Clinical Trials in Rheumatology

Clinical Trials in Rheumatology Rüdiger Müller • Johannes von Kempis Clinical Trials in Rheumatology Authors Rüd...

Author: Ruediger Mueller | Johannes Von Kempis

110 downloads 2195 Views 4MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

Clinical Trials in Rheumatology

Rüdiger Müller • Johannes von Kempis

Clinical Trials in Rheumatology

Authors Rüdiger Müller Division of Rheumatology and Rehabilitation Department of Internal Medicine Kantonsspital St. Gallen Switzerland

Johannes von Kempis Division of Rheumatology and Rehabilitation Department of Internal Medicine Kantonsspital St. Gallen Switzerland

ISBN 978-1-84996-383-1 e-ISBN 978-1-84996-384-8 DOI 10.1007/978-1-84996-384-8 Springer London Dordrecht Heidelberg New York British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2010937971 © Springer-Verlag London Limited 2011 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To our wives, and children: Sophia, and Franziska, Alexandra, Johanna, Antonius, Helena Johannes von Kempis Elke, and Ismene, Frederik and Mostafa Farmand, who was an inspiration to me during medical school Rüdiger Müller

Foreword

Over the past 20 years, rheumatologists have developed and witnessed many paradigmatic changes not only in the medication of rheumatoid arthritis (RA) but also in other autoimmune rheumatic diseases. With regard to RA, less joint damage and better physical function has been demonstrated as a consequence of an early institution of disease-modifying anti-rheumatic drugs. Furthermore, the definition of core set variables and developments of composite measurements to assess RA have allowed disease activity to be assessed reliably. Finally, new biologic active agents have shown to be of major importance for fulfilling the aim of low disease activity or even remissions, specifically if treatment is commenced at a very early stage of the disease. These obvious significant advances in the treatment options for RA and other autoimmune rheumatic diseases would not have been made possible without a new culture for conducting clinical trials starting in the mid-1980s. The book Clinical Trials in Rheumatology provides a comprehensive overview of trials in different rheumatic diseases. It presents many important clinical trials conducted over the last 40 years, ranging from complex, double-blinded or open multicentric trials, e.g., the BeSt-study to case studies in situations where real trials are still missing. The different clinical trials to rheumatologic disease entities as listed in the book are not directly comparing outcome and clinical efficacy, or giving therapeutic recommendations. (For therapeutic decisions, the authors recommend to follow national and international guidelines and ongoing discussions concerning different treatment strategies in different autoimmune rheumatic diseases.) Instead, the book presents a well-founded and comprehensive selection of the most important studies. The authors present the relevant information concerning study design, medications, patient populations, clinical endpoints, and adverse events, thus offering a quick overview on the clinical trials conducted in different autoimmune rheumatic diseases. This new form of presenting the significant data of the most important studies in a comparable form renders this book a valuable help in the constantly growing multitude of clinical data in rheumatology.

Prof. J. R. Kalden University of Erlangen

vii

Preface

The simple goal of this book is to provide a comprehensive overview of clinical trials in rheumatology in an easily readable manner. The constantly growing and increasingly confusing multitude of clinical trials in inflammatory rheumatic diseases first gave us the idea. This tremendous number of trials has been rendered possible by a steep increase in therapeutic options, such as the new therapeutic group of biologics, over roughly the last decade and by the development of more generally accepted response parameters. Many of the studies presented here were part of the clinical development program of biologics such as the TNF-inhibitors for different rheumatic diseases. They are complemented by studies with the same and older drugs, many of them investigator initiated, in different disease stages, e.g. in RA, or clinical situations, e.g. in vasculitis. The main idea of this survey in the beginning simply was to set up a list of studies named with an acronym, such as ATTAIN, ATTRACT, BeSt etc., in inflammatory joint disorders. We wanted to have such an acronym finder ready at hand at all times during the clinical day, in the laboratory and at scientific meetings. But during the selection process, more and more trials without an acronym either came to mind or appeared during online searches on public databases including ones about non-biologic DMARD in arthritis, autoimmune connective tissue diseases and vasculitis which seemed equally important. The result of all this evolutionary process is the present compilation which presents short summaries of the most relevant studies in a certain disease, without interpretation or valuation of the data. All types of studies are included, controlled prospective as well as observational ones – case studies even where real studies are still missing. We did, however, exclude analyses of cohort data except for some prominent examples. We have concentrated on autoimmune inflammatory disorders and have not included studies on inflammatory metabolic diseases. Some of the studies in this book, e.g. in Sjögren’s syndrome, don’t fulfill the requirements of a modern drug trial, mostly due to the lack of accepted and specific response criteria. Our intention, however, was to list the relevant trials for every immunomodulatory drug in a certain disease, regardless of the trial’s characteristics. For every study listed we tried to present the relevant information with regard to study design and substances used, patient population, clinical endpoints, and adverse events, and nevertheless to stay within a

ix

x

Preface

one study-one page format wherever possible. Our focus was set on clinical, not laboratory outcomes. Changes in laboratory parameters are presented in some studies, however, but only if absolute numbers -as opposed to values presented in graphs- were available. Studies mainly represent the time span between the late 80ies and the beginning of 2010, but some historically interesting ones dating back to the seventies or even earlier are included. To hold up a simple survey principle, data are neither interpreted nor commented. Sometimes, however, details not mentioned in the original publication, such as changes in a certain parameter in percent, are added. The studies are listed by disease and compound, at the end of the book a list of acronyms and of abbreviations, respectively, used throughout the text is provided. We have made considerable efforts to reach all holders of copyright material and received permissions from all we have been able to make contact with. In only very few our repeated efforts have remained without answer. We would like to emphasize that we are not comparing studies. We are also definitely not giving therapeutic recommendations. For therapeutic decisions we recommend to follow national or international guidelines and the ongoing discussion concerning treatment strategies for the different diseases. This book presents our personal selection and we may well have missed important studies. We are planning to regularly update this book and welcome any suggestions, including for additional studies to be included, if they help improving the present format, preferably by e-mail. Rüdiger Müller Johannes von Kempis St. Gallen

How to Read This Book

Trials are listed by disease according to the table of contents. In ANCA-associated vasculitis, at the beginning of a trial summary, different disease entities are listed if the trial investigated a mixture of vasculitides affecting vessels of different sizes according to the CHC-definitions. The sequence within a disease is corticosteroid trials at the beginning, followed by non biologic DMARDs in alphabetical order and trials with biologics, again alphabetically, after DMARD-trials. Several trials with one substance are presented in chronological order, beginning with the earliest. Trial

Title of the publication as published Acronym: In case of an acronym, it’s meaning is explained

Substance

Name of substances (biologic or pharmaceutic), doses used, and patient numbers in each treatment group, according to study design Only trials of registered substances or substances with far advanced registration process Concomitant medication: Additional medication permitted in the trial – if mentioned in the original publication Previous medication: Medication before start of trial – if mentioned in the original publication

Result

The main results are shortly summarized, mostly in compliance with the authors’ conclusions. Speculations the authors may have based on their findings are left out

Patients

The number of patients, the diseases treated, and, if adding to the clinical meaning of the study, details of the patient disposition at study entry, are specified The use of terms such as RA or SLE, without other details leading to the diagnosis, generally signifies that these patients fulfilled the most generally accepted international classification criteria, e.g., the ACR-criteria for RA Important inclusion and exclusion criteria are listed in some cases

Authors

Names according to original publication

Publication

Original citation xi

xii

How to Read This Book

Follow up

Total follow up of the trial as defined or seen in the publication In many trials the follow up differed from the duration of the trial’s treatment arms. In many of those trials, the duration of the trial can be seen under “Substance”

ACR 20/50/70

In RA trials with these endpoints, the ACR response criteria are listed

Note

The data defined by the authors as study end points are presented as percentages or precise numbers, depending on their description in the publication, for every treatment group Changes from baseline, if available, are listed for every group Definitions of clear primary or secondary end points are restricted to more recent, controlled trials. For the sake of a standardized description scheme and to keep the trial summaries as short as possible, they are not named The same applies to informations on statistical significance, standard deviations, ranges, other methodologic details, definitions of remission, disease activity or relapse/flair and drop-out rates. For all these, please refer to the original publications Numbers either as absolute values (e.g., n = 1) or means (e.g., duration of symptoms: 40 months), if not mentioned otherwise

Adverse events

Adverse events are listed as described for every study drug or therapy regimen

Contents

Acronym-finder............................................................................................................. xix Rheumatoid Arthritis................................................................................................... Corticosteroids........................................................................................................ Atorvastatin............................................................................................................. Azathioprine............................................................................................................ Azathioprine vs. Methotrexate................................................................................ Hydroxychloroquine vs. Sulphasalazine................................................................. Hydroxychloroquine............................................................................................... Chloroquine vs. Ciclosporin................................................................................... Ciclosporin.............................................................................................................. Ciclosporin vs. Chloroquine................................................................................... Ciclosporin vs. parenteral Gold.............................................................................. Ciclosporin.............................................................................................................. Ciclosporin vs. Methotrexate.................................................................................. Ciclosporin vs. Azathioprine.................................................................................. Cyclophosphamide.................................................................................................. Gold vs. Methotrexate............................................................................................. Gold vs. Cyclophosphamide vs. Azathioprine........................................................ Leflunomide............................................................................................................ Leflunomide vs. Sulfasalazine................................................................................ Methotrexate vs. Leflunomide................................................................................ Leflunomide............................................................................................................ Sulfasalazine vs. Leflunomide................................................................................ Leflunomide............................................................................................................ Leflunomide vs. Methotrexate................................................................................ Leflunomide............................................................................................................ Leflunomide vs. Methotrexate................................................................................ Methotrexate........................................................................................................... Sulfasalazine........................................................................................................... Sulfasalazine vs. Gold............................................................................................. Sulfasalazine........................................................................................................... Tacrolimus...............................................................................................................

1 1 13 14 16 17 18 24 25 26 27 29 32 33 34 37 38 39 41 43 45 46 49 51 53 55 56 69 71 72 73

xiii

xiv

Contents

Early DMARD therapy........................................................................................... 80 Ciclosporin + Chloroquine...................................................................................... 81 Methotrexate + Hydroxychloroquine...................................................................... 83 Methotrexate + Doxycycline.................................................................................. 84 Methotrexate + Sulfasalazine.................................................................................. 85 Methotrexate + Ciclosporin.................................................................................... 94 Methotrexate + Hydroxychloroquine + Sulfasalazine............................................ 105 Methotrexate + Leflunomide.................................................................................. 117 Methotrexate + Azathioprine.................................................................................. 120 Gold + Methotrexate............................................................................................... 123 Gold + Hydroxychloroquine................................................................................... 124 Abatacept................................................................................................................ 126 Etanercept + Abatacept........................................................................................... 150 Adalimumab............................................................................................................ 152 Anakinra.................................................................................................................. 176 Certolizumab pegol................................................................................................. 188 Etanercept............................................................................................................... 195 Anakinra + Etanercept............................................................................................ 222 Golimumab............................................................................................................. 223 Infliximab................................................................................................................ 232 Infliximab vs. Etanercept........................................................................................ 266 Anti-TNF................................................................................................................. 268 Rituximab................................................................................................................ 269 Tocilizumab............................................................................................................. 278 Ankylosing Spondylitis................................................................................................. 297 Methylprednisolone................................................................................................ 297 Cyclophosphamide.................................................................................................. 299 Leflunomide............................................................................................................ 300 Methotrexate........................................................................................................... 302 Pamidronate............................................................................................................ 306 Sulfasalazine........................................................................................................... 307 Pred., Cyc., 5FU, MTX, MMF............................................................................... 323 Adalimumab............................................................................................................ 325 Etanercept............................................................................................................... 334 Infliximab vs. Etanercept........................................................................................ 343 Golimumab............................................................................................................. 344 Infliximab................................................................................................................ 346 Psoriatic Arthritis......................................................................................................... 361 Chloroquine............................................................................................................. 361 Ciclosporin vs. Methotrexate.................................................................................. 362 Ciclosporine vs. Sulfasalazine................................................................................ 363 Ciclosporin ± Methotrexate.................................................................................... 365 Leflunomide............................................................................................................ 366

Contents

xv

Leflunomide vs. Methotrexate................................................................................ 370 Methotrexate........................................................................................................... 371 Sulfasalazine........................................................................................................... 373 Adalimumab............................................................................................................ 378 Alefacept................................................................................................................. 385 Etanercept............................................................................................................... 388 Golimumab............................................................................................................. 391 Infliximab................................................................................................................ 393 Ustekinumab........................................................................................................... 404 Systemic Lupus Erythematosus................................................................................... 407 Corticosteroids........................................................................................................ 407 Azathioprine............................................................................................................ 411 Azathioprine vs. Ciclosporin.................................................................................. 413 Chloroquine and Hydroxychloroquine................................................................... 415 Hydroxychloroquine + Mycophenolate Mofetil..................................................... 422 Cyclophosphamide vs. Azathioprine...................................................................... 423 Cyclophosphamide Followed by Azathioprine....................................................... 426 Cyclophosphamide.................................................................................................. 427 Cyclophosphamide Followed by Azathioprine....................................................... 429 Cyclophosphamide.................................................................................................. 431 Cyclophosphamide vs. Azathioprine...................................................................... 434 Leflunomide............................................................................................................ 435 Methotrexate........................................................................................................... 437 Mycophenolate Mofetil vs. Cyclophosphamide, Azathioprine.............................. 440 Mycophenolate Mofetil ......................................................................................... 442 Mycophenolate or Azathioprine after Cyclophosphamide..................................... 444 Tacrolimus............................................................................................................... 445 Infliximab................................................................................................................ 447 Rituximab................................................................................................................ 449 Antiphospholipid Syndrome........................................................................................ 455 Aspirin..................................................................................................................... 455 Aspirin vs. Heparin................................................................................................. 457 Aspirin + Heparin................................................................................................... 460 Aspirine + Prednisone............................................................................................. 463 Aspirine vs. Prednisone.......................................................................................... 464 Heparin.................................................................................................................... 465 Heparin vs. Prednisone........................................................................................... 466 Heparin vs. intravenous Immunoglobulin............................................................... 467 Intravenous Immunoglobulins................................................................................ 470 Warfarin.................................................................................................................. 471 Progressive Systemic Sclerosis..................................................................................... 473 Corticosteroids........................................................................................................ 473 Ambrisentan............................................................................................................ 474

xvi

Contents

Azathioprine............................................................................................................ 479 Azathioprine + Cyclophosphamide........................................................................ 480 Bosentan.................................................................................................................. 481 Chlorambucil........................................................................................................... 491 Ciclosprine.............................................................................................................. 492 Colchicine............................................................................................................... 493 Cyclophosphamide.................................................................................................. 494 Cyclophosphamide vs. Azathioprine...................................................................... 503 Cyclophosphamide.................................................................................................. 504 D-Penicillamine...................................................................................................... 507 Methotrexate........................................................................................................... 510 Mycophenolate Mofetil........................................................................................... 513 5-Fluorouracil......................................................................................................... 515 Etanercept............................................................................................................... 516 Rituximab................................................................................................................ 517 Plasma Exchange.................................................................................................... 519 Stem Cell Transplantation....................................................................................... 521 Autologous Stem Cell Transplantation................................................................... 523 Raynaud’s Phenomenon............................................................................................... 525 Diltiazem . .............................................................................................................. 525 Glycerol Trinitrate................................................................................................... 528 Iloprost.................................................................................................................... 529 Nifedipine............................................................................................................... 544 Sildenafil................................................................................................................. 548 Dermato/Polymyositis................................................................................................... 549 Corticosteroids........................................................................................................ 549 Azathioprine............................................................................................................ 550 Cyclosphosphamide................................................................................................ 552 Immunoglobulins.................................................................................................... 553 Methotrexate........................................................................................................... 555 Methotrexate vs. Ciclosporine................................................................................ 558 Mycophenolate Mofetil........................................................................................... 559 Anti-TNF................................................................................................................. 560 Etanercept............................................................................................................... 561 Rituximab................................................................................................................ 562 Plasma Exchange.................................................................................................... 564 Sjögren’s syndrome....................................................................................................... 565 Hydroxychloroquine............................................................................................... 565 Leflunomide............................................................................................................ 568 Methotrexate........................................................................................................... 570 Mycophenolate........................................................................................................ 571

Contents

xvii

Pilocarpine.............................................................................................................. 572 Etanercept............................................................................................................... 574 Infliximab................................................................................................................ 576 Rituximab................................................................................................................ 578 Takayasu Arteritis......................................................................................................... 583 Methotrexate........................................................................................................... 583 Mycophenolate mofetil........................................................................................... 585 Infliximab and Etanercept....................................................................................... 586 Anti-TNF................................................................................................................. 587 Giant Cell Arteritis....................................................................................................... 589 Corticosteroids........................................................................................................ 589 Azathioprine .......................................................................................................... 595 Ciclosporin.............................................................................................................. 596 Methotrexate........................................................................................................... 597 Etanercept............................................................................................................... 604 Infliximab................................................................................................................ 605 Polymyalgia Rheumatica.............................................................................................. 607 Azathioprine............................................................................................................ 607 Corticosteroids........................................................................................................ 608 Methotrexate........................................................................................................... 612 Etanercept............................................................................................................... 617 Infliximab................................................................................................................ 618 ANCA-Associated Vasculitis, Churg Strauss syndrome, Polyarteritis Nodosa, and other vasculitic entities.................................................. 619 Azathioprine............................................................................................................ 619 Co-trimoxazole....................................................................................................... 621 Cyclophosphamide.................................................................................................. 623 Methotrexate .......................................................................................................... 645 Mycophenolate mofetil........................................................................................... 658 Anti-Thymocyte Globulin....................................................................................... 662 Etanercept............................................................................................................... 663 Immunoglobulins.................................................................................................... 666 Infliximab................................................................................................................ 668 Rituximab................................................................................................................ 670 Plasma Exchange.................................................................................................... 679 Purpura Schoenlein Henoch........................................................................................ 685 Corticosteroids........................................................................................................ 685 Azathioprine............................................................................................................ 688 Ciclosporin.............................................................................................................. 689 Cyclophosphamide ................................................................................................ 690

xviii

Contents

Morbus Behçet.............................................................................................................. 693 Corticosteroids........................................................................................................ 693 Azathioprine............................................................................................................ 695 Ciclosporin vs. Colchicine...................................................................................... 698 Ciclosporine............................................................................................................ 699 Ciclosporin vs. Cyclophosphamide........................................................................ 701 Colchicine............................................................................................................... 702 Cyclophosphamide vs. Colchicine.......................................................................... 703 Dapsone................................................................................................................... 704 Methotrexate........................................................................................................... 705 Mycophenolate mofetil........................................................................................... 707 Tacrolimus............................................................................................................... 708 Thalidomide............................................................................................................ 709 Etanercept............................................................................................................... 711 Infliximab................................................................................................................ 712 Interferon alfa-2b.................................................................................................... 715 Interferon alfa-2a.................................................................................................... 716 Abbreviations................................................................................................................ 717 Index............................................................................................................................... 721

