1997.

C H A P T E R 875. Michels H, Hafner R, Morhart R, et al: Five year follow-up of a prospective cohort of juvenile chronic arthritis with recent onset. Clin Rheumatol 6 Suppl 2: 87–92, 1987. 876. Billings AG, Moos RH, Miller JJ III, et al: Psychosocial adaptation in juvenile rheumatic disease: a controlled evaluation. Health Psychol 6: 343–359, 1987. 877. Fantini F, Gerloni V, Gattinara M, et al: Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year followup. J Rheumatol 30: 579–584, 2003. 878. Aptekar RG, Decker JL, Bujak JS, et al: Adult onset juvenile rheumatoid arthritis. Arthritis Rheum 16: 715–718, 1973. 879. Hill RH, Herstein A, Walters K: Juvenile rheumatoid arthritis: follow-up into adulthood—medical, sexual and social status. Can Med Assoc J 114: 790–796, 1976. 880. FitzGerald O, Bresnihan B: Juvenile chronic arthritis: spectrum of disease in an adult rheumatology department. Ir J Med Sci 155: 266–271, 1986. 881. Zak M, Pedersen FK: Juvenile chronic arthritis into adulthood: a long-term follow-up study. Rheumatology (Oxf) 39: 198–204, 2000. 882. Guillaume S, Prieur AM, Coste J, et al: Long-term outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis. Arthritis Rheum 43: 1858–1865, 2000. 883. Lomater C, Gerloni V, Gattinara M, et al: Systemic onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive patients followed for 10 years. J Rheumatol 27: 491–496, 2000. 884. Spiegel LR, Schneider R, Lang BA, et al: Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum 43: 2402–2409, 2000. 885. Hafner R, Truckenbrodt H: Course and prognosis of systemic juvenile chronic arthritis—retrospective study of 187 patients. Klin Padiatr 198: 401–407, 1986. 886. Schuchmann L, Michels H, Morhart R, et al: Prospective observation study on the clinical course of chronic juvenile arthritis (JCA). Monatsschr Kinderheilkd 134: 164–167, 1986. 887. Packham JC, Hall MA: Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxf) 41: 1428–1435, 2002. 888. Packham JC, Hall MA, Pimm TJ: Long-term follow-up of 246 adults with juvenile idiopathic arthritis: predictive factors for mood and pain. Rheumatology (Oxf) 41: 1444–1449, 2002. 889. Packham JC, Hall MA: Long-term follow-up of 246 adults with juvenile idiopathic arthritis: social function, relationships and sexual activity. Rheumatology (Oxf) 41: 1440–1443, 2002. 890. Packham JC, Hall MA: Long-term follow-up of 246 adults with juvenile idiopathic arthritis: education and employment. Rheumatology (Oxf) 41: 1436–1439, 2002. 891. Minden K, Niewerth M, Listing J, et al: Long-term outcome in patients with juvenile idiopathic arthritis. Arthritis Rheum 46: 2392–2401, 2002. 892. Oen K: Long-term outcomes and predictors of outcomes for patients with juvenile idiopathic arthritis. Best Pract Res Clin Rheumatol 16: 347–360, 2002. 893. Foster HE, Marshall N, Myers A, et al: Outcome in adults with juvenile idiopathic arthritis: a quality of life study. Arthritis Rheum 48: 767–775, 2003. 894. Ravelli A: Toward an understanding of the long-term outcome of juvenile idiopathic arthritis. Clin Exp Rheumatol 22: 271–275, 2004. 895. Bowyer SL, Roettcher PA, Higgins GC, et al: Health status of patients with juvenile rheumatoid arthritis at 1 and 5 years after diagnosis. J Rheumatol 30: 394–400, 2003. 896. Brunner HI, Giannini EH: Health-related quality of life in children with rheumatic diseases. Curr Opin Rheumatol 15: 602–612, 2003. 897. Selvaag AM, Flato B, Lien G, et al: Measuring health status in early juvenile idiopathic arthritis: determinants and responsiveness of the child health questionnaire. J Rheumatol 30: 1602–1610, 2003. 898. Oen K, Malleson PN, Cabral DA, et al: Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort. J Rheumatol 29: 1989–1999, 2002. 899. Oen K, Reed M, Malleson PN, et al: Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis. J Rheumatol 30: 832–840, 2003. 900. LeBovidge JS, Lavigne JV, Donenberg GR, et al: Psychological adjustment of children and adolescents with chronic arthritis: a meta-analytic review. J Pediatr Psychol 28: 29–39, 2003. 901. Hutchison T: The classification of disability. Arch Dis Child 73: 91–93, 1995. 902. Peterson LS, Mason T, Nelson AM, et al: Psychosocial outcomes and health status of adults who have had juvenile rheumatoid arthritis: a controlled, population-based study. Arthritis Rheum 40: 2235–2240, 1997. 903. Flato B, Lien G, Smerdel A, et al: Prognostic factors in juvenile rheumatoid arthritis: a case-control study revealing early predictors and outcome after 14.9 years. J Rheumatol 30: 386–393, 2003. 904. Flato B, Aasland A, Vinje O, et al: Outcome and predictive factors in juvenile rheumatoid arthritis and juvenile spondyloarthropathy. J Rheumatol 25: 366–375, 1998. 905. Aasland A, Flato B, Vandvik IH: Psychosocial outcome in juvenile chronic arthritis: a nine-year follow-up. Clin Exp Rheumatol 15: 561–568, 1997.