Acronym-finder

ACRONYM Meaning behind acronym p. ix Substance: disease ADEPT Adalimumab effectiveness in psoriatic arthritis trial p. 378 Adalimumab: psoriatic arthritis ADJUST Abatacept Study to Determine the effectiveness in preventing the development of rheumatic arthritis in patients with undifferentiated inflammatory arthritis and to evaluate safety and tolerability p. 149 Abatacept: undifferentiated arthritis ADORE Add enbrel or replace methotrexate p. 212 Etanercept and/or MTX: RA AGREE Ababacept study to gauge remission and joint damage in early erosive rheumatoid arthritis p. 144 Abatacept: early RA AIM Abatacept in inadequate responders to MTX p. 133 Abatacept: RA ALMS Aspreva lupus management study p. 442 Mycophenolate mofetil: SLE-nephritis AMBITION Actemra versus methotrexate double-blind Investigative trial In monotherapy p. 293 Tocilizumab: RA APLASA Antiphospholipid antibody acetylsalicylic acid p. 456 Aspirin: APS ARIES Ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy study p. 474 Ambrisentan: PAH ARMADA Anti–tumor necrosis factor research study program of the monoclonal antibody adalimumab (D2E7), in rheumatoid arthritis p. 152 Adalimumab: RA

xix

xx

Acronym-finder

ARRIVE Abatacept researched in RA patients with an inadequate anti-TNF response to validate effectiveness p. 148 Abatacept: RA ASPIRE The active controlled study of patients receiving infliximab for treatment of rheumatoid arthritis of early onset p. 242 Infliximab: early RA ASSERT Ankylosing spondylitis study for the evaluation of recombinant infliximab therapy p. 349 Infliximab: AS ATLAS Adalimumab trial evaluating long-term efficacy and safety for ankylosing spondylitis p. 325 Adalimumab: AS ATTAIN Abatacept trial in treatment of anti-TNF inadequate p. 130 Abatacept: RA ATTEST A trial for Tolerability, efficacy and safety in treating rheumatoid arthritis p. 142 Infliximab: RA ATTRACT Anti-TNF trial in rheumatoid arthritis with concomitant therapy p. 233 Infliximab: RA BARFOT Better anti-rheumatic farmacotherapy p. 7 Prednisolone: early RA BEST Behandelings strategie p. 65 Different treatment protocols: RA BREATHE-1 Bosentan: Randomized trial of endothelin receptor antagonist therapy for pulmonary arterial hypertension p. 486 Bosentan in PAH: systemic sclerosis >> other connective tissue diseases CAPRA Circadian administration of prednisone in rheumatoid arthritis p. 11 Modified-release prednisone: RA CHANGE Clinical investigation in highly disease affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation p. 171 Adalimumab: RA CHARISMA Chugai humanized anti-Human recombinant interleukin-6 monoclonal antibody p. 279 Tocilizumab: RA CHUSPAN Churg Straus polyarteritis nodosa trial p. 635 Cyclophosphamide: Churg Strauss/Polyarteritis nodosa CIMESTRA Ciclosporin, methotrexate, steroid in RA p. 102 Methotrexate/Ciclosporin: RA

Acronym-finder

xxi

COBRA Combinatietherapie bij reumatoide artritis p. 86 Combination of DMARDs in rheumatoid arthritis COMET Combination of methotrexate and etanercept in early rheumatoid arthritis p. 217 Etanercept + methotrexate: RA COPCORD Community oriented program for control of rheumatic disease p. 323 Methylprednisolone, cyclophosphamide, methotrexate, mycopheno late mofetil, ciclosporin, 5-FU, in ankylosing spondylitis Sulphasalazine + methotrexate: RA CYCAZAREM Cyclophosphamide versus azathioprine as remission maintenance therapy for ANCA-associated vasculitis study p. 637 Cyclophosphamide/azathioprine: ANCA associated vasculitis CYCLOPS Daily oral versus pulse cyclophosphamide for renal vasculitis p. 641 Oral/pulse cyclophosphamide: renal vasculitis DANCER Dose-ranging assessment: international clinical evaluation of rituximab in rheumatoid arthritis p. 271 Rituximab: RA EDUCATE Experience diagnosing, understanding care, and treatment with etanercept p. 390 Etanercept: Psoriatic arthritis ERA Early Rheumatoid Arthritis p. 197 Etanercept: RA EXPLORER The exploratory phase II/III SLE evaluation of rituximab p. 452 Rituximab: SLE FAST Fibrosing alveolitis in scleroderma trial p. 480 Prednisolone + cyclophosphamide followed by azathioprine: Scleroderma FAST4WARD Efficacy and Safety of certolizumab pegol – 4 Weekly dosage in rheumatoid arthritis p. 193 Certolizumab pegol: RA FIN-RACO Finish RA cohort p. 105 SSZ + MTX + HCQ + prednisolone: RA FLOAT Flares in lupus out come assessment trial p. 409 Triamcinolone or methylprednisolone: SLE GISEA Gruppo italiano studio early arthritis p. 268 TNF-alpha blocker: RA GO-AFTER Golimumab after Anti-TNF in RA patients p. 227 Golimumab: RA GO-BEFORE Bolimumab in active RA before MTX therapy p. 229 Golimumab: RA

xxii

Acronym-finder

GO-FORWARD Golimumab in active RA despite MTX therapy p. 225 Golimumab: RA GO-RAISE Golimumab in active ankylosing spondylitis p. 344 Golimumab: ankylosing spondylitis GO-REVEAL Golimumab in active psoriatic arthritis p. 391 Golimumab: Psoriatic arthritis GUEPARD Guérir la polyarthrite rhumatoide débutante (cure early RA) p. 174 Adalimumab: RA HELP Hydroxychloroquine effects on lipoprotein profiles p. 418 Hydroxychloroquine: SLE HEPASA Heparin and aspirin p. 459 Heparin and aspirin: antiphospholipid syndrome HERA Hydroxychloroquine in early rheumatoid arthritis p. 19 Hydroxychloroquine: RA IMPACT/-2 Infliximab multinational psoriatic arthritis controlled trial p. 393 Infliximab: psoriatic arthritis INSSYS International network for the study of systemic vasculitides p. 602 Methotrexate: giant cell arteritis IRAMT Infliximab rheumatoid arthritis methotrexate tapering p. 245 Infliximab + methotrexate: RA MASCOT Methotrexate and sulfasalazine combination trial p. 92 Methotrexate and sulfasalazine: RA MEPEX Methyl prednisolone or plasma exchange for severe renal vasculitis p. 683 Methylprednisolone/plasma exchange: renal vasculitis METGO Methotrexate and intramuscular gold therapy in rheumatoid arthritis p. 123 Methotrexate + gold: RA NORAM Treatment of nonrenal Wegener’s granulomatosis p. 639 Methotrexate/cyclophosphamide: ANCA associated vasculitis OASIS Outcome assessment in ankylosing spondylitis international study p. 340 Etanercept: ankylosing spondylitis OPPOSITE Open-lable, pilot protocol of patients with rheumatoid arthritis who switch to Infliximab after an inadequate response to Etanercept p. 266 Infliximab/Etanercept: RA OPTION Tocilizumab pivotal trial in methotrexate inadequate responders p. 285 Tocilizumab: RA

Acronym-finder

xxiii

PREMIER Patients receiving methotrexate and infliximab for the treatment of early rheumatoid arthritis p. 165 Infliximab: RA PROMPT Probable rheumatoid arthritis: methotrexate versus placebo treatment p. 64 MTX: undifferentiated arthritis RADIATE The research on actemra determining effIcacy after anti-TNF failure p. 281 Tocilizumab: RA RAPID-1/-2 RA prevention of structural damage p. 189 Certolizumab: RA RAPIDS Randomized placebo-controlled study on prevention of Ischemic digital ulcers in scleroderma p. 484 Bosentan: digital ulcers REACT Research in active rheumatoid arthritis p. 169 Adalimumab: RA REFLEX Randomized evaluation of long-term efficacy of rituximab in RA p. 273 Rituximab: RA SAMURAI Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor p. 283 Tocilizumab: RA SATORI Study of active controlled Tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate p. 291 Tocilizumab: RA SMILE Study of methotrexate in lupus erythematosus p. 438 Methotrexate: SLE SOLUTION Treatment of refractory Wegener’s granulomatosis with antithymocyte globulin (name of study, no acronym) p. 662 Antithymocyte globulin: Wegener’s granulomatosis STAR Safety trial of adalimumab in rheumatoid arthritis p. 159 Adalimumab: RA START Safety Trial for RA with remicade therapy p. 250 Infliximab: RA STREAM Safety and efficacy of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in monotherapy p. 278 Tocilizumab: RA SWEFOT Swedish Pharmacotherapy p. 264 Addition of Infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis

xxiv

Acronym-finder

TARA Trial of atorvastatin in rheumatoid arthritis p. 13 Atorvastatin: RA TEMPO Trial of etanercept and methotrexate with radiographic patient outcomes p. 203 Etanercept: RA TICORA Tight control for rheumatoid arthritis p. 109 Therapeutic escalation SSZ – MTX – HCQ: RA TIRA An acronym in Swedish for “early intervention in rheumatoid arthritis” Functional ability: RA TOPAS Treatment with leflunomide in psoriatic Arthritis p. 366 Leflunomide: Psoriatic Arthritis TOWARD Tocilizumab in combination with traditional DMARD therapy p. 287 Tocilizumab: RA TRIPSS Trial of remicade in primary Sjögren’s syndrome p. 577 Infliximab: Sjögren’s Syndrome TRUST TRacleer Use in PAH associated with scleroderma and connective tissue Bosentan: Scleroderma and connective tissue disease ULTRA Utilization of leflunomide in the treatment of rheumatoid arthritis p. 51 Leflunomide: RA VERA Very early rheumatoid arthritis p. 80 DMARDs: RA WAPS Warfarin in the antiphospholipid syndrome p. 471 Warfarin: antiphospholipid syndrome WGET Wegener’s granulomatosis etanercept trial p. 664 Etanercept: Wegener’s granulomatosis WOSERACT West of Scotland early rheumatoid arthritis corticosteroid trial p. 6 Prednisolone: RA

Rheumatoid Arthritis

Corticosteroids

Trial

Pulsed methylprednisolone in active early rheumatoid disease: a dose-ranging study

Substance

1 ´ methylprednisolone 40 mg (n = 24) 1 ´ methylprednisolone 500 mg (n = 22) 1 ´ methylprednisolone 1g were (n = 23) Concomitant medication: No information provided Previous medication: No DMARD £ 6 months No oral corticosteroidsw £ 6 months

Result

Single doses of methylprednisolone below 1g were not helpful in the management of acute RA

Patients

71 patients with active classical or definite RA Deemed by the clinician to warrant second line treatment Disease duration < 5 years

Authors

Shipley ME, Bacon PA, Berry H, Hazleman BL, Sturrock RD, Swinson DR, Williams IA

Publication

Br J Rheumatol. 1988 Jun;27(3):211–214

Follow up

9 weeks

Note

Patient did benefit from treatment n = 10 (40 mg), n = 13 (500 mg), n = 20 (1g) Complete trial n = 9 (40 mg), n = 7 (500 mg), n = 16 (1g)

Adverse events

Total number of adverse events n = 15 (40 mg), n = 20 (500 mg), n = 32 (1g)

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_1, © Springer-Verlag London Limited 2011

1

2

Rheumatoid Arthritis: Corticosteroids

Trial

Intravenous pulsed steroids in rheumatoid arthritis: a comparative dose study

Substance

3 × 100 mg methylprednisolone (n = 17) 3 × 1,000 mg methylprednisolone (n = 19) Concomitant medication: DMARDs were permitted at the rheumatologists discretion Previous medication: DMARDs NSAIDs Oral corticosteroids 4–20 mg/day

Result

Treatment of RA flares with 3 × 100 mg methylprednisolone was as efficacious as conventional 1,000 mg methylprednisolone pulses

Patients

36 patients with RA synovitis flares Judged by the rheumatologist to require pulse steroids

Authors

Iglehart IW 3rd, Sutton JD, Bender JC, Shaw RA, Ziminski CM, Holt PA, Hochberg MC, Zizic TM, Engle EW, Stevens MB

Publication

J Rheumatol. 1990 Feb;17(2):159–162

Follow up

3 months

Note

Change of: Subjective disease activity (VAS 0–4) -2 (100 mg), -1 (1,000 mg) Pain VAS (0–17) -3 (100 mg), -6 (1,000 mg) Tender joint count -8 (100 mg), -9 (1,000 mg) Swollen joint count -17 (100 mg), -12 (1,000 mg) Morning stiffness -0.5 h (100 mg), -2.37 h (1,000 mg) Grip strength +25 mmHg (100 mg), +23 mmHg (1,000 mg) 50 m walking time -8 s (100 mg), -9 s (1,000 mg) ESR -9 mm/h (100 mg), -11 mm/h (1,000 mg) New DMARDs within 1st month n = 4 (100 mg), n = 8 (1,000 mg)

Rheumatoid Arthritis: Corticosteroids

Trial

Oral steroids as bridge therapy in rheumatoid arthritis patients starting with parenteral gold. A randomized double-blind placebo-controlled trial

Substance

10 mg prednisone/day for 12 weeks 7.5 mg prednisone/day (weeks 13, 14) 5 mg prednisone/day (weeks 15, 16) 2.5 mg prednisone/day (weeks 17, 18, n = 20) Placebo (n = 20) Concomitant medication: 10 mg aurothioglucose (first week) 50 mg aurothioglucose/week (until week 20) 50 mg aurothioglucose/2–4 weeks NSAIDs were permitted DMARDs were permitted at the rheumatologists discretion Previous medication: DMARD Corticosteroids

Result

Oral prednisone (10 mg/day) reduced short-term disease activity in 60% of patients with active RA. After tapering the dose a rebound deterioration occurred

Patients

40 patients starting aurothioglucose Patients failed DMARD therapy ≥ 3 out of: ≥ 5 tender joints ≥ 3 swollen joints Morning stiffness ≥ 60 min ESR > 28 mm/h Hemoglobulin below normal limits

Authors

van Gestel AM, Laan RF, Haagsma CJ, van de Putte LB, van Riel PL

Publication

Br J Rheumatol. 1995 Apr;34(4):347–351

Follow up

44 weeks

Note

Decrease of DAS > 1.08: Week 1 n = 8 (gold + prednisone), n = 0 (gold) Week 2 n = 8 (gold + prednisone), n = 0 (gold) Week 4 n = 12 (gold + prednisone), n = 0 (gold) Week 8 n = 14 (gold + prednisone), n = 4 (gold) Week 12 n = 13 (gold + prednisone), n = 8 (gold) Week 16 n = 13 (gold + prednisone), n = 8 (gold) Week 20 n = 7 (gold + prednisone), n = 13 (gold) Week 24 n = 7 (gold + prednisone), n = 12 (gold) Week 28 n = 11 (gold + prednisone), n = 12 (gold) Week 32 n = 11 (gold + prednisone), n = 8 (gold) Week 36 n = 13 (gold + prednisone), n = 7 (gold) Week 40 n = 12 (gold + prednisone), n = 11 (gold) Week 44 n = 14 (gold + prednisone), n = 13 (gold) Joint erosions (median) 3.5 (gold + prednisone), 5.0 (gold) Joint space narrowing (median) 2.0 (gold + prednisone), 2.0 (gold) Total joint damage (median) 4.5 (gold + prednisone), 7.0 (gold)

3

4

Rheumatoid Arthritis: Corticosteroids

Title

Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial

Substance

10 mg of oral prednisone/day (n = 41) Placebo (n = 40) After 6 months: 2 g sulfasalazine/day as rescue medication Concomitant medication: NSAIDs were allowed in both groups 500 mg calcium Local glucocorticoid injections were permitted Physical therapy was permitted Additional use of paracetamol was permitted Previous medication: No cytotoxic or immunosuppressive drugs

Result

10 mg Prednisone/day in patients with early active rheumatoid arthritis was clinically beneficial, particularly in the first 6 months. It substantially inhibited progression of radiologic joint damage

Patients

81 patients with early active, untreated rheumatoid arthritis disease Disease duration < 1year Morning stiffness ≥ 30 min Joint tenderness and swelling ≥ 3 joints ESR ≥ 28 mm/h

Authors

van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW

Publication

Ann Intern Med. 2002 Jan 1;136(1):1–12

Follow up

24 months

Note

Radiologic damage 16 (prednisone), 29 (placebo) Change of: Grip strength (kPA) +13 (prednisone), +4 (placebo) Early-morning stiffness (min) -43 (prednisone), -28 (placebo) General well-being (mm) -1 (prednisone), 0 (placebo) 28-joint score for swelling -2 (prednisone), -1 (placebo) 28-joint score for tenderness -2 (prednisone), 0 (placebo) CRP (g/L) -1 (prednisone), 0 (placebo)

Rheumatoid Arthritis: Corticosteroids

Adverse events

Skin infections n = 0 (prednisone), n = 5 (placebo) Respiratory tract infection n = 13 (prednisone), n = 13 (placebo) Intestinal tract infection n = 1 (prednisone), n = 2 (placebo) Urinary tract infections n = 3 (prednisone), n = 2 (placebo) Stomatitis n = 0 (prednisone), n = 1 (placebo) Nausea n = 2 (prednisone), 4 n = 2 (placebo) Peptic symptoms n = 7 (prednisone), n = 3 (placebo) Bleeding ulcers n = 1 (prednisone), n = 2 (placebo) Diarrhoea n = 0 (prednisone), n = 2 (placebo) Hypertension n = 7 (prednisone), n = 6 (placebo) Angina pectoris n = 3 (prednisone), n = 3 (placebo) Myocardial infarctions n = 1 (prednisone), n = 0 (placebo) Ischemic cardiovascular accident n = 0 (prednisone), n = 2 (placebo) Arterial occlusion in the leg n = 0 (prednisone), n = 1 (placebo) Calf vein thrombosis n = 0 (prednisone), n = 2 (placebo) Heart rhythm disorders n = 1 (prednisone), n = 2 (placebo) Ankle edema n = 1 (prednisone), n = 0 (placebo) Ulcus cruris n = 3 (prednisone), n = 2 (placebo) Exanthema n = 2 (prednisone), n = 1 (placebo) Petechia n = 1 (prednisone), n = 1 (placebo) Glaucoma n = 1 (prednisone), n = 0 (placebo) Cataract n = 1 (prednisone), n = 1 (placebo) Vitreous humour haemorrhage n = 1 (prednisone), n = 0 (placebo) Vertebral fractures n = 7 (prednisone), n = 4 (placebo) Pelvic fractures n = 1 (prednisone), n = 0 (placebo) Impotence n = 0 (prednisone), n = 2 (placebo) Depression n = 1 (prednisone), n = 2 (placebo) Concentration disorder n = 0 (prednisone), n = 1 (placebo) Cervix carcinoma n = 0 (prednisone), n = 1 (placebo) Medication dependent diabetes mellitus n = 2 (prednisone), n = 1 (placebo) Systemic vasculitis n = 0 (prednisone), n = 2 (placebo)

5

6

Rheumatoid Arthritis: Corticosteroids

WOSERACT Trial

Lack of radiological and clinical benefit over 2 years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial WOSERACT: West of Scotland Early Rheumatoid Arthritis Corticosteroid Trial

Substance

Prednisolone 7 mg/day (n = 84) Placebo (n = 83) Concomitant medication: Sulphasalazine (no dosage specified)

Result

no radiological or clinical benefit was conferred by low dose prednisolone in patients maintained on a DMARD over 2 years