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906. Carter BD, Kronenberger WG, Edwards JF, et al: Psychological symptoms in chronic fatigue and juvenile rheumatoid arthritis. Pediatrics 103: 975–979, 1999. 907. Huygen AC, Kuis W, Sinnema G: Psychological, behavioural, and social adjustment in children and adolescents with juvenile chronic arthritis. Ann Rheum Dis 59: 276–282, 2000. 908. Noll RB, Kozlowski K, Gerhardt C, et al: Social, emotional, and behavioral functioning of children with juvenile rheumatoid arthritis. Arthritis Rheum 43: 1387–1396, 2000. 909. von Weiss RT, Rapoff MA, Varni JW, et al: Daily hassles and social support as predictors of adjustment in children with pediatric rheumatic disease. J Pediatr Psychol 27: 155–165, 2002. 910. Hagglund KJ, Clay DL, Frank RG, et al: Assessing anger expression in children and adolescents. J Pediatr Psychol 19: 291–304, 1994. 911. Cassidy JT, Johnson JC, Hewett JE, et al: Parental distress in families of children with juvenile rheumatoid arthritis. Arthritis Rheum 37: S405, 1994. 912. Press J, Neumann L, Uziel Y, et al: Assessment of quality of life of parents of children with juvenile chronic arthritis. Clin Rheumatol 21: 280–283, 2002. 913. Wagner JL, Chaney JM, Hommel KA, et al: The influence of parental distress on child depressive symptoms in juvenile rheumatic diseases: the moderating effect of illness intrusiveness. J Pediatr Psychol 28: 453–462, 2003. 914. Gerhardt CA, Vannatta K, McKellop JM, et al: Comparing parental distress, family functioning, and the role of social support for caregivers with and without a child with juvenile rheumatoid arthritis. J Pediatr Psychol 28: 5–15, 2003. 915. Reiter-Purtill J, Gerhardt CA, Vannatta K, et al: A controlled longitudinal study of the social functioning of children with juvenile rheumatoid arthritis. J Pediatr Psychol 28: 17–28, 2003. 916. Allaire SH, DeNardo BS, Szer IS, et al: The economic impacts of juvenile rheumatoid arthritis. J Rheumatol 19: 952–955, 1992. 917. Spencer CH, Fife RZ, Rabinovich CE: The school experience of children with arthritis. Coping in the 1990s and transition into adulthood. Pediatr Clin North Am 42: 1285–1298, 1995. 918. Chamberlain MA, Rooney CM: Young adults with arthritis: meeting their transitional needs. Br J Rheumatol 35: 84–90, 1996. 919. White PH: Future expectations: adolescents with rheumatic diseases and their transition into adulthood. Br J Rheumatol 35: 80–83, 1996. 920. White PH: Resilience in children with disabilities—transition to adulthood. J Rheumatol 23: 960–962, 1996. 921. White PH: Success on the road to adulthood. Issues and hurdles for adolescents with disabilities. Rheum Dis Clin North Am 23: 697–707, 1997. 922. Baum J, Gutowska G: Death in juvenile rheumatoid arthritis. Arthritis Rheum Suppl 20: 253, 1977. 923. Bernstein B: Death in juvenile rheumatoid arthritis. Arthritis Rheum Suppl 20: 256, 1977. 924. Thomas E, Symmons DP, Brewster DH, et al: National study of cause-specific mortality in rheumatoid arthritis, juvenile chronic arthritis, and other rheumatic conditions: a 20 year followup study. J Rheumatol 30: 958–965, 2003. 925. Schuchmann L, Michels H, Renaud M, et al: Amyloidosis—a dreaded complication of juvenile chronic arthritis (JCA) (author’s transl). Klin Padiatr 193: 67–72, 1981. 926. Bywaters EGL: Deaths in juvenile chronic polyarthritis. Arthritis Rheum Suppl 20: 256, 1977. 927. Arden GP: Sepsis in juvenile chronic polyarthritis. In Arden GP, Ansell BM (eds): Surgical Management of Juvenile Chronic Polyarthritis. London, Academic Press, 1978, p 225. 928. David J, Vouyiouka O, Ansell BM, et al: Amyloidosis in juvenile chronic arthritis: a morbidity and mortality study. Clin Exp Rheumatol 11: 85–90, 1993. 929. Ansell BM: Chlorambucil therapy in juvenile chronic arthritis (juvenile idiopathic arthritis). J Rheumatol 26: 765–766, 1999. 930. Ozdogan H, Kasapcopur O, Dede H, et al: Juvenile chronic arthritis in a Turkish population. Clin Exp Rheumatol 9: 431–435, 1991. 931. Woo P: Amyloidosis in pediatric rheumatic diseases. J Rheumatol Suppl 35: 10–16, 1992. 932. Gwyther M, Schwarz H, Howard A, et al: C-reactive protein in juvenile chronic arthritis: an indicator of disease activity and possibly amyloidosis. Ann Rheum Dis 41: 259–262, 1982. 933. Burman SJ, Hall PJ, Bedford PA, et al: HLA antigen frequencies among patients with juvenile chronic arthritis and amyloidosis: a brief report. Clin Exp Rheumatol 4: 261–263, 1986. 934. Woo P, O’Brien J, Robson M, et al: A genetic marker for systemic amyloidosis in juvenile arthritis. Lancet 2: 767–769, 1987. 935. Michels H, Linke RP: Clinical benefits of diagnosing incipient AA amyloidosis in pediatric rheumatic diseases as estimated from a retrospective study. Amyloid 5: 200–207, 1998. 936. Linke RP, Gartner HV, Michels H: High-sensitivity diagnosis of AA amyloidosis using Congo red and immunohistochemistry detects missed amyloid deposits. J Histochem Cytochem 43: 863–869, 1995. 937. Hawkins PN, Myers MJ, Lavender JP, et al: Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component. Lancet 1: 1413–1418, 1988.

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938. Hawkins PN, Richardson S, Vigushin DM, et al: Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis. Arthritis Rheum 36: 842–851, 1993. 939. Jeremy R, Schaller J, Arkless R, et al: Juvenile rheumatoid arthritis persisting into adulthood. Am J Med 45: 419–434, 1968. 940. Ansell BM, Wood PHN: Prognosis in juvenile chronic polyarthritis. Clin Rheum Dis 2: 397–412, 1976.

941. Hanson V, Kornreich H, Bernstein B, et al: Prognosis of juvenile rheumatoid arthritis. Arthritis Rheum 20: 279–284, 1977. 942. Stoeber E: Prognosis in juvenile chronic arthritis. Follow-up of 433 chronic rheumatic children. Eur J Pediatr 135: 225–228, 1981. 943. Rapoff MA, Lindsley CB: The pain puzzle: a visual and conceptual metaphor for understanding and treating pain in pediatric rheumatic disease. J. Rheuatol 27 9Suppl 58); 29–33, 2000.

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( HAP T E R

POLYARTHRITIS Ross E. Petty and James T. Cassidy

~

DEFINmONS In all systems of classification of childhood arthritis, arthritis that affects more than four joints during the first 6 months of disease is defined as polyarthritis. 1-3 In the classification of the International League of Associations for Rheumatology (ILAR),3 polyarthritis is further defined as rheumatoid factor (RF)-negative if tests for RF are negative, and RF-positive if RF is detected on two occasions at least 3 months apart. The lLAR classification requires the application of exclusion criteria (Table 10-1). This chapter considers both RF-negative and RF-positive polyarthritis.

a later peak between the ages of 6 and 12 years. HIt is likely that the older group represents disease that is similar to, if not identical to, adult rheumatoid arthritis.

Sex Ratio Polyarthritis is predominantly a disease of girls, and the reported ratio of girls to boys using the ACR criteria was 3.5 to 1,9 In a study using the EULAR criteria,6 this ratio was 4.5:1.

Geographic and Racial Distribution EPIDEMIOLOGY Polyarthritis accounts for approximately 30% of patients with juvenile idiopathic arthritis OIA). A small proportion of these patients (perhaps 3% to 5%)4 are RF positive, although this proportion is as high as 42% in Native Canadian children. s

Incidence and Prevalence There are no large studies of the incidence and prevalence of polyarthritis, and estimates derived from reported investigations vary widely. In one study, Moe and Rygg6 estimated the incidence of polyarthritis (RFpositive or -negative) in northern Norway at approximately, 8.9/100,000 children per year and the point prevalence at 54.2/100,000 (European League Against Rheumatism [EULAR] criteria). In a trans-Canadian registry of patients seen in pediatric rheumatology clinics,7 polyarticular juvenile rheumatoid arthritis ORA) had an incidence of 0.49/100,000 children per year (American College of Rheumatology [ACR] criteria). These great discrepancies are not readily explicable, although genetic differences may be important. Both studies were registry based; the number of patients in the Norwegian study was only 43, whereas 154 children with polyarthritis were included in the Canadian study.