Patients

167 RA patients Disease duration < 3 years ³ 6 painful joints ³ 3 swollen joints ³ 20 min early morning stiffness Erythrocyte sedimentation rate ³ 28 mm/h C reactive protein ³ 10 mg/L

Authors

Capell HA, Madhok R, Hunter JA, Porter D, Morrison E, Larkin J, Thomson EA, Hampson R, Poon FW

Publication

Ann Rheum Dis. 2004 Jul;63(7):797–803

Follow up

2 years

Note

Change of: ESR (mm/h) -20 (prednisolone), -20 (placebo) C reactive protein (mg/L) -8 (prednisolone), -15 (placebo) Pain score -7 (prednisolone), -10 (placebo) Physician global assessment 0 (prednisolone), -1 (placebo) Patient global assessment 0 (prednisolone), 0 (placebo) Ritchie articular index -6 (prednisolone), -10 (placebo) HAQ -0.37 (prednisolone), -0.13 (placebo) Total X ray score: Rheumatologist 1: +19 (prednisolone), +15 (placebo) Rheumatologist 2: +9 (prednisolone), +5 (placebo)

Adverse events

Weight (kg) +4 kg (prednisolone), +3 kg (placebo) BMI (kg/m2) +1.3 (prednisolone), +0.9 (placebo) Bone mineral density (T score): Femoral neck -0.0185 (prednisolone), -0.0160 (placebo) Lumbar spine L2–L4 0.0060 (prednisolone), +0.125 (placebo)

Rheumatoid Arthritis: Corticosteroids

BARFOT-Trial

Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a 2-year randomized trial BARFOT Better Anti-rheumatic Farmacotherapy

Substance

7.5 mg/day prednisolone (n = 119) No prednisolone (n = 131) Concomitant medication: DMARD at the physician’s choice

Result

7.5 mg/day Prednisolone, added to the initial DMARD in patients with early RA, retarded the progression of radiographic damage after 2 years. Prednisolone treatment lead to a high remission rate and was well tolerated

Patients

Early active RA Disease duration £ 1 year DAS28 > 3.0

Authors

Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C, Hafström I

Publication

Arthritis Rheum. 2005 Nov;52(11):3360–3370

Follow up

2 years

DAS28

2.7 (prednisolone), 3.2 (no Prednisolone)

Note

Total Sharp score 1.8 (prednisolone), 3.5 (no Prednisolone) Newly eroded joints per patient 0.5 (prednisolone), 1.25 (no Prednisolone) Radiographic progression 25.9% (prednisolone), 39.3% (no Prednisolone) Disease remission 55.5% (prednisolone), 32.8% (no Prednisolone) Change of: HAQ –0.5 (prednisolone), -0.3 (no Prednisolone) CRP (mg/L) -13 (prednisolone), -13 (no Prednisolone) Bone mineral density z score -0.29 (prednisolone), -0.16 (no Prednisolone)

Adverse events

Diabetes n = 1 (prednisolone), n = 0 (no Prednisolone) Bleeding n = 1 (prednisolone), n = 0 (no Prednisolone) Nausea n = 0 (prednisolone), n = 1 (no Prednisolone) Dyspepsia n = 0 (prednisolone), n = 2 (no Prednisolone) Leucopoenia n = 1 (prednisolone), n = 3 (no Prednisolone) Thrombocytopenia n = 1 (prednisolone), n = 0 (no Prednisolone) Elevated liver enzymes n = 4 (prednisolone), n = 2 (no Prednisolone) Pneumonitis n = 1 (prednisolone), n = 0 (no Prednisolone) Proteinuria n = 2 (prednisolone), n = 0 (no Prednisolone) Alopecia n = 1 (prednisolone), n = 0 (no Prednisolone) Cushingoid appearance n = 1 (prednisolone), n = 0 (no Prednisolone) Hypertrichosis n = 0 (prednisolone), n = 1 (no Prednisolone) Rash n = 6 (prednisolone), n = 9 (no Prednisolone) Striae n = 1 (prednisolone), n = 0 (no Prednisolone) Abscess n = 0 (prednisolone), n = 1 (no Prednisolone) Stomatitis n = 1 (prednisolone), n = 0 (no Prednisolone) Fever n = 2 (prednisolone), n = 0 (no Prednisolone) Headache n = 0 (prednisolone), n = 2 (no Prednisolone) Tinnitus n = 0 (prednisolone), n = 1 (no Prednisolone) Weight gain n = 1 (prednisolone), n = 1 (no Prednisolone) Weight loss n = 1 (prednisolone), n = 0 (no Prednisolone) Vertigo n = 1 (prednisolone), n = 0 (no Prednisolone) Not specified n = 0 (prednisolone), n = 1 (no Prednisolone)

7

8

Rheumatoid Arthritis: Corticosteroids

Trial

A two year randomised controlled trial of intramuscular depot steroids in patients with established rheumatoid arthritis who have shown an incomplete response to disease modifying antirheumatic drugs

Substance

120 mg i.m. depomedrone (steroids, n = 48) Placebo (n = 43) Concomitant medication: 1 DMARD at physician`s choice i.m. Gold Penicillamine Methotrexate Azathioprine Ciclosporin

Result

Disease activity improved in the short term after i.m. depomedrone. It was associated with a small reduction in bone erosion at the cost of a significant increase in adverse events

Patients

91 RA patients Disease duration 2–10 years ³ 1 Erosion on plain X ray examination of the hands, wrists, and feet Continuous stable DMARD treatment ³ 3 months Active disease > 6 swollen joints Erythrocyte sedimentation rate >30 mm/h

Authors

Choy EH, Kingsley GH, Khoshaba B, Pipitone N, Scott DL; Intramuscular Methylprednisolone Study Group

Publication

Ann Rheum Dis. 2005 Sep;64(9):1288–1293. Epub 2005 Mar 10

Follow up

2 years

Note

Change of: Swollen joint count -3.6 (placebo), -5.2 (steroids) Tender joint count -0.7 (placebo), -2.5 (steroids) HAQ +0.1 (placebo), +0.1 (steroids) VAS pain (0–100) +0.6 (placebo), -6.7 (steroids) Patients’ global assessment -4.5 (placebo), -1.8 (steroids) Physicians’ global assessment -8.5 (placebo), -7.0 (steroids) ESR -2.9 (placebo), +1.4 (steroids) DAS -0.47 (placebo), -0.78 (steroids) Average Larsen score increase +6.27 (placebo) +0.28 (steroids)

Adverse events

Total adverse events n = 55 (placebo), n = 42 (steroids) Vertebral fracture and iatrogenic Addison’s disease n = 0 (placebo), n = 2 (steroids) Hypertension n = 1 (placebo), n = 4 (steroids) Facial swelling n = 0 (placebo), n = 3 (steroids) Bruising n = 0 (placebo), n = 3 (steroids) Osteoporosis n = 0 (placebo), n = 2 (steroids) Diabetes mellitus n = 0 (placebo), n = 1 (steroids) Myocardial infarction n = 0 (placebo), n = 1 (steroids) Hypercholesterolemia n = 0 (placebo), n = 1 (steroids)

Rheumatoid Arthritis: Corticosteroids

Trial

Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial

Substance

5 mg prednisolone/day (n = 94) Placebo (n = 98) Concomitant medication: DMARD therapy 10 mg Gold sodium thiomalate/week (increased to 50 mg/week after 3 weeks, total max. dose 2 g) 7.5 mg methotrexate (increased to 10–15 mg/week after 3 weeks) NSAIDs were permitted Calcium and vitamin D were permitted Estrogen replacement therapy for women was permitted Fluorine, bisphosphonates, and calcitonin was not allowed

Result

5 mg Prednisolone/day over 2 years in combination with background DMARD therapy substantially decreased radiographic progression in early RA at low risk

Patients

192 active RA patients Disease duration < 2 years ³ 3 positive out of: ³ 6 tender joints ³ 3 swollen joints Morning stiffness ³ 60 min Erythrocyte sedimentation rate ³ 28 mm/h

Authors

Wassenberg S, Rau R, Steinfeld P, Zeidler H

Publication

Arthritis Rheum. 2005 Nov;52(11):3371–3380

Follow up

24 months

Note

Change of: Ratingen score +1.2 (prednisolone) +4.3 (placebo) Sharp van der Heijde Score (Erosions) +2.5 (prednisolone) +7 (placebo) Sharp van der Heijde Score (joint space narrowing) +3.5 (prednisolone) +4.5 (placebo) Combined Sharp van der Heijde Score +5.3 (prednisolone) +11.4 (placebo) Joints with erosions +12.1% (prednisolone) +17.3% (placebo)

9

10

Adverse events

Rheumatoid Arthritis: Corticosteroids

Dermatitis 4% (prednisolone), 9% (placebo) Exanthema 10% (prednisolone), 8% (placebo) Hair loss 3% (prednisolone), 8% (placebo) Itching 4% (prednisolone), 2% (placebo) Aggravated rheumatoid arthritis 6% (prednisolone), 8% (placebo) Fractures 2% (prednisolone), 3% (placebo) Osteoporosis 1% (prednisolone), 3% (placebo) Synovitis 0% (prednisolone), 3% (placebo) Headache 4% (prednisolone), 0% (placebo) Cataract 5% (prednisolone), 6% (placebo) Glaucoma 3% (prednisolone), 0% (placebo) Diarrhoea 1% (prednisolone), 4% (placebo) Gastric distress 10% (prednisolone), 4% (placebo) Nausea 6% (prednisolone), 7% (placebo) Stomatitis 5% (prednisolone), 8% (placebo) Aphthous stomatitis 3% (prednisolone), 3% (placebo) Aphthous oral ulcers 0% (prednisolone), 3% (placebo) Gastric ulcers 3% (prednisolone), 0% (placebo) Cushing’s syndrome 5% (prednisolone), 0% (placebo) Hypertension 6% (prednisolone), 2% (placebo) Bronchitis 3% (prednisolone), 0% (placebo) Microhematuria 3% (prednisolone), 0% (placebo) Proteinuria 5% (prednisolone), 4% (placebo) Influenza-like syndrome 1% (prednisolone), 3% (placebo) Weight increase 4% (prednisolone), 0% (placebo)

Rheumatoid Arthritis: Corticosteroids

CAPRA-Trial

Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial CAPRA: Circadian Administration of Prednisone in Rheumatoid Arthritis

Substance

Modified-release prednisone tablet (n = 144), taken at bedtime Immediate-release prednisone tablet (n = 144), taken in the morning Concomitant medication: Glucocorticoids 2.5–10 mg ³ 3 months, stable ³ 1 month DMARDs stable for 3 months No biological 4 months before inclusion

Result

Modified-release prednisone led to a clinically relevant reduction of morning stiffness in addition to all known therapeutic effects of immediate-release prednisone. It was well tolerated and convenient to administer

Patients

288 patients with active rheumatoid arthritis Morning stiffness £ 45 min VAS ³ 30/100 mm Painful joints ³ 3 swollen joints ³ 1 ESR ³ 28 mm/h, or CRP concentration ³ 1.5 x upper limit

Authors

Buttgereit F, Doering G, Schaeffler A, Witte S, Sierakowski S, Gromnica-Ihle E, Jeka S, Krueger K, Szechinski J, Alten R

Publication

Lancet. 2008 Jan 19;371(9608):205–214

Follow up

12 weeks

Note

Change of: Morning stiffness -22.7% (modified-release), 0.4% (immediate-release) Change of pain (VAS) -5.36 (modified-release), -5.9 (immediate-release) HAQ -0.07 (modified-release), -0.09 (immediate-release) SF36 mental component score +7.37 (modified-release), +15.78 (immediate-release) SF36 physical component score +11.58 (modified-release), +15.32 (immediate-release) CRP 0.15 mg/l (modified-release), 0 mg/l (immediate-release) ESR -2.0 mm/h (modified-release), -8.0 mm/h (immediate-release) DAS 28 Change -0.53 (modified release), -0.75 (immediate release)

Adverse events

Rheumatoid arthritis 8% (modified release), 9% (immediate release) Headache 4% (modified release), 3% (immediate release) Abdominal pain 4% (modified release), 6% (immediate release) Nausea 4% (modified release), 3% (immediate release) Nasopharyngitis 3% (modified release), 6% (immediate release) Flushing 3% (modified release), 4% (immediate release) Chest pain 2% (modified release), 2% (immediate release) Hypertension 2% (modified release), 2% (immediate release) Vertigo 1% (modified release), 3% (immediate release) Dyspepsia 1% (modified release), 2% (immediate release) Bronchitis 1% (modified release), 4% (immediate release) Upper respiratory infection 1% (modified release), 2% (immediate release) Arthralgia 1% (modified release), 2% (immediate release)

11

12

Rheumatoid Arthritis: Corticosteroids

Trial

Efficacy of prednisone 1–4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial

Substance

(1) 1–4 tbl. of 1 mg prednisone for 12 weeks before randomisation (2) Substitution of a 1 mg prednisone (n = 15) Identical placebo tablet every 4 weeks (n = 16) (3) Comparison: observation over weeks taking the same number of either placebo or prednisone tablets as at baseline Concomitant medication: Almost all patients are also treated with methotrexate

Result

Significantly more patients withdrew from the trial after reduction of prednisone. The data suggested a robust effect for 1 to 4 mg prednisone for treatment of RA patients

Patients

RA patients With long-term 1–5 mg Prednisone/day

Authors

Pincus T, Swearingen CJ, Luta G, Sokka T

Publication

Ann Rheum Dis. 2009 Nov;68(11):1715–1720. Epub 2008 Dec 15

Follow up

12 weeks stable medication before randomization 24 weeks subsequent follow up

Note

Median change of: Physical function score (0–10) 0.33 (placebo), 0.00 (prednisone) Pain VAS score (0–10) 0.50 (placebo), 0.10 (prednisone) Patient global VAS score (0–10) 0.65 (placebo), 0.00 (prednisone) RAPID3 composite score (0–30) 1.20 (placebo), 0.54 (prednisone) Fatigue VAS score (0–10) 0.45 (placebo), 0.00 (prednisone) Morning stiffness (minutes) 0.00 (placebo), 0.00 (prednisone) Erythrocyte sedimentation rate -2.00 (placebo), 0.00 (prednisone) C-reactive protein 0.25 (placebo), -0.30 (prednisone) Withdrawal n = 11 (placebo), n = 3 (prednisone)

Adverse events

No meaningful toxicities were reported

Rheumatoid Arthritis: Atorvastatin

TARA-Trial

Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial TARA: Trial of Atorvastatin in Rheumatoid Arthritis

Substance

40 mg atorvastatin/day (n = 58) Placebo (n = 58) Concomitant medication: DMARD therapy was continued Intraarticular injections with corticosteroids were permitted NSAIDs were permitted Oral corticosteroids were permitted

Result

Atorvastation displayed a modest but clinically apparent anti-inflammatory effect in RA patients

Patients

116 patients with active RA Despite DMARD therapy ³ 6 swollen joints + 2 out of: ³ 6 tender joints Early morning stiffness ³ 30 min Erythrocyte sedimentation rate ³ 28 mm/h

Authors

McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N

Publication

Lancet. 2004 Jun 19;363(9426):2015–2021

Follow up

6 months

Note

Change of: DAS28 -0.5 (atorvastatin), 0.03 (placebo) Erythrocyte sedimentation rate (mm/h) -5.03 (atorvastatin), 1.91 (placebo) C-reactive protein (log mg/L) -0.46 (atorvastatin), 0.12 (placebo) Tender joint count -1.21 (atorvastatin), 0.38 (placebo) Early morning stiffness (log) -0.47 (atorvastatin), -0.13 (placebo) · Visual analogue score -5.07 (atorvastatin), 1.97 (placebo) Swollen joint count -2.69 (atorvastatin), -0.53 (placebo) Patient global assessment -4.14 (atorvastatin), 0.15 (placebo) Health assessment questionnaire 0.02 (atorvastatin), 0.04 (placebo) Cholesterol (mmol/L) -1.48 (atorvastatin), -0.01 (placebo) Triglyceride (mmol/L) -0.24 (atorvastatin), 0.07 (placebo) LDL-cholesterol (mmol/L) -1.40 (atorvastatin), -0.07 (placebo) HDL-cholesterol (mmol/L) 0.03 (atorvastatin), -0.04 (placebo) Fibrinogen (g/L) –0.38 (atorvastatin), 0 (placebo) Plasma viscosity (mPa/s) -0.05 (atorvastatin), 0·(placebo) Von Willebrand factor (IU/dL) -8.5 (atorvastatin), -4.53 (placebo) Intercellular adhesion molecule 1 (ng/mL) -22.6 (atorvastatin), 2.37 (placebo) Interleukin 6 (pg/mL) -6.6 (atorvastatin), 3.84 (placebo)

Adverse events

No significant liver function or muscle abnormality was detected

13

14

Rheumatoid Arthritis: Azathioprine

Trial

Disparity between clinical and immune responses in a controlled trial of Azathioprine in rheumatoid arthritis

Substance

1.5–2.0 mg/kg azathioprine/day (n = 30) Placebo (n = 30) Concomitant medication: All NSAIDs were permitted at stable doses Corticosteroids were permitted ³ 5 mg at stable doses ³ 2 months Intraarticular steroids were permitted Indomethacin was permitted at stable doses

Result

Azathioprine treatment was beneficial

Patients

60 RA patients No information on the patient cohort was provided

Authors

Goebel KM, Janzen R, Joseph K, Börngen U

Publication

Eur J Clin Pharmacol. 1976 Mar 22;09(5–6):405–410

Follow up

12 weeks

Note

Number of inflamed joints –60% (Aza) +30% (placebo) Grip strength +40% (Aza) not depicted (placebo)

Rheumatoid Arthritis: Azathioprine

Trial

Azathioprine in rheumatoid arthritis: double-blind study of full versus half doses versus placebo

Substance

Azathioprine 2.5 mg/kg/day (n = 15) Azathioprine 1.25 mg/kg/day (n = 14) Placebo (n = 13)

15

Concomitant medication: NSAIDs were continued Result

2.5 mg/kg azathioprine was superior to 1.25 mg/kg azathioprine and placebo

Patients

42 RA patients

Authors

Woodland J, Chaput de Saintonge DM, Evans SJ, Sharman VL, Currey HL

Publication

Ann Rheum Dis. 1981 Aug;40(4):355–359

Follow up

24 weeks

Note

Change of: Morning stiffness -1.2 min (placebo), -45 min (1.25 Aza), -27 min (2.5 Aza) Patient assessment -13.65 (placebo), -25.39 (1.25 Aza), -38.74 (2.5 Aza) Joint score -2.03 (placebo), -2.81 (1.25 Aza), -4.32 (2.5 Aza) Grip strength -2.2 (placebo), +12.9 (1.25 Aza), +31.6 (2.5 Aza) ESR change -4.7 mm/h (placebo), -11.8 mm/h (1 25 Aza), -8.1 mm/h (2.5 Aza)

Adverse events

All azathioprine treated patients: Vomiting n = 3 Rash n = 2 General unwell n = 1 Headache n = 3 Itching n = 1 Sore tongue n = 1 Leucopoenia n = 1 Giddiness n = 1 Left ventricular failure n = 1 Weakness n = 1

16

Rheumatoid Arthritis: Azathioprine vs. Methotrexate

Trial

Influence of Methotrexate and Azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double-blind study

Substance

100 mg azathioprine/day increased to 150 mg (n = 33) 7.5 mg methotrexate/week increased to 15 mg/week (n = 31) Concomitant medication: NSAIDS at stable dosages Prednisone £ 10 mg/day at stable dosage

Result

Low-dose methotrexate treatment of patients with rheumatoid arthritis showed significantly less radiologic progression than treatment with azathioprine

Patients

64 patients with active rheumatoid arthritis Non responded to parenteral gold and D-penicillamine ESR ³ 28 mm/h Morning stiffness ³ 45 min

Authors

Jeurissen ME, Boerbooms AM, van de Putte LB, Doesburg WH, Lemmens AM

Publication

Ann Intern Med. 1991 Jun 15;114(12):999–1004

Follow up

48 weeks

Note

Change of: Total score +4.0 (MTX), +7.6 (Aza) Erosion score +1.5 (MTX), +4.7 (Aza) Radiologic stabilization 29% (MTX), 10% (Aza)

Rheumatoid Arthritis: Hydroxychloroquine vs. Sulphasalazine

Trial

Effects of Hydroxychloroquine and Sulfasalazine on progression of joint damage in rheumatoid arthritis

Substance

500 mg sulphasalazine/day, increased by 500 mg/4 day to 2 g/day (n = 22) 200 mg hydroxychloroquine/day (n = 28) Concomitant medication: NSAIDs at stable doses Previous medication: No DMARDs No corticosteroids

Result

The increase in number of erosions and total score was significantly greater in the hydroxychloroquine than the sulfasalazine group

Patients

60 patients with rheumatoid arthritis Not effectively controlled by NSAIDs Morning stiffness ³ 60 min ³ 7 painful joints ³ 4 swollen joints ESR ³ 28 mm/h

Authors

van der Heijde DM, van Riel PL, Nuver-Zwart IH, Gribnau FW, van de Putte LB

Publication

Lancet. 1989 May 13;1(8646):1036–1038

Follow up

48 weeks

Note

Median erosion score 16 (HCQ), 5 (SSZ) New erosions 8.3 (HCQ), 2.1 (SSZ)

17

18

Rheumatoid Arthritis: Hydroxychloroquine

Trial

A double-blind comparative study of hydroxychloroquine and dapsone, alone and in combination, in rheumatoid arthritis

Substance

250 mg hydroxychloroquine/day (n = 28) 100 mg dapsone (n = 27) Hydroxychloroquine + dapsone (n = 25) Concomitant medication: NSAIDs were continued Previous medication: No DMARDs £ 2 weeks

Result

Combination therapy of hydroxychloroquine and dapsone was more effective, but less well tolerated than single drug treatments

Patients

80 RA patients Not adequately controlled by NSAIDs ³ 3 tender joints ³ 1 swollen joint ESR ³ 28 mm/h Haptoglogin ³ 2.8 g/l

Authors

Haar D, Sølvkjaer M, Unger B, Rasmussen KJ, Christensen L, Hansen TM

Publication

Scand J Rheumatol. 1993;22(3):113–118

Follow up

24 weeks

Note

Change of: Morning stiffness (h) -0.5 (HCQ), –0.75 (Dapsone), -1.38 (Dapsone + HCQ) Pain Score (Vas, mm) -4.0 (HCQ), -15 (Dapsone), -24 (Dapsone + HCQ) Tender joint count -1.2 (HCQ), -1.6 (Dapsone), -5.5 (Dapsone + HCQ) Swollen joint count -2 (HCQ), -4.7 (Dapsone), -8.5 (Dapsone + HCQ) ESR –5.5 (HCQ), -11 (Dapsone), -20.5 (Dapsone + HCQ) CRP (mg/l) +3 (HCQ), -9.8 (Dapsone), -9.5 (Dapsone + HCQ) Larsen score +15 (HCQ), +0.5 (Dapsone), +5.0 (Dapsone + HCQ)

Adverse events

Dyspepsia n = 2 (HCQ), n = 2 (Dapsone), n = 3 (Dapsone + HCQ) Anemia n = 0 (HCQ), n = 2 (Dapsone + HCQ), n = 0 (Dapsone + HCQ) Rash n = 1 (HCQ), n = 1 (Dapsone + HCQ) Ulcer bleeding n = 0 (HCQ), n = 1 (Dapsone), n = 0 (Dapsone + HCQ)

Rheumatoid Arthritis: Hydroxychloroquine

HERA-Trial

A randomized trial of Hydroxychloroquine in early rheumatoid arthritis: the HERA Study HERA: Hydroxychloroquine in early rheumatoid arthritis

Substance

Hydroxychloroquine 7 mg/kg per day (max. 400 mg/day, n = 59) Placebo tablets (n =60 pts) Concomitant medication: NSAIDs were continued Acetaminophen, propoxyphene, and codein were permitted Intraarticular corticosteroid injections from week 2 to week 24 were permitted Previous medication: No DMARDs £ 1 month No corticosteroids (oral or injection) £ 1 month

Result

Hydroxychloroquine in early RA had a significant benefit on synovitis, pain, and physical disability

Patients

148 RA patients with active disease Despite NSAID treatment Disease £ 2 years Never received a second-line drug

Authors

The HERA study group

Publication

Am J Med. 1995 Feb;98(2):156–168

Follow up

36 months

Note

Change of: Tender joint count -10 (HCQ), -7 (placebo) Swollen joint score -4 (HCQ), 0 (placebo) Grip strength +57 mmHg (HCQ), +28 mmHg (placebo) Morning stiffness -79 min (HCQ), -59 min (placebo) HAQ -0.5 (HCQ), -0.2 (placebo)

19

20

Rheumatoid Arthritis: Hydroxychloroquine

Trial

Dose-loading with Hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension

Substance

Phase 1 (screening visit – week 1): 2 × 250 mg naproxen/day Phase 2 (Week 1–6): 400 mg hydroxychloroquine/day (n = 71) 800 mg hydroxychloroquine/day (n = 71) 1,200 mg hydroxychloroquine/day (n = 66) Phase 3 (week 7–24): Open-label hydroxychloroquine 400 mg/day Concomitant medication: 2 × 250 mg naproxen/day Prednisone £ 10 mg/day Effective contraception No i.a. injections of steroids or other agents were during phases 1 or 2 A single injection of 1 joint was allowed during phase 3 Previous medication: I.a. or intramuscular steroids £ 1 month I.m. gold salts, D-penicillamine, methotrexate, or cytotoxic or immunosuppressive agents ³ 2 months

Result

Higher dose of hydroxychloroquine increased the degree of clinical response in patients with early, predominantly seronegative RA at 6 weeks. Adverse gastrointestinal events were dose related. Adverse ocular events were dose independent

Patients

212 early RA patients Stabilized with 1,000 mg naproxen/day ³ 6 tender joints ³ 3 swollen joints Erythrocyte sedimentation rate ³ 28 mm/h Morning stiffness ³ 1 hour

Authors

Furst DE, Lindsley H, Baethge B, Botstein GR, Caldwell J, Dietz F, Ettlinger R, Golden HE, McLaughlin GE, Moreland LW, Roberts WN, Rooney TW, Rothschild B, Sack M, Sebba AI, Weisman M, Welch KE, Yocum D

Publication

Arthritis Rheum. 1999 Feb;42(2):357–365

Follow up

24 weeks

Rheumatoid Arthritis: Hydroxychloroquine

Note

21

Change of at week 6 Tender joint count -4.2 (HCQ 400), -3.6 (HCQ 800), -5.2 (HCQ 1200) Swollen joint count -2.6 (HCQ 400), -2.0 (HCQ 800), -3.1 (HCQ 1200) Physician global assessment (10-cm VAS) -12.3 (HCQ 400), -7.4 (HCQ 800), -18.0 (HCQ 1200) Patient global assessment (10-cm VAS) -15.1 (HCQ 400), -14.8 (HCQ 800), -20.1 (HCQ 1200) Patient pain assessment (10-cm VAS) -13.4 (HCQ 400), -15.2 (HCQ 800), -17.1 (HCQ 1200) Morning stiffness (minutes) -14 (HCQ 400), -3 (HCQ 800), -5 (HCQ 1200) M-HA -0.16 (HCQ 400), -0.27 (HCQ 800), -0.15 (HCQ 1200) ESR (mm/h) -2.6 (HCQ 400), -2.7 (HCQ 800), -8.0 (HCQ 1200) Change of at week 24 Tender joint count -6.9 (HCQ 400), -4.6 (HCQ 800), -6.4 (HCQ 1200) Swollen joint count -2.2 (HCQ 400), -2.4 (HCQ 800), -4.6 (HCQ 1200) Patient global assessment (10-cm VAS) -13.6 (HCQ 400), -11.8 (HCQ 800), -17.9 (HCQ 1200) Physician global assessment (10-cm VAS) -14 (HCQ 400), -10 (HCQ 800), -18 (HCQ 1200) Patient pain assessment (10-cm VAS) -16.8 (HCQ 400), -18.4 (HCQ 800), -17.4 (HCQ 1200) Morning stiffness (minutes) -38 (HCQ 400), -21 (HCQ 800), -15 (HCQ 1200) M-HAQ -0.26 (HCQ 400), -0.26 (HCQ 800), -0.21 (HCQ 1200) ESR (mm/h) -8.3 (HCQ 400), -1.1 (HCQ 800), -11.8 (HCQ 1200) CRP (mm/h) -0.2 (HCQ 400), +0.3 (HCQ 800), -0.5 (HCQ 1200)

Adverse events

Body as a whole n = 12 (HCQ 400), n = 14 (HCQ 800), n = 7 (HCQ 1200) Central nervous system n = 6 (HCQ 400), n = 12 (HCQ 800), n = 4 (HCQ 1200) Headache n = 1 (HCQ 400), n = 8 (HCQ 800), n = 3 (HCQ 1200) Gastrointestinal n = 19 (HCQ 400), n = 12 (HCQ 800), n = 13 (HCQ 1200) Nausea, vomiting n = 9 (HCQ 400), n = 8 (HCQ 800), n = 7 (HCQ 1200) Hearing n = 2 (HCQ 400), n = 0 (HCQ 800), n = 3 (HCQ 1200) Psychiatric n = 2 (HCQ 400), n = 3 (HCQ 800), n = 0 (HCQ 1200) Respiratory n = 11 (HCQ 400), n = 10 (HCQ 800), n = 11 (HCQ 1200) Skin n = 6 (HCQ 400), n = 6 (HCQ 800), n = 8 (HCQ 1200) Vision n = 5 (HCQ 400), n = 4 (HCQ 800), n = 1 (HCQ 1200)

22

Rheumatoid Arthritis: Hydroxychloroquine

HERA-Trial

Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year follow-up on the Hydroxychloroquine in early rheumatoid arthritis (HERA) study HERA: Hydroxychloroquine in early rheumatoid arthritis

Substance

Hydroxychloroquine 7 mg/kg per day (max. 400 mg/day, n = 59) Placebo tablets (n = 60) Concomitant medication: NSAIDs were continued Acetaminophen, propoxyphene, and codein were permitted Intraarticular corticosteroid injections from week 2 to week 24 were permitted Previous medication: No DMARDs £ 1 month No corticosteroids (oral or injection) £ 1 month After the initial trial (9 months): No restrictions were made on treatment Second line agents: HCQ n = 39 (HCQ), n = 32 (placebo) MTX n = 14 (HCQ), n = 17 (placebo) I.m. gold n = 9 (HCQ), n = 10 (placebo) Other (oral gold, Aza, D-penicillamine) n = 8 (HCQ), n = 12 (placebo) Oral corticosteroids n = 8 (HCQ), n = 11 (placebo) Injected corticosteroids n = 20 (HCQ), n = 28 (placebo)

Result

Hydroxychloroquine had a positive effect on long-term subjective patient outcome

Patients

115 RA patients Disease duration < 2 a No DMARD therapy After finishing the first 9 months of HERA trial

Authors

Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne JC, M’Seffar A, Joseph L, Bombardier C, Esdaile JM

Publication

J Rheumatol. 2000 Mar;27(3):623–629

Follow up

3 years

Note

Change of (month 45): Pain -1.29 (HCQ), -1.09 (placebo) Physical disability index -0.48 (HCQ), -0.4 (placebo) Psychological disability –0.36 (HCQ), –0.55 (placebo) Effect on global wellbeing -0.59 (HCQ), -0.58 (placebo)

Rheumatoid Arthritis: Hydroxychloroquine

23

Trial

Efficacy and safety of Hydroxychloroquine sulphate in rheumatoid arthritis: a randomized, double-blind, placebo controlled clinical trial - an Indian experience

Substance

2 × 200 mg hydroxychloroquine/day for 8 weeks (n = 61) Followed by 1 × 200 mg hydroxychloroquine/day for 4 weeks (n = 61) Placebo (n = 61) Concomitant medication: 2 × 100 mg nimesulide/day Previous medication: No i.m. gold £ 3 months No methotrexate £ 3 months No D-penicillamine £ 3 months No sulphasalazine £ 3 months No chloroquine £ 3 months No corticosteroids £ 3 months

Result

Hydroxychloroquine treatment of RA patients was effective and well-tolerated

Patients

122 RA patients Failed NSAID treatment ³ 5 painful joints ³ 5 swollen joints VAS 25–75/100 mm Morning stiffness ³ 30 min

Authors

Das SK, Pareek A, Mathur DS, Wanchu A, Srivastava R, Agarwal GG, Chauhan RS

Publication

Curr Med Res Opin. 2007 Sep;23(9):2227–2234

Follow up

12 weeks

ACR 20

40.4% (HCQ), 20.7% (placebo)

Note

20% improvement in: Swollen joint count 57.9% (HCQ), 37.9% (placebo) Tender joint count 52.6% (HCQ), 29.3% (placebo) VAS pain score 57.9% (HCQ), 31% (placebo) Patients global assessment 50.9% (HCQ), 37.9% (placebo) Physicians global assessment 49.1% (HCQ), 32.8% (placebo) ESR 42.1% (HCQ), 34.5% (placebo) ARA functional class 45.6% (HCQ), 29.3% (placebo)

Adverse events

Gastritis n = 1 (HCQ), n = 1 (placebo) Epigastric pain n = 1 (HCQ), n = 2 (placebo) Anorexia n = 0 (HCQ), n = 1 (placebo) Nausea n = 1 (HCQ), n = 0 (placebo) Burning sensation in the epigastrium n = 1 (HCQ), n = 0 (placebo) Hepatitis n = 0 (HCQ), n = 1 (placebo) Retrosternal pain n = 0 (HCQ), n = 1 (placebo) Headache n = 1 (HCQ), n = 0 (placebo)

24

Rheumatoid Arthritis: Chloroquine vs. Ciclosporin

Trial

A randomized, double-blind, 24-week controlled study of low-dose Ciclosporin versus chloroquine for early rheumatoid arthritis

Substance

2.5 mg/kg Ciclosporin/day (maintenance dose 3.6 mg/kg/day, n = 22) 300 mg Chloroquine/day (maintenance dose 100 mg/day, n = 22) Concomitant medication: NSAIDs at stable dose Previous medication: No DMARDs Adequate Dose of NSAIDs ³ 3 months

Result

Treatment of active early RA patients with ciclosporin or chloroquine was effective. Slight renal function impairment was observed after 24 weeks of drug administration of either drug

Patients

Early RA with active disease Duration £ 2 years + min. 3 out of: ³ 3 swollen joints ³ 6 tender joints Morning stiffness ³ 30 min. ESR ³ 28 mm/h

Authors

Landewé RB, Goei Thè HS, van Rijthoven AW, Breedveld FC, Dijkmans BA

Publication

Arthritis Rheum. 1994 May;37(5):637–643

Follow up

24 weeks

Note

Change of: Swollen joint count -7 (CsA), -7 (HCQ) Tender joint count -5 (CsA), -4 (HCQ) Morning stiffness -34 (CsA), -48 (HCQ) Pain (VAS, cm) -1.6 (CsA), -0.9 (HCQ) ESR (mm/h) +3 (CsA), -5 (HCQ) CRP –6 (CsA), -4 (HCQ)

Adverse events

Gastrointestinal symptoms n = 11 (CsA), n = 11 (HCQ) Paresthesia n = 11 (CsA), n = 4 (HCQ) Serum creatinine >130% n = 7 (CsA), n = 3 (HCQ) Gingival symptoms n = 4 (CsA), n = 0 (HCQ) Hyperkalemia n = 4 (CsA), n = 0 (HCQ) Exanthema n = 0 (CsA), n = 4 (HCQ) Edema n = 3 (CsA), n = 0 (HCQ) Headache n = 3 (CsA), n = 2 (HCQ) Hypomagnesaemia n = 2 (CsA), n = 0 (HCQ) Hypertrichosis n = 1 (CsA), n = 1 (HCQ) Tremor n = 1 (CsA), n = 0 (HCQ) Liver function abnormality n = 1 (CsA), n = 1 (HCQ)

Rheumatoid Arthritis: Ciclosporin

25

Trial

Radiologic evidence of disease modification in rheumatoid arthritis patients treated with Ciclosporin. Results of a 48-week multicenter study comparing low-dose Ciclosporin with placebo. Norwegian Arthritis Study Group

Substance

5 mg/kg ciclosporin A/day (n = 61) Placebo (n = 61) Concomitant medication: NSAIDs at stable dose 15 mg prednisolone/day Tapered from 3,75 mg/day over 16 weeks Anti hypertensive therapy according to local standards Previous medication: No DMARDs 1 month prior randomization No cytotoxic agents

Result

Ciclosporin treatment of RA patients had a disease-modifying effect

Patients

122 patients with active RA ³ 3 swollen joints + 2 out of: ³ 9 tender joints ³ 45 min morning stiffness ESR ³ 28 mm/h

Authors

Førre O

Publication

Arthritis Rheum. 1994 Oct;37(10):1506–1512

Follow up

48 weeks

Note

Change of: Ritchie articular index -7.7 (CsA), -2.4 (placebo) Number of swollen joints -3.6 (CsA), -0.3 (placebo) Pain score (max 4) -0.5 (CsA), -0.1 (placebo) Grip strength +6.6 mmHg (CsA), +7.3 mmHg (placebo) Morning stiffness -46.2 min (CsA), -12.2 (placebo) Patient’s global assessment +2.02 (CsA), +0.79 (placebo) Physicians global assessment +1.79 (CsA), +0.67 (placebo) ESR (mm/h) -3.5(CsA), -2 (placebo) CRP (mg/dl) -13.4 (CsA), +5 (placebo) Larsen Score -0.01 (CsA), +0.17 (placebo) Number of erosions: +0.06 (CsA), +1.03 (placebo)

Adverse events

Nephrotoxicity in high dose >7.5 mg/kg/day CsA 5 patients had to be treated with antihypertensive drugs 2 patients were withdrawn from the study because of increased serum creatinine Hypertrichosis 42% (CsA), 5% (placebo) Tremor 18% (CsA), 2% (placebo) Headache 17% (CsA), 5% (placebo) Dysplesia 15% (CsA), 8% (placebo) Nausea 12% (CsA), 8% (placebo) Parasthesia 10% (CsA), 3% (placebo) Flushing 10% (CsA), 5% (placebo) Diarrhea 2% (CsA), 2% (placebo)