Age at Onset Using the ACR criteria for polyarticular JRA, the distribution of ages at onset appears to be biphasic (Fig. 10-1), with an early peak between the ages of 1 and 4 years and

Boyer and colleagues lO suggested that the incidence of RF-positive polyarthritis (ACR criteria) is increased in Southeast Alaska. In an extensive review of the epidemiology of childhood arthritis, Oen and Cheang ll analyzed the reported proportion of children with polyarthritis in different racial groups. Polyarthritis accounted for a much higher proportion of East Indian (61%), and North American Indian (64%) children with chronic arthritis, compared with white children (27%).

ETIOLOGY AND PATHOGENESIS The etiology of polyarthritis is unknown. The immunoinflammatory pathogenesis is multifactorial and is discussed in Chapter 9. No environmental agent has been consistently associated with polyarthritis, but it is likely that genetic polymorphisms play an important role, particularly in RF-positive polyarthritis. Interleukins, cytokines, and other products of inflammatory cells, such as macrophages and T lymphocytes, are undoubtedly involved in disease pathogenesis (see Chapter 3) A pro-inflammatory cytokine profile predominates. Most studies of cytokines in children with polyarthritis have not distinguished between children with and without RF. In general, the soluble interleukin-2 receptor (SIL-2R) is moderately increased in the blood J2-16 and synovial fluid, J6 and its level correlates with the activity of the arthritis. There is increased IL-1a16 in the blood, and IL1[3,16 IL-6, IL-1a, and tumor necrosis factor-a (TNF-a)l7 in the synovial fluid. The soluble TNF-a receptor p55 is increased in both,12.IH but the ratio of sTNF to TNF-a may be low. 19 Serum levels of IL-6 are higher in polyarthritis

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• TABLE 10 1

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POLYARTHRITIS

ILAR Crilerid for C1dssificatioll of Polyarthritis

RF-Negatlve Polyarthrftls Arthritis affecting five or more joints during the first 6 mo of disease; a test for RF is negative Exclusions: • Psoriasis or a history of psoriasis in the patient or first-degree relative • Arthritis in an HLA-B27-positive male beginning after the sixth birthday • Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter's syndrome, or acute anterior uveitis or a history of one of these disorders in a firstdegree relative • IgM RF on at least two occasions at least 3 mo apart • The presence of systemic ]IA in the patient

RF-Posltlve Polyarthrftls Arthritis affecting five or more joints during the first 6 mo of disease; two or more tests for RF at least 3 mo apart during the first 6 mo of disease are positive Exclusions: • Psoriasis or a history of psoriasis in the patient or first-degree relative • Arthritis in an HLA-B27-positive male beginning after the sixth birthday • Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter's syndrome, or acute anterior uveitis or a history of one of these disorders in a firstdegree relative • The presence of systemic ]IA in the patient IgM, immunoglobulin M; lLAR, International League of Associations for Rheumatology; ]lA, juvenile idiopathic artbritis; RF, rheumatoid factor,

B cells are not necessary for the development of inflammatory joint disease such as polyarthritis, and children with agammaglobulinemia may develop inflammatory joint disease. Immune complexes were detected in 64% of children with polyarticular JRA, especially those with active disease. 23 In 24%, immunoglobulin A (IgA)-containing immune complexes were present, and in synovial fluid immune complexes containing IgA, but not IgM, were detected.

GENETIC BACKGROUND Polyarthritis is seldom familial; if two siblings are affected with ]IA, concordance for polyarticular onset type is 42%.9 The human leukocyte antigen alleles HLA-Dw4, -DR1, and -DR4 are risk factors for polyarthritis. 24- 29 DRI (DQA1*OlOl) is also a risk factor for polyarthritis in older children and is associated with TCR-~6S1 null alleles. 24 The strong association between RF-seropositive polyarthritis and DR4-related susceptibility alleles and their shared epitope parallels that in RF-seropositive rheumatoid arthritis (RA) in adults. White children with RFseropositive polyarthritis have a high frequency of two copies of alleles of DR4, particularly for the combinations of Dw4 (DRB1*0401) and Dw14 (DRB1*0404)Y·29 Data from a study of Native Canadian children indicated that DRB1*0901 may be a risk factor in that population, whereas DRBl*08 alleles were possibly protective. 50 Inconsistent HLA typing has been found in RF-negative polyarthritis. Dw4 is only slightly increased in frequency,31 but there are increases in the frequencies of DRS, DR8, and DP3Y-35 These data support the understanding that children with RF have a disease that is different from that of children without RF, but they also suggest that RF-negative polyarthritis may, in itself, be quite heterogeneous. Genes outside the major histocompatibility locus also play a part in predisposition to ]IA, although most studies have examined these relationships in systemic arthritis or oligoarthritis. 36

CLINICAL MANIFESTATIONS

2

In children with polyarthritis, articular disease predominates, although systemic features occur in some patients. Children with RF-positive polyarthritis tend to have more severe disease than those who are RF negative, and they are subject to the development of rheumatoid nodules and, rarely, vasculitis.

Joint Disease (particularly in those with active disease) than in controls, but not as high as in those with systemic ]IA.20 Levels of IL12 were also associated with active disease in this study.20 Serum levels of adhesion molecules sE-selectin, sPselectin, and soluble intercellular adhesion molecule-l (sICAM-l) were not increased in children with active polyarticular ]IA. 21 RF may have a pathogenic role as a component of immune complexes, in fixing complement, and in causing damage to blood vessels in synovium,22 but it has been demonstrated that

Children with arthritis in five or more joints during the first 6 months of disease (Fig. 10-2), are classified as having arthritis of polyarticular onset by the ACR criteria!; as having either polyarticular onset (if RF negative) or ]RA (if RF positive) by the EULAR criteria 2; and as haVing RFnegative or RF-positive polyarthritis by the lLAR classitlcation (see Table 10-1).3 Onset may be acute, but it is more often insidious, with progressive involvement of additional joints. Morning stiffness or gelling after inactivity is an important indicator of active arthritis and may persist for hours, or occasionally all day. The arthritis

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Systemic Manifestations Systemic manifestations in children with polyarthritis include low-grade fever, anorexia, growth failure, and, occasionally, weight loss. Fatigue may be a prominent symptom, particularly in children with RF-positive polyarthritis. There may be slight-to-moderate hepatosplenomegaly or lymphadenopathy, but this is less prominent than in children with systemic JIA. Chronic asymptomatic uveitis develops less frequently 00%) than in early-onset oligoarticular disease and is more common in children with RF-negative compared with RF-positive polyarthritis (see Chapter 11). • figure 10-2 Symmetric polyarthritis affecting the metacarpophalangeal, proximal interphalangeal, and radiocarpal joints.