26

Rheumatoid Arthritis: Ciclosporin vs. Chloroquine

Trial

Low dose Ciclosporin in early rheumatoid arthritis: effective and safe after two years of therapy when compared with Chloroquine

Substance

2.5 mg/kg ciclosporin A/day (n = 22, increased by 25 mg/day to 5 mg/kg/day) 200 mg chloroquine/day (n = 22, after the first month 100 mg/day) Concomitant medication: NSAIDs at stable dose Anti hypertensive therapy according to local standards Previous medication: No previous DMARD treatment Treated with an adequate dose of NSAIDs ³ 3 months

Result

Treatment of early RA patients with low dose ciclosporin A developed the maximal efficacy after one year of therapy. Ciclosporin A maintained clinical efficacy and safety comparable to chloroquine

Patients

44 RA patients Disease duration < 2 years ³ 3 swollen joints ³ 6 tender joints Morning stiffness ³ 30 min. ESR ³ 28 mm/h

Authors

van den Borne BE, Landewé RB, The HS, Breedveld FC, Dijkmans BA

Publication

Scand J Rheumatol. 1996;25(5):307–316

Follow up

2 years

Note

End of follow up (study completers): Mean CsA dose 2.7 mg/kg/day (n = 15) Mean Chloroquine dose (n = 11) 100 mg/day Paulus 50% response 80% (CsA) 45% (Chloroquine) Paulus 20% response 93% (CsA) 82% (Chloroquine) Change of: Swollen joint count -11 (CsA) -6 (Chloroquine) Ritchie articular index -14 (CsA) -8 (Chloroquine) Pain assessment (VAS 0–10) -1 (CsA) -2.7 (Chloroquine) D-HAQ (0–3) -0.41 (CsA) -0.31 (Chloroquine) ESR (mm/h) 0 (CsA) -13 (Chloroquine) CRP (mg/l) -25 (CsA) -14 (Chloroquine) Joint space narrowing +2 (CsA) +3 (Chloroquine) Erosion score +2 (CsA) +6 (Chloroquine) Joints affected +2 (CsA) +4 (Chloroquine)

Adverse events

Decrease of creatinine clearance 20% (CsA), 14% (Chloroquine)

Rheumatoid Arthritis: Ciclosporin vs. parenteral Gold

27

Trial

Progression of joint damage in early active severe rheumatoid arthritis during 18 months of treatment: comparison of low-dose ciclosporin and parenteral gold

Substance

3 mg/kg Ciclosporin/day (n = 45, after week 4 increased to max. 5 mg/kg) 10 mg parenteral Gold/week (n = 65, increased weekly to max 50 mg/week) Concomitant medication: NSAIDs were permitted Prednisolone £ 10 mg/day, average £ 7.5 mg/day Corticosteroid injection £ 4/joint No other DMARDs Previous medication: Failing min 1 DMARD

Result

Retardation of joint damage progression was similar in patients treated with ciclosporin or parenteral gold. Ciclosporin was better tolerated and adherence to therapy was increased as compared to gold

Patients

375 active severe RA patients Disease duration < 3 years Iuxtraarticular erosions detected by X ray Positive Rheumatoid factor + ³ 3 out of: ³ 6 tender joints ³ 3 swollen joints Morning stiffness ³ 1 hour ESR ³ 28 mm/h CRP ³ 20 mg/l

Authors

Zeidler HK, Kvien TK, Hannonen P, Wollheim FA, Førre O, Geidel H, Hafström I, Kaltwasser JP, Leirisalo-Repo M, Manger B, Laasonen L, Markert ER, Prestele H, Kurki P

Publication

Br J Rheumatol. 1998 Aug;37(8):874–882

Follow up

18 months

28

Note

Rheumatoid Arthritis: Ciclosporin vs. parenteral Gold

Change of: Larsen dale joint damage score +11.7 (ciclosporin), +9.8 (gold) Erosion score change +3.2 (ciclosporin), +3.0 (gold) Number of erosions +8.7 (ciclosporin), +7.2 (gold) At end point: HAQ 1.1 (ciclosporin), 1.1 (gold) RAI 18.1 (ciclosporin), 18.4 (gold) Number of swollen joints 8.6 (ciclosporin), 8.7 (gold) Pain (VAS) 53.6 (ciclosporin), 49.1 (gold) Morning stiffness 119 min (ciclosporin), 105.7 min (gold) Grip strength (mmHg, left hand) 234.3 (ciclosporin), 256.9 (gold) Grip strength (mmHg, right hand) 239.8 (ciclosporin), 262.2 (gold) Erythrocyte sedimentation rate (mm/h) 48.1 (ciclosporin), 42.0 (gold) CRP (g/l) 37.6 (ciclosporin), 33.1 (gold)

Adverse events

Leading to withdrawal: Renal n = 20 (ciclosporin), n = 9 (gold) Neoplasm n = 2 (ciclosporin), n = 0 (gold) Infections n = 1 (ciclosporin), n = 1 (gold) Gastrointestinal disorders n = 10 (ciclosporin), n = 15 (gold) Skin disorder n = 3 (ciclosporin) n = 40 (gold) Hypertension n = 11 (ciclosporin), n = 0 (gold) Red and white cell disorder n = 3 (ciclosporin), n = 2 (gold) Thrombopenia n = 0 (ciclosporin), n = 4 (gold) Central and peripheral nervous system n = 3 (ciclosporin), n = 2 (gold) Liver and biliary system n = 1 (ciclosporin), n = 1 (gold) Other n = 10 (ciclosporin), n = 4 (gold)

Rheumatoid Arthritis: Ciclosporin

Trial

Ciclosporin A in the treatment of early rheumatoid arthritis. A prospective, randomized 24-month study

Substance

3 mg/kg ciclosporin A /day (n = 52) 0.15 mg/kg methotrexate/week (n = 51)

29

Concomitant medication: Prednisone £ 7.5 mg/day Paracetamol was permitted Acetaminophen was permitted No DMARDs were permitted No NSAIDs were permitted No colchicine was permitted No phenytoin was permitted No ketoconazole was permitted Previous medication: No prior DMARD treatment Result

Ciclosporin A was effective, well tolerated and safe in the long-term treatment of RA. Early intervention appeared to be crucial to limit the development of joint damage in RA patients

Patients

Early diagnosis of RA Disease duration < 3 years

Authors

Drosos AA, Voulgari PV, Papadopoulos IA, Politi EN, Georgiou PE, Zikou AK

Publication

Clin Exp Rheumatol. 1998 Nov-Dec;16(6):695–701

Follow up

24 months

Note

Change of: Morning stiffness (min) -57.5 (CsA), -59.5 (MTX) Grip strength right hand (mmHg) +106.2 (CsA), +107.7 (MTX) Grip strength left hand (mmHg) 103.3 (CsA), +109.0 (MTX) Total joint count -13.7 (CsA), -13.3 (MTX) Tender joint count -12.4 (CsA), -12.5 (MTX) Swollen joint count -8.6 (CsA), -9.6 (MTX) Pain Score (cm) -4.2, (CsA) -4.2 (MTX) ESR (mm/h) -26.2 (CsA), -27.5 (MTX) CRP -23.3 (CsA), -24.9 (MTX)

Adverse events

Hypertension 10% (CsA), 0% (MTX) Hypertrichosis 4% (CsA), 0% (MTX) Gingival Hyperplasia 2% (CsA), 0% (MTX) Increased liver enzymes 0% (CsA), 6% (MTX) Nausea and vomiting 0% (CsA), 6% (MTX)

30

Rheumatoid Arthritis: Ciclosporin

Trial

Ciclosporin A in Rheumatoid Arthritis: Randomized, Placebo Controlled Dose Finding Study

Substance

Placebo (n = 61) 1.5 mg/kg ciclosporin A/day (n = 89) 2.5 mg/kg ciclosporin A/day (n = 94) Concomitant medication: Prednisone £ 10 mg/day NSAIDs were permitted Contraception was required Previous medication: Failed parenteral gold Failed D-penicillamine Failed chloroquine/hydroxychloroquine Failed MTX

Result

2,5 mg/kg ciclosporin A/day lead to an improvement of the disease activity in RA patients. 1.5 mg/kg/day ciclosporin A was not effevtive

Patients

246 RA patients who have Failed min 1 DMARD therapy ³ 6 painful or tender joints ESR ³ 30 mm

Authors

Altman RD, Schiff M, Kopp EJ, and the Ciclosporin A Study Group

Publication

The Journal of Rheumatology 1999;26(2):2102–2109

Follow up

16 weeks randomized trial and 4 weeks follow up

ACR 20

16% (placebo), 19% (1.5 mg CsA), 33% (2.5 mg CsA)

Rheumatoid Arthritis: Ciclosporin

Note

Change of: Number of painful and tender joints -0.4 (placebo), -0.8 (1.5 mg CsA), -5.8 (2.5 mg CsA) Patients’ glogal assessment -0.2 (placebo), -0.8 (1.5 mg CsA), -0.9 (2.5 mg CsA) Physicians’ Global assessment -0.1 (placebo), -0.6 (1.5 mg CsA), -0.9 (2.5 mg CsA)

Adverse events

New serum creatinine >1.2 mg/dL 0% (placebo), 10% (1.5 mg CsA), 18% (2.5 mg CsA) Proteinuria 8% (placebo), 9% (1.5 mg CsA), 0% (2.5 mg CsA) Abdominal discomfort 7% (placebo), 10% (1.5 mg CsA), 19% (2.5 mg CsA) Diarrhea 8% (placebo), 8% (1.5 mg CsA), 5% (2.5 mg CsA) Nausea 10% (placebo), 7% (1.5 mg CsA), 14% (2.5 mg CsA) Canker scores 8% (placebo), 7% (1.5 mg CsA), 4% (2.5 mg CsA) Vomiting 5% (placebo), 7% (1.5 mg CsA), 2% (2.5 mg CsA) Throat discomfort 5% (placebo), 6% (1.5 mg CsA), 1% (2.5 mg CsA) Hypertension 3% (placebo), 9% (1.5 mg CsA), 8% (2.5 mg CsA) Cough 3% (placebo), 8% (1.5 mg CsA), 6% (2.5 mg CsA) Nasal congestion 2% (placebo), 2% (1.5 mg CsA), 6% (2.5 mg CsA) Headache 11% (placebo), 9% (1.5 mg CsA), 9% (2.5 mg CsA) Dizziness 2% (placebo), 7% (1.5 mg CsA), 4% (2.5 mg CsA) Hirsutism 0% (placebo), 3% (1.5 mg CsA), 12% (2.5 mg CsA) Hyperglycemia 5% (placebo), 6% (1.5 mg CsA), 5% (2.5 mg CsA) Discontinuation: Total 2% (placebo), 3% (1.5 mg CsA), 1% (2.5 mg CsA) Hypercreatinemia 0% (placebo), 2% (1.5 mg CsA), 0% (2.5 mg CsA) Nephritis 2% (placebo), 0% (1.5 mg CsA), 0% (2.5 mg CsA) Hematuria 0% (placebo), 1% (1.5 mg CsA), 0% (2.5 mg CsA) Infection 2% (placebo), 0% (1.5 mg CsA), 0% (2.5 mg CsA)

31

32

Rheumatoid Arthritis: Ciclosporin vs. Methotrexate

Trial

Influence of Ciclosporin A on radiological progression in early rheumatoid arthritis patients: a 42-month prospective study

Substance

3 mg/kg ciclosporin A/day (n = 52) 0.15 mg/kg methotrexate per week (n = 51) Concomitant medication: Prednisone £ 7.5 mg/day Paracetamol was permitted Acetaminophen was permitted Previous medication: No DMARDs

Result

Radiological disease progression and joint damage deterioration was delayed in early RA patients treated with ciclosporin A or methotrexate. Early intervention in RA patients wsa crucial for the future development of joint damage

Patients

103 early RA patients

Authors

Drosos AA, Voulgari PV, Katsaraki A, Zikou AK

Publication

Rheumatol Int. 2000;19(3):113–118

Follow up

42 months

Note

Radiographically stable 71% (CsA), 76% (MTX) Change of: Morning stiffness change -55.4 min (CsA), -68.1 min (MTX) Tender joint count -12.2 (CsA), -12.5 (MTX) Swollen joint count -8.4 (CsA), -9.4 (MTX) Pain score -4.2 cm (CsA), -4.2 cm (MTX) ESR change -25.4 mm/h (CsA), -28.1 mm/h (MTX) CRP change -23.3 per mille (CsA), -25.2 per mille (MTX)

Adverse events

Hypertension 15% (CsA), 0% (MTX) Hypertrichosis 6% (CsA), 0% (MTX) Gingival hyperplasia 6% (CsA), 0% (MTX) Nausea 0% (CsA), 14% (MTX) Increase liver enzymes 0% (CsA), 8% (MTX) Interstitial pneumonitis 0% (CsA), 2% (MTX)

Rheumatoid Arthritis: Ciclosporin vs. Azathioprine

Trial

A randomised double-blind trial of Ciclosporin and Azathioprine in refractory rheumatoid arthritis

Substance

5 mg/kg ciclosporin A/day (mean dose 4.2 mg/kg, n = 25) 1.5–2 mg/kg azathioprine/day (after 2 month dose could be increased to 2.5 mg/kg/day, mean dose 1.7 mg/kg, n = 27) Concomitant medication: Oral corticosteroids were permitted NSAIDs were permitted Analgetics were permitted Previous medication: Failded NSAId therapy Failed therapy with gold or D-penicillamine

Result

Treatment of severely affected RA patients with ciclosporin and azathioprine was effective. Ciclosporin toxicities were predictable and manageable but required close monitoring

Patients

RA patients with active disease min. 6 tender joints ESR > 30 mm/h Morning stiffness ³ 45 NSAIDs, gold, or D-penicillamine failed

Authors

Ahern MJ, Harrison W, Hollingsworth P, Bradley J, Laing B, Bayliss C

Publication

Aust N Z J Med. 1991 Dec;21(6):844–849

Follow up

6 months

Note

Change of: Morning stiffness -84 min (CsA), -64 min (Aza) Ritchie index -8 (CsA), -6 (Aza) Tender joint count -5 (CsA), -3 (Aza) Swollen joint count -3 (CsA), -3 (Aza) VAS Pain -24 (CsA), -21 (Aza) ESR +6 (CsA), -3 (Aza) CRP -15 (CsA), -7 (Aza) Rheumatoid factor -32 (CsA), -154 (Aza) VAS function -17 (CsA), -24 (Aza) Index of Lee -2 (CsA), -4 (Aza) HAQ –0.1 (CsA), -0.1 (Aza)

Adverse events

Ciclosporin A: Gastrointestinal symptoms Paresthesia Tremor Hypertension Renal dysfunction Azathioprine: Gastrointestinal symptoms No precise percentages were listed

33

34

Rheumatoid Arthritis: Cyclophosphamide

Trial

A controlled trial of Cyclophosphamide in rheumatoid arthritis

Substance

150 mg Cyclophosphamide/day (n = 20) 15 mg Cyclophosphamide/day (n = 28) Concomitant medication: Contraception was required Corticosteroids were permitted NSAIDs were permitted No other cytotoxic agents No gold salts No phenylbutazone Previous medication: Failed to improve on gold salts Failed to improve on corticosteroids No prior cytotoxic agents

Result

RA patients treated with 150 mg cyclophosphamide/day showed a greater reduction of disease activity and developed fewer erosions than patients treated with 15 mg cyclophosphamide/day

Patients

48 patients with severe RA

Authors

Cooperating Clinics Committee of the American rheumatism Association

Publication

New England Journal of Medicine 283, 1970: p.883

Follow up

32 weeks

Note

Morning stiffness improved 41% (15 mg), 76% (150 mg) Grip strength improved 43% (15 mg), 70% (150 mg) No. of painful joints improved 43% (15 mg), 90% (150 mg) No. of swollen joints improved 46% (15 mg), 85% (150 mg) 50 m foot walk improved 38% (15 mg), 83% (150 mg) ESR improved 54% (15 mg), 44% (150 mg)

Adverse events

Hemorrhagic cystitis n = 0 (15 mg), n = 2 (150 mg) Dysuria without hematuria n = 0 (15 mg), n = 7 (150 mg) Herpes zoster n = 0 (15 mg), n = 1 (150 mg) Nausea and vomiting n = 9 (15 mg), n = 9 (150 mg) Diarrhoea n = 4 (15 mg), n = 3 (150 mg) Major hair loss n = 2 (15 mg), n = 7 (150 mg)

Rheumatoid Arthritis: Cyclophosphamide

Trial

Arthritis Rheum. 1973 Mar-Apr;16(2):148–153

Substance

0.87–1 mg/kg cyclophosphamide/day (n = 10) Placebo (n = 11) Concomitant medication: 5 mg prednisone/day n = 1 Previous medication: No chrysotherapy No chloroquine

Result

Cyclophosphamide therapy in RA patients was not beneficial

Patients

22 RA patients

Authors

Lidsky MD, Sharp JT, Billings S

Publication

Arthritis Rheum. 1973 Mar-Apr;16(2):148–153

Follow up

1 year

Note

Change of: Swollen joint count change large joints –1.1 (Cyc), –0.9 (placebo) Small joints -5.1 (Cyc), -2.6 (placebo) Change of walking time +0.4 (Cyc), -1.1 (placebo) Change of shoe trying time +1.5 (Cyc), -0.7 (placebo) Change of ring size -2.2 (Cyc), -1.8 (placebo) Change of grip strength -5.5 (Cyc), -32.5 (placebo)

35

36

Rheumatoid Arthritis: Cyclophosphamide

Trial

Controlled Trial of Cyclophosphamide in Rheumatoid Arthritis

Substance

Cyclophosphamide 2 mg/kg/day (n = 13) Placebo (n = 11) Concomitant medication: Prednisone/day £ 10 mg Previous medication: No prior gold therapy No antimalarials £ 2 months

Result

Cyclophosphamide treatment of RA patients resistant to conventional therapy had a profound clinical effect. However, it was associated with severe adverse events

Patients

24 patients with severe progressive rheumatoid arthritis Disease duration > 2a Joint deformations or radiological changes Persistently active in multiple joints Failed DMARD or corticosteroid treatment Failed NSAID treatment

Authors

Townes AS, Sowa J, Shulman LE

Publication

Arthritis and Rheumatism. 1976;19(3):5630

Follow up

9 months

Note

Change of: Painful joints -13 (Cyc), 0 (placebo) Swollen joints -13 (Cyc), +1 (placebo) Grip strength right hand (mmHg) +40 (Cyc), +2 (placebo) Grip strength left hand (mmHg) +37 (Cyc), 4 (placebo) 50 foot walk time (sec) -2 (Cyc), -1 (placebo) Morning stiffness (min) -60 (Cyc), +15 (placebo) ESR (mm/h) -18 (Cyc), +5 (placebo)

Adverse events

Hemorrhagic cystitis 23% (Cyc), 9% (placebo) Microhematuria 23% (Cyc), 0% (placebo) Dysuria 31% (Cyc), 9% (placebo) Amenorrhea 23% (Cyc), 0% (placebo) Thrombopenia 7.6% (Cyc), 0% (placebo) Alopecia 84% (Cyc), 36% (placebo) Nail pigmentation 46% (Cyc), 0% (placebo) Nausea 100% (Cyc), 81% (placebo) Vomiting 69% (Cyc), 18% (placebo) Diarrhoea 15.2% (Cyc), 18% (placebo) Upper respiratory tract infection 100% (Cyc), 100% (placebo) Herpes zoster 7.6% (Cyc), 0% (placebo)

Rheumatoid Arthritis: Gold vs. Methotrexate

Trial

Gold sodium thiomalate compared to low dose Methotrexate in the treatment of rheumatoid arthritis–a randomized, double-blind 26-week trial

Substance

12.5 mg MTX/week (n = 18) Gold sodium thiomalate (GSTM) 50 mg IM weekly after initial test dose of 10 and 25 mg (n = 17) Dose reductions from (i.e. MTX 5.0 mg and GSTM 25 mg) were permitted at Weeks 6 and 12 Concomitant medication: Prednisone/day £ 10 mg No other DMADs Adequate birth control NSAIDs were permitted

Result

Gold sodium thiomalate and methotrexate treatment of RA patients was similarly efficacious

Patients

35 patients with definite or classic RA Unresponsive to ³ 2 non-steroidal anti-inflammatory medications and/or antimalarials ³ 1 h morning stiffness Pain VAS ³ 3.5/10 Tenderness and swelling ³ 6 joints Radiologic joint erosions ESR ³ 20 mm/h Discontinue antimalarials ³ 6 weeks Prednisone £ 10 mg/day

Authors

Morassut P, Goldstein R, Cyr M, Karsh J, McKendry RJ

Publication

J Rheumatol. 1989 Mar;16(3):302–306

Follow up

26 weeks

Note

Change of: PIP circumference (mm) -18 (gold), -25 (MTX) No. of swollen joints -10 (gold), -4.5 (MTX) Pain score VAS -2.0 (gold), -3.4 (MTX) Lansbury joint count -43 (gold), -39 (MTX) ESR (mm/h) -12 (gold), -12 (MTX) Grip strength (mmHg) +79 (gold), +41 (MTX) ADL (max. 21) -4 (gold), -4 (MTX) Global assessment -0.75 (gold), -0.80 (MTX) Morning stiffness (h) -0.8 (gold), -0.43 (MTX)

Adverse events

Liver enzymes > 2 ´ upper normal limits n = 0 (gold), n = 1 (MTX) Leucopoenia n = 0 (gold), n = 1 (MTX) Proteinuria n = 1 (gold), n = 0 (MTX) Mucosal ulcers n = 4 (gold), n = 3 (MTX) Rash n = 2 (gold), n = 0 (MTX) Anorexia n = 0 (gold), n = 1 (MTX) Nausea n = 0 (gold), n = 5 (MTX)

37

38

Rheumatoid Arthritis: Gold vs. Cyclophosphamide vs. Azathioprine

Trial

Comparison of Azathioprine, Cyclophosphamide, and Gold in treatment of rheumatoid arthritis

Substance

2.5 mg/kg azathioprine/day (n = 44) 1.5 mg/kg cyclophosphamide/day (n = 39) 10 mg sodium aurothiomalate/day (n = 38) Increased to 20–50 mg/day Concomitant medication: Corticosteroids were permitted Paracetamol and salicylates were permitted Previous medication: No prior azathioprine treatment No prior cyclophosphamide treatment No prior gold treatment

Result

Cyclophosphamide was marginally more effective than azathioprine, or gold. Azoospermia was observed in males after cyclophosphamide treatment

Patients

121 RA patients Positive rheumatoid factor Positive joint erosions

Authors

Currey HL, Harris J, Mason RM, Woodland J, Beveridge T, Roberts CJ, Vere DW, Dixon AS, Davies J, Owen-Smith B

Publication

Br Med J. 1974 Sep 28;3(5934):763–766

Follow up

48 weeks

Note

Number of affected joints after 18 months 4.4 (Aza), 5.9 (Cyc), 10.2 (gold) Change of: ESR (mm/h) -25 (Aza), -17 (Cyc), -29 (gold) Reduction of initial joint score -33 (Aza), -66 (Cyc), -45 (gold) Change of radiological score ³ –1 (1–4) n = 10 (Aza), n = 14 (Cyc), n = 3 (gold)

Adverse events

Proteinuria n = 1 (Aza), n = 0 (Cyc), n = 5 (gold) Skin rash n = 2 (Aza), n = 7 (Cyc), n = 10 (gold) Bone marrow depression n = 7 (Aza), n = 11 (Cyc), n = 4 (gold) Gastrointestinal disturbance n = 5 (Aza), n = 2 (Cyc), n = 1 (gold) Herpes zoster n = 1 (Aza), n = 0 (Cyc), n = 0 (gold) Hematuria n = 0 (Aza), n = 1 (Cyc), n = 0 (gold) Alopecia n = 0 (Aza), n = 2 (Cyc), n = 0 (gold) Amenorrhoea n = 0 (Aza), n = 1 (Cyc), n = 0 (gold)

Rheumatoid Arthritis: Leflunomide

Trial

Safety and Effectiveness of Leflunomide in the Treatment of Patients with Active Rheumatoid Arthritis

Substance

Placebo (n = 102) Leflunomide 5 mg/day (n = 95) Leflunomide 10 mg/day (n = 101) Leflunomide 25 mg/day (n = 104)

39

Concomitant medication: Prednisone £ 10 mg/day were permitted NSAID were permitted Previous medication: Prior gold required a washout period of 3 months Prior MTX required a washout period of 3 months Prior azathioprine required a washout period of 3 months Result

Treatment of active RA patients with 10 and 25 mg leflunomide/day was effective

Patients

402 RA patients with active disease ³ 8 tender joints > 8 swollen joints Morning stiffness ³ 45 min ESR ³ 40 mm/h

Authors

Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J, Popoviv M, Dimitrijeviv M, Zivkovic M, Campion G, Musikic P, Löw-Friedrich I, Oed C, Seifert H, Strand V

Publication

Arthritis and Rheumatism. 1995,38(11):1595–1603

Note

Changes from baseline: Swollen joint score -12.8 (placebo), -16.9 (5 mg Lef), -20.2 (10 mg Lef), -20.4 (25 mg Lef) Tender joint score -23.6 (placebo), -25.1 (5 mg Lef), -31 (10 mg Lef), -35.3 (25 mg Lef) Swollen joint count -6.5 (placebo), -7.6 (5 mg Lef), -10.4(10 mg Lef), -11.7 (25 mg Lef) Tender joint count -9.7 (placebo), -10.5 (5 mg Lef), -13.6(10 mg Lef), -16.5 (25 mg Lef) Patients global assessment 0.5 (placebo), -0.6 (5 mg Lef), 1.1 (10 mg Lef), 1.0 (25 mg Lef) Physicians global assessment 0.6 (placebo), 0.7 (5 mg Lef), 1.1 (10 mg Lef), 1.1 (25 mg Lef) HAQ -8.1 (placebo), -5.8 (5 mg Lef), –14.5 (10 mg Lef), -13.6 (25 mg Lef) Pain assessment (VAS) +0.3 (placebo), +0.3 (5 mg Lef), -0.91 (10 mg Lef), -1.0 (25 mg Lef) Grip strength (mmHg) +14.5 (placebo), +4.6 (5 mg Lef), +30.8 (10 mg Lef), +52.4 (25 mg Lef) Morning stiffness (min) -33.7 (placebo), -48.3 (5 mg Lef), -55.3 (10 mg Lef), -71.8 (25 mg Lef) ESR (mm/h) +3.1 (placebo), +4.2 (5 mg Lef), –5.2 (10 mg Lef), -5.4 (25 mg Lef) CRP returned to normal n = 14 (placebo), n = 9 (5 mg Lef), n = 26 (10 mg Lef), n = 32 (25 mg Lef)

40

Adverse events

Rheumatoid Arthritis: Leflunomide

Allergic reactions n = 5 (placebo), n = 6 (5 mg Lef), n = 4 (10 mg Lef), n = 8 (25 mg Lef) Gastrointestinal symptoms n = 3 (placebo), n = 15 (5 mg Lef), n = 10 (10 mg Lef), n = 12 (25 mg Lef) Weight loss n = 2 (placebo), n = 2 (5 mg Lef), n = 4 (10 mg Lef), n = 4 (25 mg Lef) Reversible alopecia n = 1 (placebo), n = 1 (5 mg Lef), n = 1 (10 mg Lef), n = 7 (25 mg Lef) No of patients with liver enzyme elevation n = 6 (placebo), n = 6 (5 mg Lef), n = 13 (10 mg Lef), n = 14 (25 mg Lef)

Rheumatoid Arthritis: Leflunomide vs. Sulfasalazine

Trial

Efficacy and safety of Leflunomide compared with placebo and Sulfasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group

Substance

20 mg leflunomide/day (after 3 days of loading dose 100 mg/day, n = 133) Placebo (n = 92) 0.5 g sulphasalazine/day (titrated to 2.0 g daily at week 4, n = 133)

41

Concomitant medication: Prednisone £ 10 mg/day were permitted NSAID were permitted Adequate methods of contraception Previous medication: Sulfasalazine n = 2 (Lef), n = 1 (placebo), n = 0 (SSZ) DMARDs were discontinued 28 days prior randomization Result

Leflunomide was effective in treatment of RA. The efficacy was similar to sulfasalazine. Leflunomide was well tolerated

Patients

358 patients with RA ³ 6 tender joints ³ 6 swollen joints Phycicians and patients global assessment: fair, poor or very poor CRP ³ 20 mg/dL ESR ³ 28 mm/h Stable NSAIDs

Authors

Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A, Loew-Friedrich I, Oed C, Rosenburg R

Publication

Lancet. 1999 Jan 23;353(9149):259–266

Follow up

24 weeks

Note

Change of: Tender joint count -9.7 (Lef), -4.3 (placebo), -8.1 (SSZ) Swollen joint count -7.2 (Lef), -3.4 (placebo), -6.2 (SSZ) Physician’s overall assessment -1.1 (Lef), -0.3 (placebo), -1.0 (SSZ) Patient’s overall assessment -1.1 (Lef), -0.4 (placebo), -1.1 (SSZ) ESR (mm/h) -7.4 (Lef), 3.4 (placebo), -16.6 (SSZ) Rheumatoid factor (U/mL) -141 (Lef), 17 (placebo), 2154 (SSZ) CRP (mg/L) -23 (Lef), +2 (placebo), -11(SSZ) Morning stiffness (min) -93 (Lef), -68 (placebo), -42 (SSZ) Pain (VAS, mm) -27.3 (Lef), -8.8 (placebo), -19.8 (SSZ) Health assessment questionnaire -0.50 (Lef), -0.04 (placebo), -0.29 (SSZ) Radiographic disease progression was significantly slower with Leflunomide and Sulfasalazine than with placebo

42

Adverse events

Rheumatoid Arthritis: Leflunomide vs. Sulfasalazine

Diarrhoea n = 16 (Lef), n = 5 (placebo), n = 9 (SSZ) Respiratory infections n = 14 (Lef), n = 20 (placebo), n = 15 (SSZ) RA flair n = 11 (Lef), n = 17 (placebo), n = 14 (SSZ) Nausea n = 10 (Lef), n = 7 (placebo), n = 17 (SSZ) Rash n = 10 (Lef), n = 4 (placebo), n = 9 (SSZ) Alopecia n = 8 (Lef), n = 2 (placebo), n = 5 (SSZ) Back pain n = 8 (Lef), n = 2 (placebo), n = 2 (SSZ) Accidental injury n = 7 (Lef), n = 5 (placebo), n = 1 (SSZ) Headache n = 7 (Lef), n = 3 (placebo), n = 11 (SSZ) Hypertension n = 6 (Lef), 1% (placebo), n = 4 (SSZ) Dyspepsia n = 5 (Lef), n = 8 (placebo), n = 9 (SSZ) Pruritus n = 5 (Lef), n = 4 (placebo), n = 3 (SSZ) Gastrointestinal pain n = 5 (Lef), n = 7 (placebo), n = 6 (SSZ)

Rheumatoid Arthritis: Methotrexate vs. Leflunomide

Trial

Treatment of active rheumatoid arthritis with Leflunomide compared with placebo and Methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group

Substance

20 mg leflunomide/day (n = 182) Placebo (n = 118) 7.5 mg methotrexate/week (n = 182) Concomitant medication: Prednisone £ 10 mg/day were permitted NSAID were permitted at stable dosage Adequate methods of contraception Previous medication: DMARDs were discontinued ³ 30 days Not previously treated with methotrexate

Result

Leflunomide treatment of RA was superior to placebo and equivalent to methotrexate treatment. Metotrexate and leflunomide delayed disease progression, joint erosions, and improved function and health-related quality of life

Patients

482 active RA patients 3 of the following 4 criteria: ³ 9 or more tender joints ³ 6 or more swollen joints Morning stiffness ³ 45 min ESR ³ 28 mm/h

Authors

Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, Fox R, Moreland L, Olsen N, Furst D, Caldwell J, Kaine J, Sharp J, Hurley F, Loew-Friedrich I

Publication

Arch Intern Med. 1999 Nov 22;159(21):2542–2550

ACR 20

52% (Lef), 46% (MTX), 26% (placebo)

ACR 50

34% (Lef), 23% (MTX), 8% (placebo)

ACR 70

20% (Lef), 9% (MTX), 4% (placebo)

43

44

Rheumatoid Arthritis: Methotrexate vs. Leflunomide

Note

Change of: Tender joint count change -7.7 (Lef), -3.0 (placebo), -6.6 (MTX) Swollen joint count change -5.7 (Lef), -2.9 (placebo), -5.4 (MTX) Patient’s global assessment change -2.1 (Lef), +0.1 (placebo), -1.5 (MTX) Physician’s global assessment change -2.8 (Lef), -1.0 (placebo), -2.4 (MTX) HAQ change -0.3 (Lef), +0.1 (placebo), -0.2 (MTX) Pain (VAS), change -2.2 (Lef), -0.4 (placebo), -1.7 (MTX) ESR change -6.3 mm/h (Lef), +2.6 mm/h (placebo), -6.5 (MTX) CRP change -0.62 mg/dL (Lef), +0.47 mg/dL (placebo), -0.5 (MTX) Total sharp score change +0.53 (Lef), +2.16 (placebo), +0.88 (MTX) Erosion score +0.23 (Lef), +0.84 (placebo), +0.48 (MTX) Joint space narrowing +0.31 (Lef), +1.24 (placebo), +0.41 (MTX)

Adverse events

Total gastrointestinal adverse events 60.4% (Lef), 41.5% (placebo), 51.6% (MTX) Diarrhoea 33.5% (Lef), 16.9% (placebo), 19.8% (MTX) Nausea/vomiting 20.9% (Lef), 18.6% (placebo), 19.2% (MTX) Abdominal pain 13.7% (Lef), 6.8% (placebo), 15.4% (MTX) Dyspepsia 13.7% (Lef), 11.9% (placebo), 13.2% (MTX) Gastroenteritis 2.2% (Lef), 1.7% (placebo), 5.5% (MTX) Oral ulcers 6.0% (Lef), 5.9% (placebo), 9.9% (MTX) Allergic reactions 24.2% (Lef), 14.4% (placebo), 17.0% (MTX) Infections 56.6% (Lef), 48.3% (placebo), 59.9% (MTX) Hypertension 11.0% (Lef), 5.1% (placebo), 2.7% (MTX) New-onset hypertension 2.1% (Lef), 0% (placebo), 1.6% (MTX) Alopecia 9.9% (Lef), 0.8% (placebo), 6.0% (MTX)

Rheumatoid Arthritis: Leflunomide

Trial

Slowing of disease progression in rheumatoid arthritis patients during long-term treatment with Leflunomide or Sulfasalazine

Substance

20 mg leflunomide/day (after 3 days 100 mg loading dose, n = 133) 0.5 mg sulfasalazine/day (increased to 2 g/day over 4 weeks, n = 60) Placebo (n = 26) Concomitant medication: Prednisone £ 10 mg/day were permitted Max 3 intraarticular injections of 60 mg triamcinolone equivalent NSAID were permitted at stable dosage Adequate methods of contraception Previous medication: DMARDs discontinued ³ 8 days

Result

Leflunomide treatment of RA patients slowed disease progression as observed at 6 months. This was maintained long term over 2 years of treatment

Patients

RA patients ³ 6 tender joints ³ 6 swollen joints Phycicians and patients global assessment: fair, poor or very poor CRP > 2.0 g/dL ESR > 28 mm/h Stable NSAIDs

Authors

Larsen A, Kvien TK, Schattenkirchner M, Rau R, Scott DL, Smolen JS, Rozman B, Westhovens R, Tikly M, Oed C, Rosenburg R; European Leflunomide Study Group

Publication

Scand J Rheumatol. 2001;30(3):135–142

Follow up

24 months

Note

Changes of: Total Larsen scores -0.07 (Lef), -0.03 (SSZ), -0.03 (Placebo/SSZ) Larsen scores (hands) -0.06 (Lef), 0.00 (SSZ), -0.06 (Placebo/SSZ) Larsen scores (feet) -0.12 (Lef), -0.10 (SSZ), -0.08 (Placebo/SSZ) After 24 months: % Patients worsened 39 (Lef), 37 (SSZ), 60 (Placebo/SSZ) % Patients unchanged 4 (Lef), 7 (SSZ), 10 (Placebo/SSZ) % Patients improved 57 (Lef), 56 (SSZ), 30 (Placebo/SSZ) % Patients without progression 61 (Lef), 63 (SSZ), 40 (Placebo/SSZ)

Adverse events

Withdrawal 18% (Lef), 23% (SSZ) Diarrhea (Lef) 17% (12 month), 2% (24 months) Alopecia (Lef) 13% (24 months), 5% (24 months) Nausea (Lef) 12% (12 months), 0% (24 months) RA flares 15% (Lef), 12% (SSZ) Rash 10% (Lef), 5% (SSZ)

45

46

Rheumatoid Arthritis: Sulfasalazine vs. Leflunomide

Trial

Treatment of active rheumatoid arthritis with Leflunomide: two year follow up of a double-blind, placebo controlled trial versus Sulfasalazine

Substance

0–6 months: Leflunomide 20 mg/day (n = 133, after loading dose 100 mg for 3 days) Placebo (n = 92) Sulfasalazine 2 g/day (n = 133) 6–12 months: Leflunomide 20 mg/day (n = 80) Placebo => sulfasalazine (n = 41) Sulfasalazine 2 g/day (n = 76) 12–24 months: Leflunomide 20 mg/day (n = 60) Placebo => sulfasalazine (n = 26) 0.5 g sulfasalazine/day (increased every week to 2 g/day, n = 60) Concomitant medication: Prednisolone £ 10 mg/day were permitted Intraarticular injections with triamcinolone £ 3 NSAID were permitted at stable dosage Adequate methods of contraception

Result

Leflunomide was an efficacious and safe DMARD for RA patients

Patients

358 patients with rheumatoid arthritis ACR functional class I, II, or III Tender joint count ³ 6 Swollen joint count ³ 6 CRP > 20 mg/l Erythrocyte sedimentation rate >28 mm/h

Authors

Scott DL, Smolen JS, Kalden JR, van de Putte LB, Larsen A, Kvien TK, Schattenkirchner M, Nash P, Oed C, Loew-Friedrich I; European Leflunomide Study Group

Publication

Ann Rheum Dis. 2001 Oct;60(10):913–923

Follow up

24 months

ACR 20

0–6 months: 55% (Lef), 56% (SSZ) 0–12 months: 67% (Lef), 69% (SSZ) 0–24 months: 82% (Lef), 60% (SSZ)