may be remittent or indolent, tends to be symmetric, and usually involves the large joints of the knees, wrists, elbows, and ankles. The cervical spine and temporomandibular joints are often involved in polyarticular JRA. Small-joint disease of the hands or feet may occur early or late in the course of the disease. 37 The interphalangeal joint of the thumb, the second and third metacarpophalangeal (MCP) joints, and the proximal interphalangeal (PIP) joints are most commonly involved; the other MCP and PIP joints are less frequently involved. The distal interphalangeal (DIP) joints are affected in 10% to 45% of children in association with involvement of the other small joints. The joints are swollen and warm but usually are not erythematous. Often, the digits exhibit soft tissue swelling between the joints as much as around them. Boutonniere deformities (PIP joint flexion and DIP hyperextension) and flexion contractures are more common than swan-neck deformities (PIP joint hyperextension and DIP flexion).38 Children with RF-positive polyarticular JIA have onset late in childhood or adolescence. These patients often develop a pattern of symmetric small and large joint involvement that resembles that of adult RA, with rheumatoid nodules, early onset of erosive synovitis, and a chronic course persisting well into adulthood. In children with RF-seronegative polyarthritis, there is less tendency for the disease to encompass a large number of joints, to be symmetric, to involve the small joints of the hands or feet, or to be associated with rheumatoid nodules. AnselP" found that the knees, wrists, and ankles were most commonly affected in children with polyarticular juvenile chronic arthritis OCA; EULAR criteria) and that the arthritis was usually symmetric. Approximately 20% of children had MCP joint disease, and a similar number, but not necessarily the same children, had PIP joint involvement. Approximately one fourth had involvement of the DIP joints. Joints of the second and third fingers were most commonly affected. Tenosynovitis of the dorsal flexor tendon sheaths of the hands occurred in one sixth of the patients, and in one or more of the other flexor tendons in one fifth. Involvement of a PIP joint or flexor tendon sheath was particularly common in children younger than 5 years of age. Arthritis of the metatarsophalangeal or PIP joints of the feet was also common.

Liem and Rosenberg40 studied growth in children with JRA and reported that in those with polyarthritis height-for-age Z scores (an expression of the number of standard deviations from the normal mean) fell slightly during the first 3 to 4 years of followup but returned to normal by 8 years after diagnosis. However, in those children with RF, the negative deviation was much more marked and prolonged, although it was statistically significantly different only at year 5. There was no demonstrable influence of corticosteroid use in this study. Evaluation of the Z scores for levels of alkaline phosphatase indicated that those children with RF polyarthritis had significantly higher scores by 4 years after diagnosis, an unexplained finding.

Nodules Rheumatoid nodules occur in 5% to 10% of children with JRA, almost always in those with RF-positive polyarthritis (Fig. 10-3).41-43 Nodules most frequently occur below the olecranon, but they also occur at other pressure points and on the digital flexor tendon sheaths, Achilles tendons, and occiput, as well as on the bridge of the nose in a child who wears glasses.

• AlIIIre 10-3 Multiple rheumatoid nodules over the metacarpophalangeal (MCP) and proximal interphalangeal joints were a constant feature of polyarticular JIA in this girl.They appeared over joints, pressure points, and tendon sheaths. Note also the radial deviation of the second and third MCP joints, the ulnar deviation of the radiocarpal joint, and the loss of extension of the interphalangeal joint of the thumb.

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Typical rheumatoid nodules are Hrm or hard, usually mobile, and nontender. The overlying skin may be erythematous. They may be solitary or multiple, may change in size over time, and they may persist for months to years. They are almost always associated with RF seropositivity, and in this respect they are generally regarded as a poor prognostic sign. Rheumatoid nodules must be distinguished from those of rheumatic fever and the so-called benign rheumatoid nodules that are not associated with objective arthritis (Table 10-2). Benign rheumatoid nodules or pseudorheumatoid nodules occur as isolated abnormalities in otherwise healthy children (Fig. 10-4).44-49 They are painless, may be single or multiple, and sometimes become quite large (greater than 5 cm). They occur especially over bony prominences such as the anterior tibia or scalp and are characterized by spontaneous regression and recurrence. They frequently recur after surgical excision. In a very few patients, arthritis may develop at an older age. 46 RF and antinuclear antibody (ANA) are absent. Histologically, they resemble the nodules of adult RA. Subcutaneous granuloma annulare, a relatively common disease in children, may be histologically indistinguishable from either rheumatoid or pseudorheumatoid nodules. 50 Its clinical appearance, location (shins, dorsum of the foot), umbilicated appearance, and the absence of other disease confirm the diagnosis. Other diseases, such as multicentric reticulohistiocytosis, are associated with subcutaneous nodules. 51

.' III TABLE 10 2 Nodules in Children with Rheumatic Diseases

Nodule Type

AssocIated Disease

Rheumatoid nodules Benign rheumatoid nodules Deep granuloma annulare Rheumatic fever nodules Extensor sheath nodules Calcinotic nodules

Polyarticular JRA No associated disease No associated disease Acute rheumatic fever Scleroderma Scleroderma Dermatomyositis Postinfectious Polyarteritis nodosa

Erythema nodosum Superficial aneurysms

Vasculitis Rheumatoid vasculitis is rare and occurs most often in the older child with RF-positive polyarthritis (Table 10-3; Fig. 10-5). This devastating, widespread complication involves small to medium-sized vessels and must be distinguished from the more frequent benign digital vasculitis (see Figure 9-8) and may occasionally be associated with vascular calcification that is apparent on radiographs along the course of the digital arteries. 52 •53 A second skin change has been described in children with polyarticular JRA.54 This consists of a dark coloration of the skin over the PIP joints of the fingers. The presence of this finding may reflect disease chronicity. In children with tender joints, retention keratosis may simulate a pigmented lesion.

Felty Syndrome Felty's syndrome, the presence of splenomegaly and neutropenia in a patient with RF-positive polyarthritis, is very rare in children and youth. 55

Cardiac Disease Small pericardiaI effusions may be detected on echocardiographs, but clinically evident pericarditis or pleuritiS is infrequent. Cardiac valve disease is an uncommon but important complication. Leak and associates 56 reported the occurrence of aortic regurgitation in four children with

I!' III

TABLE 10-3

Clinical Features of Rheumatoid Vaslllhlis

Fever Peripheral neuropathy Cutaneous ulcers Digital arteritis Raynaud's phenomenon Gastrointestinal hemorrhage Mesenteric thrombosis Myocardial infarction Nephritis

• Figure 10-4 A, Alarge benign rheumatoid nodule overlies the tibial tuberde in this young boy. 8,The lesion of granuloma annulare is histologically indistinguishable from the benign rheumatoid nodule shown in A. (8, Courtesy of Dr. J. Prendiville.)

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• FIgure 10-5 Systemic. necrotizing vasculitis in a 6-year-old boy with systemic. JIA. He developed widespread cutaneous and visceral vasculitis that led to his death 1 year after onset of disease.

RF-positive polyarthritis. Several other instances of aortic or mitral valve regurgitation have also been reported. 57.5S

Pulmonary Disease Pulmonary disease is rare, but interstitial pneumonitis59 and bronchiolitis obliterans6o have been reported. Rarely, pulmonary disease precedes the onset of arthritis. 60 A familial form of deforming RF-positive polyarthritis with pulmonary fibrosis and renal and cutaneous vasculitis has been reported,61 but it is unlikely that this represents simple JIA.

DIAGNOSIS The differential diagnosis of polyarthritis is considerably different from that of oligoarthritis (Table 10-4). Septic polyarthritis is unusual (see Chapter 28), although arthritis caused by Neisseria gonorrhoeae may have an early migrato!)' polyarticular phase, and infectious arthritis in children may involve more than one joint. Lyme disease may be polyarticular, but it can usually be differentiated

II III .-

TABU 10-4 Poly,nthrilis

Differential Diagnosis of Inflammatory

RF-Negative

RF-Posltlve

]IA polyarthritis RF-negative Enthesitis-related arthritis Inflammatory bowel disease Systemic ]IA Psoriatic ]IA Polyarthritis related to infection Lyme disease Reactive arthritis Sarcoidosis

]TA polyarthritis RF-positive Systemic lupus erythematosus

.rIA. juvenile idiopathic arthritis; RF. rheumatoid factor.

10

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from polyarticular JIA by its intermittent pattern of activity and the accompanying cutaneous, neurologic, and cardiac abnormalities (see Chapter 29). The onset of polyarthritis in a preadolescent or adolescent girl should suggest the possible diagnosis of systemic lupus erythematosus (SLE) (see Chapter 16), The arthritis of SLE may mimic that of JIA, and without serologic studies the correct diagnosis may be difficult or impossible to make until the later occurrence of one of the more characteristic clinical hallmarks of SLE: butterfly rash, alopecia, nephritis, central nervous system disease, Raynaud's phenomenon, leukopenia, or hemolytic anemia. Any of these clinical findings, or the presence of an active urinary sediment in a child with polyarthritis, strongly suggests the diagnosis of SLE. This diagnosis would be supported by the presence of anti-dsDNA antibodies or hypocomplementemia. Ragsdale and colleagues62 presented the course of 10 children who developed SLE after an initial diagnosis of JRA. In all cases, anti-dsDNA antibodies were detectable before the development of clinical disease characteristic of SLE. Raynaud's phenomenon in the child with polyarthritis should always include a differential diagnosis such as scleroderma, SLE, or mixed connective tissue disease; in the authors' experience, Raynaud's phenomenon is very rarely associated with JRA. Although anemia is common in severe polyarthritis, it is not Coombs' test positive, and the presence of hemolytic anemia would support the diagnosis of another connective tissue disease, usually SLE. The differential diagnosis of polyarthritis also includes enthesitis-related arthritis (ERA) (or juvenile ankylosing spondylitis), in which large-joint oligoarthropathy of the lower extremities usually predominates at onset rather than disease of the axial skeleton (see Chapter 13). Transient pain in the lower back or buttock may be an early sign. The diagnosis of ERA should be considered particularly in a boy older than 10 years of age who has enthesitis or a family history of ankylosing spondylitis. RF and ANA are absent in children with ERA; on the other hand, the HLA-B27 antigen is present in more than 92% of children with juvenile ankylosing spondylitis, compared with 6% to 8% in the general North American white population. Occult inflammatory bowel disease may manifest as, or be complicated by, polyarthritis that is usually more transient than that of JRA. Whipple's disease can cause peripheral arthritis in children but is very rare (see Chapter 15). Dermatomyositis or scleroderma occasionally manifest with arthritis. The associated features of these illnesses generally lead quickly to a correct diagnosis. Dermatomyositis is almost invariably associated with a characteristic skin rash, and isolated polymyositis is rare. Scleroderma, on the other hand, may begin insidiously, and subtle subcutaneous calcifications may be misinterpreted as rheumatoid nodules. Malignant infiltration of bone or synovium can mimic polyarthritis, although in most instances the lesion is in juxta-articular bone rather than in the joint (see Chapter 39). Sometimes, however, joint effusions occur in children with malignancies. Nonarticular bone pain or tenderness, back pain with rest or activity, and severe constitutional symptoms may be warning clues. In addition

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to the systemic manifestations of malignancy, many children with hematologic malignancies have moderateto-severe anemia or elevation of the erythrocyte sedimentation rate (ESR) that is out of keeping with other features of their disease. The leukocyte count or platelet count may be low or normal, whereas in children with JIA, these laboratory measurements usually are increased. The serum level of lactic dehydrogenase is often very high. Radiographs of affected joints may suggest one of these disorders; however, the correct diagnosis in some children may be delayed for 3 to 6 months. Examination of the bone marrow is usually diagnostic (e.g., leukemia, neuroblastoma). Arthritis as a manifestation of malignancy becomes increasingly uncommon during late adolescence as red marrow ceases to occupy the metaphyses of the long bones. Sickle cell anemia in the very young child causes a dactylitis (hand-foot syndrome) that may mimic true arthritis, and in other children it causes microinfarcts that give rise to periostitis and periarthritis. It is reported that joint effusions adjacent to infarcted bone occur in 20% of acute sickle cell crises,63 and the coexistence of polyarthritis and sickle cell disease has been reported.64 Occasionally, the hypermobility syndrome or one of the Ehlers-Danlos syndromes presents as polyarthralgia. Swelling, pain, and temperature and color changes associated with reflex sympathetic dystrophy are usually unilateral and are readily differentiated from signs of JIA. Rarely, a child with a mucopolysaccharidosis, particularly Morquio's or Scheie's syndrome, has joint stiffness or bony enlargement suggesting polyarthritis. Children with immunodeficiencies, especially selective IgA deficiency and hypogammaglobulinemia, may have a polyarthritis that mimics JIA (see Chapter 33). Children with the velocardialfacial syndrome (22q11 deletion) develop chronic polyarthritis that may be clinically indistinguishable from JIA. 65 Jacobs and associates 66 and Athreya and Schumacher!>7 described children with familial hypertrophic synovitis who developed characteristic flexion contractures of the finger joints during the first few months of life. A bent thumb, the first diagnostic sign of this disorder, was often noted soon after birth. Symmetrical effusions affected the large joints. Progressive but minimal limitation of motion of the joints developed with age. There was usually no pain or systemic manifestation of fever or inflammation. Autosomal dominant inheritance was suggested in some families. Hypertrophic villi with giant cells but no other inflammatory infiltrates were present on histologic examination of the synovium. Synovial lining cells were hyperplastic, but vascular endothelial proliferation was not prominent. Radiographs demonstrated flattening of the proximal ossification centers of the femurs. Familial arthritis and camptodactyly has also been described6B and in some cases was associated with pericarditis. 69.7o The authors have seen two children with an isolated joint contracture resembling JIA in whom the eventual diagnosis was myositis ossificans progressiva (see Chapter 20). This diagnosis was not evident in either child until later in the course, when typical ossifications in muscle were observed radiographically. Familial osteochondritis dissecans also can mimic polyarticular JIA.7 1 The generalized soft tissue puffiness of the dorsa of the hands and feet in disorders such as lymphedema praecox, Noonan's syndrome, and Turner's syndrome

may mimic swelling caused by a combination of small joint effusions and tenosynovitis in children with polyarticular JIA.72 The absence of other evidence of inflammation in these patients should readily differentiate such conditions from polyarticular JIA. Other rare causes of diagnostic confusion include Poncet's disease (see Chapter 31)73 and the Torg osteolysis74 or related syndromes. 75