ACR 50

0–6 months: 24% (Lef), 24% (SSZ) 0–12 months: 42% (Lef), 39% (SSZ) 0–24 months: 52% (Lef), 25% (SSZ)

ACR 70

0–6 months: 9% (Lef), 6% (SSZ) 0–12 months: 17% (Lef), 19% (SSZ) 0–24 months: 25% (Lef), 17% (SSZ)

Rheumatoid Arthritis: Sulfasalazine vs. Leflunomide

Note

Change of tender joint count: 0–6 months: –52% (Lef), –48% (SSZ), –26% (placebo) 0–12 months: –58% (Lef), –63% (SSZ), –61% (Placebo => SSZ) 0–24 months: –71% (Lef), –62% (SSZ), –60% (Placebo => SSZ) Change of swollen joint count: 0–6 months: –44% (Lef), –40% (SSZ), –21% (placebo) 0–12 months: –55% (Lef), –59% (SSZ), –56% (Placebo => SSZ) 0–24 months: –63% (Lef), –52% (SSZ), –58% (Placebo => SSZ) Doctors global assessment: 0–6 months: –32% (Lef), –29% (SSZ), –9% (placebo) 0–12 months: –38% (Lef), –37% (SSZ), –30% (Placebo => SSZ) 0–24 months: –50% (Lef), –32% (SSZ), –24% (Placebo => SSZ) Patients global assessment: 0–6 months: –30% (Lef), –31% (SSZ), –11% (placebo) 0–12 months: –38% (Lef), –40% (SSZ), –32% (Placebo => SSZ) 0–24 months: –46% (Lef), –29% (SSZ), –27% (Placebo => SSZ) ESR (mm/h): 0–6 months: –7.4 (Lef), –16.6 (SSZ), +3.4 (placebo) 0–12 months: –12.4 (Lef), –20.5 (SSZ), –19.8 (Placebo => SSZ) 0–24 months: –16.1 (Lef), –15.0 (SSZ), –14.8 (Placebo => SSZ) CRP (mg/L): 0–6 months: –23 (Lef), –11 (SSZ), –20 (placebo) 0–12 months: –27 (Lef), –16 (SSZ), –11 (Placebo => SSZ) 0–24 months: –27 (Lef), –13 (SSZ), –11 (Placebo => SSZ) Rheumatoid factor (U/l): 0–6 months: –143 (Lef), –152 (SSZ), +31 (placebo) 0–12 months: –168 (Lef), –120 (SSZ), –107 (Placebo => SSZ) 0–24 months: –158 (Lef), –200 (SSZ), –89 (Placebo => SSZ) Pain (VAS): 0–6 months: –27.3 (Lef), –19.8 (SSZ), –8.8 (placebo) 0–12 months: –35.5 (Lef), –24.1 (SSZ), –28.7 (Placebo => SSZ) 0–24 months: –41.7 (Lef), –26.6 (SSZ), –23.8 (Placebo => SSZ) HAQ: 0–6 months: –0.50 (Lef), –0.29 (SSZ), –0.04 (placebo) 0–12 months: –0.58 (Lef), –0.41 (SSZ), –0.29 (Placebo => SSZ) 0–24 months: –0.65 (Lef), –0.36 (SSZ), –0.20 (Placebo => SSZ) Disability index: 0–6 months: –0.66 (Lef), –0.41 (SSZ), –0.09 (placebo) 0–12 months: –0.67 (Lef), –0.53 (SSZ), –0.39 (Placebo => SSZ) 0–24 months: –0.89 (Lef), –0.60 (SSZ), –0.30 (Placebo => SSZ) Larsen Score: 0–6 months: +0.01 (Lef), +0.01 (SSZ), +0.05 (placebo) 0–12 months: +0.02 (Lef), +0.02 (SSZ), +0.06 (Placebo => SSZ) 0–24 months: –0.07 (Lef), –0.03 (SSZ), –0.03 (Placebo => SSZ)

47

48

Adverse events

Rheumatoid Arthritis: Sulfasalazine vs. Leflunomide

Diarrhoea 17% (LEF 0–6 months), 2% (LEF 12–24 months), 9% (SSZ 0–6 months), 8% (SSZ 12–24 months) Nausea 10% (LEF 0–6 months), 0% (LEF 12–24 months), 17% (SSZ 0–6 months), 7% (SSZ 12–24 months) Alopecia 8% (LEF 0–6 months), 5% (LEF 12–24 months), 5% (SSZ 0–6 months), 0% (SSZ 12–24 months) Headache 7% (LEF 0–6 months), 2% (LEF 12–24 months), 11% (SSZ 0–6 months), 0% (SSZ 12–24 months) Hypertension 6% (LEF 0–6 months), 5% (LEF 12–24 months), 4% (SSZ 0–6 months), 3% (SSZ 12–24 months) Pruritus 5% (LEF 0–6 months), 2% (LEF 12–24 months), 3% (SSZ 0–6 months), 3% (SSZ 12–24 months) Gastrointestinal pain 5% (LEF 0–6 months), 5% (LEF 12–24 months), 6% (SSZ 0–6 months), 3% (SSZ 12–24 months)

Rheumatoid Arthritis: Leflunomide

49

Trial

The efficacy and safety of Leflunomide in patients with active rheumatoid arthritis: a five-year follow up study

Substance

10 or 20 mg leflunomide/day after 3 days of loading dose 100 mg/day Concomitant medication: Corticosteroids were permitted, dose changes were permitted Intraarticular injections with triamcinolone £ 3 NSAID were permitted at stable dosage Adequate methods of contraception

Result

Leflunomide treatment of RA patients resulted in improvements in both functional ability and physician-based efficacy measures after 1 year. This effect was maintained for up to 5 years. The long-term safety profile of Leflunomide was no different from that observed in phase III trials

Patients

214 RA patients ³ 6 tender joints ³ 6 swollen joints Physicians and patients global assessment: fair, poor or very poor CRP ³ 20 mg/dL ESR ³ 28 mm/h Stable NSAIDs

Authors

Kalden JR, Schattenkirchner M, Sörensen H, Emery P, Deighton C, Rozman B, Breedveld F

Publication

Arthritis Rheum. 2003 Jun;48(6):1513–1520

Follow up

Open label follow up after 2 years randomized trial, range 2.8–5.8 years

ACR 20

Year 4: 69.2%

ACR 50

Year 4: 43.0%

ACR 70

Year 4: 19.6%

Note

Year 4: CRP 1.2 mg/dL ESR 33.8 mm/h Rheumatoid factor 176.1 units/mL HAQ change -0.5

Adverse events

Upper respiratory tract infection 23% Rash 4% Diarrhoea 8% Alopecia 2% Bronchitis 6% Dyspepsia 4% Urinary tract infection 3% Increased cough 3% Pruritus 2% Gastrointestinal pain 2% Nausea 6% Maculopapular rash <1% Tenosynovitis 4% Hypertension 5% Back pain 7% Headache 1% Arthralgia 0% Serum alanine transaminase > 3 ´ upper normal limit 0.5% Serum aspartate transaminase > 3 ´ upper normal limit 2.2% Discontinuation due to liver function abnormalities 2.2%

50

Rheumatoid Arthritis: Leflunomide

Trial

Efficacy and safety of Leflunomide 10 mg versus 20 mg once daily in patients with active rheumatoid arthritis: multinational double-blind, randomized trial

Substance

10 mg leflunomide/day (n = 202; loading dose on day 1–3, 100 mg) 20 mg leflunomide/day (n = 200; loading dose on day 1–3, 100 mg) Concomitant medication: Prednisolone £ 10 mg No intraarticular injections NSAID were permitted at stable dosage Adequate methods of contraception Previous medication: DMARDs discontinued for 4 weeks

Result

10 mg leflunomide was inferior as compared to 20 mg daily maintenance doses of leflunomide. More treatment discontinuation due to adverse events and SAEs were found in patients receiving 10 mg leflunomide/day

Patients

402 RA patients ³ 6 tender joints ³ 6 swollen joints CRP > 2 mg/L ESR > 28 mm/h

Authors

Poór G, Strand V; Leflunomide Multinational Study Group

Publication

Rheumatology (Oxford). 2004 Jun;43(6):744–749. Epub 2004 Mar 16

Follow up

24 weeks

ACR 20

50% (10 mg), 57% (20 mg)

ACR 50

20% (10 mg), 26% (20 mg)

ACR 70

7% (10 mg), 10% (20 mg)

Note

Change of: Tender joint count -7.57 (10 mg), -8.89 (20 mg) Swollen joint count -6.38 (10 mg), -6.96 (20 mg) HAQ -0.37 (10 mg), -0.49 (20 mg) Change of concomitant NSAID and corticosteroid medication: Increase 22.3% (10 mg), 6.6% (20 mg) No change 59.5% (10 mg), 67.2% (20 mg) Decrease or stop 18.2% (10 mg), 26.2% (20 mg)

Adverse events

Diarrhoea 8.9% (10 mg), 12.0% (20 mg) Alopecia 6.4% (10 mg), 10.0% (20 mg) Nausea 4.5% (10 mg), 9.0% (20 mg) Hypertension 5.9% (10 mg), 5.0% (20 mg)

Rheumatoid Arthritis: Leflunomide vs. Methotrexate

ULTRA-Trial

Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with Leflunomide compared with Methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group ULTRA: Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis

Substance

20 mg leflunomide/day (depending on tolerability decreased to 10 mg/day, n = 98) Placebo (n = 36) 15 mg methotrexate/week (n = 101, increased to 20 mg/week) Concomitant medication: Prednisolone £ 10 mg No intraarticular injections NSAID were permitted at stable dosage Adequate methods of contraception Previous medication: DMARDs discontinued ³ 30 days

Result

Leflunomide was superior to methotrexate in improving physical function over 24 months of treatment. Clinical benefit was sustained over 2 years of treatment without evidence of new or increased toxicity

Patients

235 active RA patients ³ 3 of the following four criteria: ³ 9 tender joints ³ 6 swollen joints Morning stiffness lasting £ 45 min ESR ³ 28 mm/h

Authors

Cohen S, Cannon GW, Schiff M, Weaver A, Fox R, Olsen N, Furst D, Sharp J, Moreland L, Caldwell J, Kaine J, Strand V

Publication

Arthritis Rheum. 2001 Sep;44(9):1984–1992

Follow up

2 years

ACR 20

79% (Lef), 67% (MTX)

ACR 50

56% (Lef), 43% (MTX)

ACR 70

26% (Lef), 20% (MTX)

Note

Change of: Tender joint count -10.1 (Lef), -8.8 (MTX) Swollen joint count -8.2 (Lef), -7.7 (MTX) Patient’s global assessment -3.3 (Lef), -2.4 (MTX) Physician’s global assessment -4.1 (Lef), -3.4 (MTX) HAQ -0.43 (Lef), -0.28 (MTX) Pain (VAS) -3.3 (Lef), -2.4 (MTX) ESR -6.5 mm/h (Lef), -7.9 mm/h (MTX) CRP -9.8 mg/dL (Lef), -5.4 mg/dL (MTX) Total sharp score +1.6 (Lef), +1.2 (MTX) Morning stiffness -149.8 min (Lef), -90.8 min (MTX) Erosion score +1.0 (Lef), +0.6 (MTX) Joint space narrowing +0.5 (Lef), +0.6 (MTX)

51

52

Adverse events/100 patient years

Rheumatoid Arthritis: Leflunomide vs. Methotrexate

Respiratory infection 32.1 (LEF), 32.0 (placebo), 32.3 (MTX) Diarrhoea 31.7 (LEF), 26.0 (placebo), 18.1 (MTX) Headache 17.2 (LEF), 22.0 (placebo), 19.5 (MTX) Nausea 15.8 (LEF), 24.0 (placebo), 17.3 (MTX) Dyspepsia 15.8 (LEF), 21.0 (placebo), 11.9 (MTX) Hypertension 15.8 (LEF), 11.0 (placebo), 4.0 (MTX) Rash 14.9 (LEF), 11.0 (placebo), 9.3 (MTX) Liver enzymes elevations 13.1 (LEF), 4.0 (placebo), 9.7 (MTX) Abdominal pain 10.0 (LEF), 5.0 (placebo), 6.6 (MTX) Arthralgia 9.5 (LEF), 12.0 (placebo), 8.8 (MTX) Accidental injury 9.0 (LEF), 11.0 (placebo), 12.4 (MTX) Asthenia 9.0 (LEF), 12.0 (placebo), 6.2 (MTX) Sinusitis 9.0 (LEF), 11.0 (placebo), 10.2 (MTX) Urinary tract infection 7.2 (LEF), 12.0 (placebo), 4.9 (MTX) Increased cough 6.3 (LEF), 12.0 (placebo), 7.5 (MTX)

Rheumatoid Arthritis: Leflunomide

RELIEF-Trial

Efficacy and safety of leflunomide and predisposing factors for treatment response in patients with active rheumatoid arthritis: RELIEF 6-month data RELIEF: Rheumatoid arthritis Evaluation of Leflunomide further Insights into its EFficacy

Substance

20 mg leflunomide/day after 3 days of 100 mg/day loading dose

53

Concomitant medication: Stable doses of NSAIDs Stable doses of prednisone £ 10 mg/day or equivalent Adequate contraception Previous medication: No other DMARDs £ 4 weeks Intraarticular injections of corticosteroids (maximum dose 60 mg prednisone or equivalent) were not permitted within the 4 weeks Analgesics were allowed Result

Leflunomide was well tolerated, with a safety profile similar to that seen previously in Phase III studies. The efficacy of leflunomide across a range of patient categories was confirmed

Patients

969 RA patients DAS 28 > 3.2 American Rheumatology Association (ARA) functional classification I – III

Authors

Dougados M, Emery P, Lemmel EM, de la Serna R, Zerbini CA, Brin S, van Riel P

Publication

J Rheumatol. 2003 Dec;30(12):2572–2579

Follow up

6 months

ACR 20

60.6%

ACR 50

33.5%

ACR 70

9.6%

54

Note

Rheumatoid Arthritis: Leflunomide

Das 28 responders 69.6% Moderate Das 28 responders 45.4% Good Das 28 responders 24.2% Low disease activity 24.8% Remission 12.7% Change of: Pain (VAS) –32 mm CRP (mg/L) –12.4 Swollen joint count –7.7 Tender joint count –10.5

Adverse events

Diarrhea 14.6% (possibly treatment related), 1.3% (led to discontinuation) Hair loss 13.8% (possibly treatment related), 0.7% (led to discontinuation) Headache 6.1% (possibly treatment related), 0.6% (led to discontinuation) Nausea 5.8% (possibly treatment related), 0.6% (led to discontinuation) Hypertension 5.4% (possibly treatment related), 0.8% (led to discontinuation) Rash 4.5% (possibly treatment related), 0.8% (led to discontinuation) Abdominal pain 3.5% (possibly treatment related), 0.9% (led to discontinuation) Liver function test abnormal (increased hepatic enzymes) 2.9% (possibly treatment related), 0.7% (led to discontinuation) White blood cell abnormalities 2.6% (possibly treatment related), 0.3% (led to discontinuation) Leukopenia 2.1% (possibly treatment related), 0.6% (led to discontinuation) ALT increased 1.6% (possibly treatment related), 0.4% (led to discontinuation)

Rheumatoid Arthritis: Leflunomide vs. Methotrexate

Trial

Eight versus 16-week re-evaluation period in rheumatoid arthritis patients treated with Leflunomide or Methotrexate accompanied by moderate dose prednisone

Substance

20 mg leflunomide/day (after 3 days of 100 mg/day, n = 19) 25 mg MTX/week intramuscularly (n = 21) Concomitant medication: 20 mg prednisolone Tapered weekly by 5 mg/day Previous medication: No prior DMARDs therapy

Result

Methotrexate or leflunomide in combination with moderate dose prednisone was effective in RA patients

Patients

40 RA patients MTX naive

Authors

Fiehn C, Jacki S, Heilig B, Lampe M, Wiesmüller G, Richter C, Röther E, Rochel E, Gao I

Publication

Rheumatol Int. 2007 Aug;27(10):975–979. Epub 2007 Apr 12

Follow up

16 weeks

Note

DAS28: Day 0: 5.36 (MTX), 5.46 (LEF) Week 8: 2.59 (MTX), 3.16 (LEF) Week 16: 2.58 (MTX), 3.25 (LEF) EULAR remission (week 16) Week 16 n =11 (MTX), n = 8 (LEF)

55

56

Rheumatoid Arthritis: Methotrexate

Trial

Low Dose Oral Methotrexate in Rheumatoid Arthritis: An Uncontrolled Trial and Review of the Literature

Substance

7.5 mg MTX/Week Increased by 2.5 mg depending on response and toxicity Concomitant medication: Prednisolone £ 10 mg Joint injections with corticosteroids were permitted NSAIDs were continued Contraception was required

Result

MTX was effective in 67% of the patients

Patients

28 RA patients Functional class II/III All failed gold before

Authors

Groff GD, Shenberger KN, Wilke SW, Taylor TH

Publication

Seminars in Arthritis and Rheumatism. 1983;12(4):333

Note

Positive overall response n = 19 Uncertain response n = 7 No response n = 1

Adverse events

Oral ulcers n = 2 Gastritis n = 1 Nausea n = 5 Zoster n = 2 Leukopenia n = 2 Tinnitus n = 1 Fatigue n = 1

Rheumatoid Arthritis: Methotrexate

57

Trial

Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis

Substance

10 mg/sqm MTX/week i.v. or p.o. Concomitant medication: NSAIDs at stable dose ³ 4 weeks Prednisone ³ 10 mg/day Adequate contraception No folic acid, sulfonamines, phenylbutazone, oxyphenbutazone, or lithium No DMARDs £ 3 months Previous medication: Failed 1 DMARD n = 45 Failed 2 DMARDs n = 44 Failed ³ 3 DMARDs n = 34

Result

Treatment of RA patients with MTX was associated with adverse events occurring in 96% of patients. The discontinuation rate was 44% over 176 weeks. No hepatic or pulmonary fibrosis occurred

Patients

45 RA patients ³ 3 out of: ³ 6 tender joints ³ 3 swollen joints Morning stiffness ³ 45 min ESR ³ 28 mm/h

Authors

Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA

Publication

J Rheumatol. 1990 Dec;17(12):1628–1635

Follow up

176 weeks

Adverse events

Stomatitis n = 26 (total), n = 13 (limiting) Ulcers n = 8 (total), n = 2 (limiting) Gastrointestinal bleeding n = 4 (total), n = 1 (limiting) Abdominal pain n = 11 (total), n = 10 (limiting) Dyspepsia n = 26 (total), n = 8 (limiting) Nausea n = 20 (total), n = 9 (limiting) Vomiting n = 12 (total), n = 6 (limiting) Diarrhea n = 8 (total), n = 2 (limiting) Weight loss n = 2 (total), n = 2 (limiting) Noncirrhotic ascites n = 1 (total), n = 1 (limiting) Herpes zoster n = 3 (total), n = 1 (limiting) Skin/mucous membranes n = 4 (total), n = 0 (limiting) Bronchitis n = 4 (total), n = 0 (limiting) Pneumonia n = 3 (total), n = 1 (limiting) Cellulitis n = 4 (total), n = 0 (limiting) Sinusitis n = 2 (total), n = 0 (limiting) Sepsis n = 2 (total), n = 2 (limiting) Aspergillosis n = 1 (total), n = 1 (limiting) Histoplasmosis n = 1 (total), n = 1 (limiting) Hb decrease > 2 g/dL n = 14 (total), n = 7 (limiting) White blood cell count < 3,500/mm3 n = 10 (total), n = 8 (limiting) Platelets < 100,000/mm3 n = 3 (total), n = 3 (limiting) >3 x increase GOT n = 13 (total), n = 3 (limiting) > 3 x increase GPT n = 15 (total), n = 7 (limiting) >2 x increase Alkaline Phosphatase n = 5 (total), n = 3 (limiting) Decrease Albumin < 3.5 g/dL n = 11 (total), n = 6 (limiting) Creatinine > 1.5 mg/dL n = 7 (total), n = 4 (limiting)