PATHOLOGY The histologic appearance of the synovium is nonspecific and does not materially differ from that seen in other chronic inflammatory arthritides. The synovial lining layer is hyperplastic, and there is villous hypertrophy. The subsynovial tissue is edematous. The vascular endothelium is hyperplastic and infiltrated by lymphocytes and plasma cells (see Figure 9-9). In adult RA, the primary infiltrating cell is the T lymphocyte, which may be distributed diffusely throughout the synovium or form nodules or germinal centers. 76 In addition, macrophages and dendritic cells abound, and, in late disease, B lymphocytes and RF-producing plasma cells are evident. Hypertrophy of synovial lining cells, fibroblasts, and blood vessels leads to the development of papillary fronds that may reach 2.5 x 0.2 cm in size. Extension of the inflammatory granulation tissue or pannus that spreads from the synovium and invades the cartilage and bone results in osteolysis, which is visible radiographically as erosion and subchondral cyst formation. Erosions occur preferentially in the "bare" areas of the joint, where bone is not covered by articular cartilage (see Chapter 2). They are irregular but sharply defined. Dissolution of the cartilage (chondrolysis) results from enzymatic digestion by neutral proteases, cathepsin, and collagenase from cells of the pannus. Immune complexes may also contribute to chondrolysis. 77 Metaplasia of the granulation tissue may result in formation of new cartilage, bone, or fibrous tissue, resulting in ankylosis. 76 End-stage disease is characterized by def01mity, subluxation, and fibrous or bony ankylosis. Joint destruction usually occurs much later in the course of JIA than in adult RA, and permanent joint damage is absent in many children with JIA even after years of chronic inflammation. (Newer studies with magnetic resonance imaging are likely to change this impression of the extent of joint damage in early disease.) The greater thickness of juvenile cartilage may offer some protection in this regard. The hyaline cartilage of the hip is destroyed in progressive stages during the course of severe]lA, and during healing it may be replaced by a fibrocartilaginous layer. 7R Rice bodies consist primarily of amorphous fibrous material, fibrin, and small amounts of collagen (Fig. 10-6).79--81 Viable cells are incorporated within this matrix and appear more normal than the synovial cells of the inflammatory foci. The majority of these cells resemble type B synovial lining cells, although a few type A cells are also visible. Residual blood vessels in some of these bodies attest to their former attachment to the synovial membrane. Subcutaneous nodules may be histopathologically typical of rheumatoid nodules (Fig. 10-7), or they may have a looser connective tissue framework resembling that of the nodules of rheumatic fever. 4 1,82 Classic rheumatoid nodules consist of three distinct zones: a central area of necrosis and granulation tissue, surrounded by a radially

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white blood cell counts and platelet counts and have a normocytic hypochromic anemia characteristic of chronic inflammation. These changes are usually more severe than those seen in children with oligoarthritis but less severe than in children with systemic arthritis (see also Chapter 9).

Autoantibodies Rheumatoid Factors

• figure 10-& Rice bodies from the knee of a 15-year-old boy with persistent arthritis of knees and ankle.

• figure 10-7 Photomicrograph of a rheumatoid nodule shows a central area of fibrinoid necrosis surrounded by a palisade of epithelioid cells and peripheral fibroblastic proliferation.

arranged palisade of connective tissue cells, which in turn is enveloped by chronic inflammatory cells. In ]IA, the central area of fibrinoid necrosis and the epithelioid palisades may be absent or less structured.

LABORATORY EXAMINAnON As is the case in other types of idiopathic arthritis, the

laboratory provides evidence of inflammation, is useful in excluding other diagnoses, and is important in classification, prognostication, and guiding therapy. There is no single diagnostic test, however.

Indicators of Inflammation Children with polyarthritis, particularly those with RFpositive polyarthritis, almost always have significant elevation of indices of inflammation such as ESR, C-reactive protein (CRP), and immunoglobulins. Many have elevated

The latex fixation test for the detection of classic IgM antiIgG RFs is positive in a variable percentage of children with polyarthritis. Classic RFs occur more frequently in children with polyarthritis than in any other category of ]IA. In the u.s. Pediatric Rheumatic Disease Registry,83 20 (3%) of 686 children with a polyarticular onset of]RA were RF positive. In a study by Oen and colleaguesll4 in Native Canadian children, the high frequency of RF-positive polyarticular disease (42%) was undoubtedly related to the high prevalence of HLA-DRB1 antigens bearing the RA shared epitope. RFs are unusual in a child younger than 7 years of age and are seldom helpful diagnostically at onset of disease. The diagnostic importance of RF seropositivity in a child with possible JRA is mitigated by the frequent occurrence of abnormal titers in the other connective tissue diseases of childhood, especially in SLE. In a study of the diagnostic utility of RF serology in children,8s RF tests were as likely to be positive in children with diseases other than ]RA as in those with JRA (Table 10-5). As a diagnostic aid, therefore, tests for RFs are of little utility. However, children with high titers of RFs most likely represent a subgroup distinct from the larger number of children with seronegative polyarthritis. The evidence for this hypothesis is not unequivocal, because studies often identify the seropositive group in retrospect. RFs are more common in children with later age at onset of arthritis and in those who are older, have subcutaneous rheumatoid nodules or articular erosions, or are in a poor functional class (Table 10_6).86 The percentage of children with RF seropositivity also rises progressively as the age at onset or duration of disease of the cohort group under study increases. These observations suggest that RFs might be a result rather than a determining event in children who go on to develop unremitting, disabling disease during the early adult years. Many studies have demonstrated other types of antiglobulins in the sera of children with ]RA or have reported more sensitive and specific tests for RFs. The

I=. ~

TABLE 10-5

Utility of Rheumatoid Factor as a Diagnosti( Test'

Juvenile Rheumatoid Arthritis Rheumatoid Fador Present Absent

Present

Absent

5

6 326

100

'Sensitivity = 5/105 (4.8%); specificity = 326/332 (98%). Modified from Eichenfield AH, Athteya BH, Doughty RA, Cebui RO: Utility of rheumatoid factor in the diagnosis of juvenile rheumatoid arthritis. Pediatrics 78: 480, 1986.

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TABLE 10-6 Clinital and Laboratory Correlations with RheumatoId Fador Positivity

Late age at disease onset Long duration of disease Poor functional capacity Rheumatoid nodules Rheumatoid vasculitis Erosions

majority of children with IgM RF-negative JRA can be shown to have IgG anti-IgG antibodies by immunosorbent techniques. A7 Miller and colleaguesHH employed five different immunosorbents to search for occult antiglobulins. Antiglobulins detected by binding to sepharose-linked globulin followed by acid elution were found in 8 normal children and in 52 children with JRA; only 4 children with JRA had significantly elevated levels. They concluded that the presence of these antiglobulins per se was not diagnostically helpful in distinguishing children with JRA. In the review by Lawrence and associates,H9 up to 75% of children with ]RA were shown to have "hidden RFs," defined as IgM 195 antiglobulins detected by acid elution of IgM-containing fractions of serum from a gel filtration column. Titers correlated with activity of the disease and did not differ significantly between polyarticular and oligoarticular disease. Most studies have focused on North American and European patients. In a survey of 43 children from Turkey,90 195 IgM hidden RFs were found in 56% of the patients (46% with oligoarthritis, 64% with polyarthritis, and 80% with systemic onset). The latex fixation test was positive in only one patient who had polyarticular disease. Hidden RFs were present in lower percentages in India91 .92 and in GreeceY3 RFs of IgA and IgE isotypes are reportedY4-96

Oen and colleagues99 reported the findings in a group of children with RF-negative and RF-positive polyarthritis. In early radiographs (taken within 2 years after disease onset), joint space narrowing (including decreased joint space, ankylosis, and carpal collapse) was demonstrated in 12% of 39 children in the RF-negative group and 31% of 21 children in the RF-positive group. In late films (taken at last follow-up, a median of 6.5 years after onset in RF-negative polyarthritis, and 8.7 years in RFpositive polyarthritis), the frequency of joint space narrowing had increased to 42% and 80%, respectively. Erosions and growth abnormalities likewise increased with time (Table 10-7). Details of the location of radiographic abnormalities are shown in Table 10--8 and Table 10-9. Pedersen and colleagues lOO studied the temporomandibular joint (TM]) using orthopantomograms in 169 consecutive patients with leA. Radiographic abnormalities of the TM] were more severe and more frequent in those with polyarthritis (65.8%) than in those with other onset types. More severe disease also correlated with early age at onset of arthritis and with long duration of disease. The presence of RF in young children was associated with severe TM] disease.

TREATMENT Polyarthritis, perhaps to a greater extent than in any other category of JIA, requires both intensive pharmacotherapy and the application of physical modalities such as physical therapy. Recognition of these diseases, particularly in the presence of RF positivity, should prompt early aggressive therapy to minimize joint damage and functional loss. The probability of a benign

Antinuclear Antibodies ANAs of unknown specificities are commonly present in children with polyarthritis. They are present in low to medium titers (up to 1:640, occasionally higher) in a proportion of these children. Low and colleagues97 found that 75% of children with RF-positive polyarthritis had antibodies to cyclic citrullinated peptides (CCP), although there was considerable variation depending on the substrate used in the assays, and these antibodies were also demonstrable at lower frequency in children with RF-negative polyarthritis, oligoarthritis, or systemic arthritis. Another study of 100 children with JRA (ACR criteria)9A showed that anti-CCP was present in half of those with RF-positive polyarthritis but in none of those with polyarticular RF-negative polyarthritis, oligoarthritis, or systemic arthritis. Standardization of the techniques used to measure anti-CCP antibodies is critical, and the clinical applicability of this laboratory investigation is not certain at present.

RADIOLOGIC EXAMINATION Radiologic changes often occur early and, particularly in children with RF, may be severe. Examples of typical changes are seen in Figures 10--8 through 10-10 (also see Figures 9-10, 9-14, and 9-17).

• Figure 10-8 Extensive ankylosis of the carpal and metacarpal joints in a 12-year-old girl 2 years after onset of polyarticular JlA.The entire carpus is ankylosed, and there are fusions between the carpals and the second and third metacarpals as well. There is also undergrowth of the fourth right metacarpal and disruption of the radiocarpal relationship.

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11[·. TABLE to-7 -

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269

Radiographic Abnormalities in Polyarthritis

("'" of Patients)

Polyarthritis RF·Negatlve Abnonnallty Joint space nan'owing Erosions Growth abnormalities

PoIyartbrltls RF-PosItIve

Early

Late

Early

Late

(n=39)

(n = 54)

(n= 21)

(n = 28)

12

42

31

80

17

40

55

75

16

42

45

31

RF. rheumatoid factor, From Oen KG. Reed M, Malleson PN, et al: Radiologic outcome and its relationship to functional disability in iuvenile rheumatoid arthritis, .J Rheum 30: 832-840. 2003.

Medical Management

• fItpn 10-' Radiograph of the hand of a 15-year-old girl taken shortly before her death. Severe polyarthritis was present, with marked bony overgrowth and enlargement of the epiphyses. Erosions and destruction of the small joints were evident, with invagination of the abutting bones.The distal interphalangeal joints were also involved, and partial ankylosis of the carpus was present.

course of short duration is very low, and a prolonged disease course with the threat of significant joint damage should be anticipated. The effects of systemic manifestations of the disease must also be monitored carefully. The principles outlined in Chapter 8 should be applied.

• figure 10-10 Protrusio acetabuli of the left hip in a girl with longstanding JlA. Pain in the hip was accompanied by marked reduction in range of motion, although at the time the overall disease activity was minimal.

Initial treatment with nonsteroidal anti-inflammatory drugs (NSAlDs) is appropriate. Naproxen or ibuprofen is most commonly used in North America, but indomethacin is favored by some pediatric rheumatologists in Europe and elsewhere. Some physicians combine initial NSAID therapy with a disease-remittive agent, usually methotrexate, particularly in children with RF-positive polyarthritis, In any event, failure of NSAlDs to control the disease within 6 to 8 weeks should prompt the addition of methotrexate. This drug is usually given by mouth initially, in doses of 0.35 to 0.65 mg/kg/week, but in the absence of an adequate response, once an oral dose of 15 mg/week is reached, administration should be changed to the subcutaneous route. The response to methotrexate is usually excellent. IOt-103 Although methotrexate has become the drug of choice, leflunomide may have a place, although this is not yet established. 104 .105 In a study of 40 children from China with active polyarticular JRA,I04 leflunomide plus methotrexate was reported to be superior to methotrexate alone. In a North American multicenter trial, Silverman and colleagues lO5 reported that leflunomide alone was an effective agent in patients with polyarthritis for whom methotrexate had failed. The anti-TNF agents have joined the ranks of effective agents in children with polyarthritis,106-11O and, as experience with these and other biologic agents increases, it is likely that they will find an important place in the management of patients with methotrexate-resistant disease. In the double-blind, randomized, controlled trial conducted by the Pediatric Rheumatology Collaborative Study Group,106 etanercept in a dose of 0.4 mg/kg was given subcutaneously twice a week to all patients. Seventy-four percent of patients demonstrated a response by the core criteria and were entered into the double-blind study. During this phase of the study, patients receiving etanercept had many fewer disease flares, and, when flares did occur, they occurred much later than in the group receiving placebo. Follow-up studies indicated that etanercept offered sustained clinical improvement for longer than 2 years and was well tolerated. 107 ,108 The combination of methotrexate and etanercept was effective in a small group of children with

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TABlE 10 R Pnlydrlhlllts

Lo(alion alld I rl'lllU'lI( Y (II II) of Rddioljr
Joint Space Narrowing location Cervical spine Shoulders Elbows Wrists Hands Hips Knees Ankles Feet

Early

Erosions

Late

Early

0 0 0

7 0 8

5

9 O·

6 6 5 6

3 4 0 <1 0

12 1 3 0

Nl'lj
Growth Abnormalities

Late

3 0 0 0 0

In

0 6 5 6 12 11 2 1 11

Early 0 0 0 4 4 0 1 0 2

Late 0 0 3

9 20 8 3 2

9

RF, rheumatoid factor. From Oen KG, Reed M, Malleson PN, et al: Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis. J Rheum 30: 832-840, 2003.

polyarthritis resistant to methotrexate and sulfasalazine or cyclosporine.109 A comparison of the efficacy and toxicity of etanercept and infliximab in children with active polyarthritis was reported by Lahdenne and colleagues yo Both agents were found to be very rapidly effective, and at 12 months Core Set 75 was achieved by 67% of patients. Five patients in the infliximab group withdrew because of lack of efficacy, as did one patient in the etanercept group. The patients were not randomized in this study, so it is uncertain whether one agent has greater benefit or toxicity than the other. Glucocorticoids are important as intra-articular therapy. Breit and colleagues 111 reported a longer median duration of response in children with ]CA who were RF negative (lOS weeks), than in those who were RF positive (63 weeks). Glucocorticoids have a limited role as systemic agents, particularly acting as a "bridge" until disease-modifying agents begin to have their effect. Drugs such as the gold compounds and penicillamine are seldom used, but hydroxychloroquine probably has a role as an adjunctive agent, used in combination with methotrexate (see Chapter 5). Autologous stem cell transplantation has not found a significant role in the management of polyarthritis,

I! III

TABLE 10 9 Pnlydrlhrilb

Cervical spine Shoulders Elbows Wrists Hands Hips Knees Ankles Feet

Physical and Occupational Therapy Children with polyarthritis, like those with other types of chronic arthritis, should be encouraged to participate in school and recreational activities with other children. Additional rest may be needed by some children. In general, these patients are quite capable of judging their own physical limitations. At the same time, joint protection should be promoted. Undesirable play is that which places undue stress on affected joints. Tricycle and bicycle riding and swimming are almost always helpful and do not add undue loading to the joints. Swimming has the added advantage of providing active range of motion and muscle strengthening without weight-bearing. Notwithstanding the advantages of active exercise, it is important to have a carefully designed passive therapy program: Children tend to function within the range of motion they have, not the range they should be trying to achieve. Physical therapy should be instituted as soon as the degree of inflammation subsides sufficiently to facilitate

I O(
Joint Space Narrowing Location

except in children with systemic ]IA and a polyarticular course (see Chapter 10).

Erosions

Growth Abnormalities

Early

Late

Early

Late

Early

Late

5 0 0 4 2 0 0 1 6

8 25 11 16 10 11 0 6 17

0 6 2 11 5 0 0 0 5

0 18 2 14 8 5 1 1 14

0 0 0 5 3 0 0 2 3

0 13 0 3 3 0 0 4 2

RF. rheumatoid factor. From Oen KG, Reed M, Malleson PN, et al: Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis. J Rheum 30: 832--840, 2003,

C HAP T E R

the child's cooperation. Physical therapy aimed at restoration of normal range of motion can be facilitated by pretreatment with an analgesic such as acetaminophen and the application of heat or ice. Major contractures are often more amenable to therapy after intra-articular injection of triamcinolone hexacetonide. A cast applied at the time of joint injection can make use of the conscious sedation used to inject the joint, and may be changed in 24 to 48 hours (serial casting). Arthritis of the small joints of the hands is a particularly important problem in children with polyarthritis and requires early and ongoing management. Loss of range of motion at the MCP and PIP joints is frequent, causing diminished tuck and grasp strength. Subluxation of the MCP joints may occur, particularly in children with RFpositive polyarthritis.

Surgery Surgical management of polyarthritis is less common than in the past, thanks to the effectiveness of methotrexate and, potentially, the biologic agents. Nonetheless, some children with resistant or untreated disease will require replacement of hips, knees or, occasionally, small joints of the hands. Such procedures are seldom needed in childhood, but in adults with long-standing disease of juvenile onset they add greatly to function and quality of life.

COURSE OF THE DISEASE AND PROGNOSIS The child most at risk for an unsatisfactory outcome is the one who has been referred late after onset or the one who has a relatively late age at onset and long duration of disease, early involvement of the small joints of the hands and feet, rapid appearance of erosions, unremitting inflammatory activity, RF seropositivity, and subcutaneous nodules (see Table 10-6).112 These children have the greatest number of joints involved, often 20 or more, and eventual disability is largely related to the extent of

,~.

1l\BLE 10-10

Prot....ls Remission' Before age 16 yr After age 16 yr CHAQ score 0 >0 but <0.5 O.S-l.S >1.5

POLYARTHRITIS

271

articular involvement. Widespread symmetrical involvement of the PIP and MCP joints of the hands or feet is characteristically associated in polyarthritis with a more guarded outlook than for disease that is confined to the large joints. This is the so-called adult pattern of JIA, and it is related to development of RF seropositivity. Hip disease occurs in approximately one half of the children and almost always is accompanied by persistent inflammatory diseasey,115 It often leads inexorably to destruction or abnormal development of the femoral heads and acetabula. This type of severe hip disease is a major cause of disability in JIA, and hip involvement is justifiably interpreted as a poor prognostic sign. Limitation of range of articular motion often develops early and is related to synovial proliferation, effusion, or muscle spasm. Later on, it may result from contractures of soft tissues, joint destruction, or ankylosis. Remission is unlikely if arthritis has persisted longer than 7 years. Onset of puberty has no relation to activity of the disease or likelihood of a remission. In the Cincinnati series, 45% of the patients still had active arthritis 10 years after onset. 1l6 Fantini and colleagues ll7 noted that 15.7% of their patients with polyarticular JCA were in remission at last visit, 8.3% had a temporary remission, but 75.9% had never had a remission. Oen and colleagues lB described the outcome of children with JRA in a multicenter cohort that included 80 children with RF-negative polyarticular JRA and 40 with RF-positive polyarticular JRA (Table 10-10). All had been diagnosed between 1977 and 1994 and had been monitored for a minimum of 5 years. Although the ACR criteria were used for classification, children with psoriatic arthritis, ERA, seronegative enthesitis arthritis syndrome, juvenile ankylosing spondylitis, or arthritis with inflammatory bowel disease were excluded. Oen's group concluded that for children with RF the disease was unremitting; only 25% of children with negative tests for RF had gone into remission by age 16 years. Furthermore, children who had not gone into remission by this age were likely to have ongoing active arthritis into their late 20s or early 30s. These quite recent data suggest that polyarthritis continues to be associated with significant morbidity and functional disability.

REFERENCES

Prognosis 01 Polyarthritis

RF-Negatlve Polyarticular IRA (n= SO)

10

RF-PosIUve Polyarticular IRA (n= 40)

19 (24%) 4 (5%) 1509%)

0 0 0

36% 31% 25% 8%

8% 34% 40% 18%

'Remission - absence of active arthritis while off medication for at least 2 yr (no. and "", of patients), CHAQ, Childhood Health Assessment Questionnaire; JRA, juvenile rheumatoid arthritis; RF, rheumatoid factor. Data modified from Oen K, Malleson PN, Cabral DA. et al: Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specifiC correlations. J Rheumatol 30: 585-593. 2003.

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