58

Rheumatoid Arthritis: Methotrexate

Trial

Every-other-week Methotrexate in patients with rheumatoid arthritis. A double-blind, placebo-controlled prospective study

Substance

MTX every week (n = 23) MTX every other week (n = 24) Concomitant medication: Low dose corticosteroids were permitted NSAIDs were permitted No other DMARDs Previous medication: MTX

Result

Some patients with stable RA due to MTX treatment were able to change from weekly to every-other-week dosing without developing a flare in their disease activity

Patients

47 RA patients Who received MTX for min. 8 months

Authors

Kremer JM, Davies JM, Rynes RI, Fink S, Lawrence DA, Petrillo GF, Mullaly PM

Publication

Arthritis Rheum. 1995 May;38(5):601–607

Follow up

8 months

Note

Patient withdrawing because of flair: 47.8% (MTX/2 weeks), 12.5% (MTX/week) Change of (week 24): Tender joint count -2 (MTX/2 weeks), -2.3 (MTX/week) Swollen joint count +0.83 (MTX/2 weeks), +0.43 (MTX/week) Patients global assessment +0.25 (MTX/2 weeks), +0.05 (MTX/week) Physicians global assessment -0.17 (MTX/2 weeks), -0.5 (MTX/week) Morning stiffness 4.9 (MTX/2 weeks), 0.71 (MTX/week) Grip strength (mmHg) -2.4(MTX/2 weeks), +3.0 (MTX/week) Rheumatoid factor (IU) +133.7(MTX/2 weeks), -16.7 (MTX/week) ESR (mm/h) +0.42(MTX/2 weeks), -1.5 (MTX/week)

Adverse events

AST (IU) -1.7(MTX/2 weeks), +3.1 (MTX/week)

Rheumatoid Arthritis: Methotrexate

Trial

Long-term prospective study of Methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy

Substance

15 mg MTX/week Mean MTX dose 8.9 mg/week (month 48) Mean MTX dose 10.2 mg (month 84) Mean MTX dose 10.0 mg (month 132) Concomitant medication: Mean prednisone dose 7.1 mg/day (study entry) Mean prednisone dose 3.6 mg/day (last visit)

Result

Methotrexate treatment of RA patients effectively reduced signs and symptoms of the disease

Patients

26 RA patients

Authors

Weinblatt ME, Maier AL, Fraser PA, Coblyn JS

Publication

J Rheumatol. 1998 Feb;25(2):238–242

Follow up

132 months

Note

Change of: Painful joints -29.9 Swollen joints -22.2 Physician’s global assessment -1.8 Patient’s global assessment -1.7 ESR (mm/h) -33.4

Adverse events

Pneumonitis n = 2 Alopecia n = 7 Gastrointestinal toxicity n = 11 Headache n = 5 Nodulosis n = 3

59

60

Rheumatoid Arthritis: Methotrexate

Trial

Comparison of two schedules for administering oral low-dose Methotrexate (weekly versus every-other-week) in patients with rheumatoid arthritis in remission: a 24 week, single blind, randomized study

Substance

Weekly MTX (n = 26) Every-other-weekly MTX (EOW, n = 25) Concomitant medication: Chloroquine was permitted Low-dose steroids were permitted NSAIDs were permitted

Result

RA patients with a short disease duration achieving remission early after disease onset with weekly MTX had a higher probability of success with the every other week MTX schedule

Patients

RA patients Clinical remission according to the ACR criteria ³ 6 months Stable dosage of weekly MTX ³ 9 months

Authors

Luis M, Pacheco-Tena C, Cazarín-Barrientos J, Lino-Pérez L, Goycochea MV, Vazquez-Mellado J, Burgos-Vargas R

Publication

Arthritis Rheum. 1999 Oct;42(10):2160–2165

Follow up

24 weeks

Note

Remission >90% (both groups) Change of: Tender joint count +0.38 (weekly), +0.56 (EOW) Swollen joint count +0.36 (weekly), +0.12 (EOW) Ritchie Articular Index -0.30 (weekly), +1.24 (EOW) HAQ Disability Index -0.03 (weekly), –0.06 (EOW) ACR functional class 0.0 (weekly), –0.2 (EOW) Morning stiffness, minutes +0.25 (weekly), +0.12 (EOW) Pain by VAS (0–100 mm) -0.69 (weekly), -3.84 (EOW) Patient’s global assessment (1–4 points) +0.53 (weekly), -0.16 (EOW) Physician’s global assessment (1–4 points) -0.42 (weekly), –0.2 (EOW) Erythrocyte sedimentation rate (mm/h) +2.33 (weekly), +2.26 (EOW) C-reactive protein (mg/dL) -1.22 (weekly), -1.72 (EOW)

Adverse events

Serum aspartate aminotransferase and alanine aminotransferase levels decreased in the every other week MTX group

Rheumatoid Arthritis: Methotrexate

Trial

Methotrexate twice weekly vs. once weekly in rheumatoid arthritis: a pilot double-blind, controlled study

Substance

10 mg MTX once weekly (n = 34) 5 mg MTX twice weekly (n = 32) Concomitant medication: Prednisolone £ 10 mg/day (or equivalent) No other DMARDs £ 3 months Previous medication: NSAIDs

Result

Treatment of RA patients with MTX twice weekly had no advantage over once weekly

Patients

80 patients with rheumatoid arthritis Synovitis despite NSAID therapy Morning stiffness > 30 min ³ 4 tender joints ³ 4 swollen joints CRP > 0.6 mg/dL

Authors

Pandya S, Aggarwal A, Misra R

Publication

Rheumatol Int. 2002 May;22(1):1–4

Follow up

16 weeks

ACR 20

72.4% (once weekly), 79.2% (twice weekly)

ACR 50

41.18% (once weekly), 43.75% (twice weekly)

Note

Patient’s global assessment (0–10) –2.84 (once weekly) -3.24 (twice weekly) Physician’s global assessment (0–10) -2.42 (once weekly) -2.10 (twice weekly) Early morning stiffness (min) -9.74 (once weekly) -2.93 (twice weekly) Intensity of pain (0–100) -21.46 (once weekly) -13.32 (twice weekly) Tender joint count (0–28) -4.77 (once weekly) -2.7 (twice weekly) Swollen joint count (0–28) -0.6 (once weekly) -0.24 (twice weekly) HAQ (1–3) -0.51 (once weekly) -0.26 (twice weekly) ESR -27.68 (once weekly) -15.88 (twice weekly)

Adverse events

Mild ALT/AST rise n = 5 (once weekly), n = 5 (twice weekly)

61

62

Rheumatoid Arthritis: Methotrexate

Trial

Dose escalation of parenteral Methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of Methotrexate: a randomized, controlled trial

Substance

Phase 1: 15 mg/week i.m. MTX (all patients) Phase 2, if DAS 28 > 3.2 at week 4 and 6: 15 mg/week i.m. MTX (n = 27) Escalating doses of i.m. MTX monthly up to 45 mg/week 15 mg/week MTX + “escalating doses” of placebo (n =27) Dose escalation was performed if DAS 28 > 2.5 Concomitant medication: Oral steroid £ 10 mg/day No other DMARDs £ 3 months Max. 2 intraarticular injections with 40 mg methylprednisolone acetate Previous medication: Stable oral 15–20 mg/week MTX ³ 2 months ³1 other DMARD ³4 months with ³ 2 months at full dose

Result

Switching therapy of RA patients from oral to parenteral methotrexate resulted in a minor improvement in disease control. Increasing the methotrexate dose up to 45 mg/week did not improve disease control. Higher doses of methotrexate were well tolerated

Patients

64 RA patients >18 years with active RA DAS28 of > 3.2

Authors

Lambert CM, Sandhu S, Lochhead A, Hurst NP, McRorie E, Dhillon V

Publication

Arthritis Rheum. 2004 Feb;50(2):364–371

Follow up

22 weeks

ACR 20

3.7% (control), 3.7% (MTX escalation)

Rheumatoid Arthritis: Methotrexate

Note

Change of: DAS28 of <3.2 week 22 3.7% (controls), 3.7% (MTX escalation) EULAR response: good 0% (controls), 0% (MTX escalation) Moderate 26% (controls), 30% (MTX escalation) None 74% (controls), 70% (MTX escalation) DAS28 -0.7 (controls), -0.5 (MTX escalation) ESR (mm/h) -5.4 (controls), +2.2 (MTX escalation) Swollen joint count -2 (controls), -1 (MTX escalation) Tender joint count -3 (controls), -4 (MTX escalation) Patients’ global assess. -10 (controls), -12 (MTX escalation) Physicians’ global assess. -6.6 (controls), -3.5 (MTX escalation) Pain (VAS scale 0–100), -18 (controls), -9 (MTX escalation) HAQ +0.14 (controls), -0.05 (MTX escalation) Withdrawal inefficacy 11.2% (controls), 14.9% (MTX escalation)

Adverse events

Withdrawal SAE 3.7% (controls), 3.7%(MTX escalation) Nausea 18.6% (control), 37% (MTX escalation) Oral ulcers 14.8% (control), 14.8% (MTX escalation) Headache 29.6% (control), 25.9% (MTX escalation) Dizziness 0% (control), 14.8% (MTX escalation) Cough 18.5% (control), 25.9% (MTX escalation) Fever 0% (control), 0% (MTX escalation) Hair loss 0% (control), 14.8% (MTX escalation) Liver function test > 2 normal 3.7% (control), 3.7% (MTX escalation) Creatinine 30% rise 7.4% (control), 0% (MTX escalation)

63

64

Rheumatoid Arthritis: Methotrexate

PROMPT-Trial

Efficacy of Methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial PROMPT: PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment

Substance

15 mg methotrexate/week (n = 55) Every 3 months the dosage was increased if the DAS28 was >2.4 After 12 months, the study medication was tapered and discontinued Placebo (n = 55) Concomitant medication: No corticosteroids No other DMARDs NSAIDs were permitted

Result

Methotrexate treatment of patients with undifferentiated arthritis retarded the diagnosis and radiological disease progression of RA

Authors

van Dongen H, van Aken J, Lard LR, Visser K, Ronday HK, Hulsmans HM, Speyer I, Westedt ML, Peeters AJ, Allaart CF, Toes RE, Breedveld FC, Huizinga TW

Publication

Arthritis Rheum. 2007 May;56(5):1424–1432

Patients

110 patients with early undifferentiated arthritis

Follow up

30 months

Note

Progression to RA 40% (MTX), 53% (placebo) Fulfilled the ACR criteria n = 22 (MTX), n = 29 (placebo) Radiographic progression over 18 months was lower among MTX treated patients Progression to RA, CCP pos. patients 66% (MTX), 93% (placebo) Progression to RA, CCP neg. patients 33% (MTX), 38% (placebo)

Adverse events

Gastrointestinal 20% (MTX), 11% (placebo) Dermal/mucosal 16.3% (MTX), 12.7% (placebo) Neurologic 5.4% (MTX), 9% (placebo) Cardiologic 5.4% (MTX), 0% (placebo) Pulmonary 5.4% (MTX), 1.8% (placebo) Hematologic 1.8% (MTX), 1.8% (placebo) Ophthalmologic 5.4% (MTX), 0% (placebo) Elevated serum liver enzyme levels 11% (MTX), 1.8% (placebo) Tiredness 1.8% (MTX), 1.8% (placebo) Giant cell tumor 1.8% (MTX), 0% (placebo) Rhinitis 1.8% (MTX), 0% (placebo) Not feeling well 3.6% (MTX), 0% (placebo) Fracture 0% (MTX), 1.8% (placebo) Hair loss 0% (MTX), 1.8% (placebo) Synovectomy 0% (MTX), 1.8% (placebo) Gastrointestinal 1.8% (MTX), 1.8% (placebo) Erythema annulare centrifugum 1.8% (MTX), 0% (placebo) General unwellness 0% (MTX), 1.8% (placebo) Dyspnoea, insomnia, weight Gain 0% (MTX), 1.8% (placebo) Pancreatitis 1.8% (MTX), 0% (placebo) Knee replacement surgery 1.8% (MTX), 0% (placebo) Erosive arthritis 1.8% (MTX), 0% (placebo) Meningitis 0% (MTX), 1.8% (placebo)

Rheumatoid Arthritis: Methotrexate

65

BeSt-Trial

Limited efficacy of conventional DMARDs after initial Methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score BeSt: Behandelings Strategie

Substance

Group 1 (sequential monotherapy, n = 126): 1. MTX 2. SSZ 3. Leflunomide 4. MTX + Infliximab Group 2 (step up, n = 121): 1. MTX 2. SSZ added to MTX 3. Hydroxychloroquine added 4. Prednisone added, and 5. Switched to MTX + IFX Groups 3 and 4 of the Best trial are not depicted Concomitant medication: Intraarticular injections with corticosteroids were permitted NSAIDs were permitted

Result

Treatment of early RA patients after initial treatment failure of MTX with subsequent conventional DMARDs was unlikely to achieve clinical remission (DAS £ 2.4) in early RA. Joint damage progressed in parallel

Patients

244 RA patients of the BeSt-Study Initially treated with MTX 15–25 mg/week Patients who discontinued MTX because of: – Insufficient clinical response (disease activity score, DAS >2.4) – Toxicity were classified as “MTX failures”

Authors

van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, van Zeben D, Kerstens PJ, Gerards AH, van Groenendael JH, Hazes JM, Breedveld FC, Allaart CF, Dijkmans BA

Publication

Ann Rheum Dis. 2007 Oct;66(10):1356–1362. Epub 2007 Feb 9

Follow up

21 months

Note

66% patients discontinued MTX because of insufficient response or toxicity 78% also failed on SSA 87% subsequently failed on Leflunomide (group 1) 64% failed on MTX + SSZ + HCQ (in group 2) 71% in groups 1 and 2 were successfully treated with MTX + IFX Total Sharp/van der Heijde score progression 3 units (MTX success) 9 units (MTX faillure)

66

Rheumatoid Arthritis: Methotrexate

CAMERA-Trial

Intensive treatment with Methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). CAMERA: Computer Assisted Management in Early Rheumatoid Arthritis

Substance

Treatment protocol: 7,5 mg MTX/week (both groups starting dose) Step up strategy in case of insufficient response: MTX dose + 5 mg/week to max. 30 mg/week, administered s.c. + 2,5 mg/kg CsA/day (increased by 0.5 mg/kg/day to max. 4 mg/day/kg), MTX continued at 15 mg/week Sustained response: Decrease of MTX dose –2,5 mg/week Intensive care group: Visits every 4 weeks to the outpatient clinic The minimum time to 30 mg/week MTX was 18 weeks Conventional care group: Visits every 3 months to the outpatient clinic The minimum time to 30 mg/week MTX was 52 weeks Inadequate response (intensive care group): Swollen joints > 50% from baseline + No improvement of (min. 2 out of): ESR Tender joint count VAS Inadequate response (conventional care group): Swollen joints ³ 6 Tender joint count ³ 3 ESR ³ 28 mm/h Morning stiffness ³ 45 min. Sustained response: No swollen joints + Min. 2 out of: ESR £ 20 mm/h Tender joint count £ 3 VAS £ 20 mm/h Concomitant medication: 0.5 mg folic acid/day NSAIDs were permitted Intraarticular injections were avoided in so far as possible Oral glucocorticoids were not allowed unless unavoidable Previous medication: No DMARDs < 3 months No corticosteroids < 3 months No cytotoxic agents < 3 months

Rheumatoid Arthritis: Methotrexate

67

Result

Intensified treatment with MTX in early RA patients enhanced the clinical efficacy

Patients

299 patients with early rheumatoid arthritis Disease duration > 1 a No prior DMARDs or Corticosteroids

Authors

Verstappen SM, Jacobs JW, van der Veen MJ, Heurkens AH, Schenk Y, ter Borg EJ, Blaauw AA, Bijlsma JW; Utrecht Rheumatoid Arthritis Cohort study group

Publication

Ann Rheum Dis. 2007 Nov;66(11):1443–1449. Epub 2007 May 22

Follow up

110 weeks

ACR 50

58% (1 year intensive care), 46% (2 years intensive care), 43% (1 year conventional care), 45% (2 years conventional care)

Note

Remission: 50% (intensive care), 37% patients (conventional care) Change of: ESR –22 mm/h (intensive care), -19 mm/h patients (conventional care) Morning stiffness -60 min (intensive care), -69 min patients (conventional care) Number of swollen joints -13 (intensive care), -13 patients (conventional care) Number of tender joints -12 (intensive care), -11 patients (conventional care) VAS (well being) -37 (intensive care), -28 patients (conventional care) HAQ -0.55 (intensive care), -0.54 patients (conventional care)

Adverse events

Gastrointestinal 24.6 (intensive), 25.2% (conventional) Mucocutaneous 14.8 (intensive), 18.2% (conventional) Neurological 18.8 (intensive), 18.8% (conventional) Renal events 2.4 (intensive), 2.8% (conventional) Liver toxicity 23.2 (intensive), 18.6% (conventional) Hematologic abnormalities 7.1% (intensive), 4.2% (conventional) Pulmonary symptoms 2.0% (intensive), 5.3% (conventional) Post-dosing reactions 1.8% (intensive), 2.1% (conventional) Others 5.2% (intensive), 4.8% (conventional)

68

Rheumatoid Arthritis: Methotrexate

Trial

Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of Methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial

Substance

15 mg MTX/week Subcutaneous (n = 188 patients) Oral (n = 187 patients) Rescue if at week 16 ACR20 was not reached: => Switch from 15 mg oral to 15 mg s.c. MTX => Switch from 15 mg s.c. to 20 mg s.c. MTX Concomitant medication: NSAIDs were permitted at stable dosages Corticosteroid £ 10 mg/day No intraarticular injections of corticosteroids No antiemesis Previous Medication: No MTX No other DMARDs £ 2 weeks (Lef £ 4 weeks) No biologic agents

Result

Subcutaneous administration of MTX in RA patients was significantly more effective than oral administration of the same MTX dosage. There was no difference in tolerability

Patients

MTX-naïve, active RA patients DAS 28 ³ 4

Authors

Braun J, Kästner P, Flaxenberg P, Währisch J, Hanke P, Demary W, von Hinüber U, Rockwitz K, Heitz W, Pichlmeier U, Guimbal-Schmolck C, Brandt A; MC-MTX.6/RH Study Group

Publication

Arthritis Rheum. 2008 Jan;58(1):73–81

Follow up

24 weeks

ACR 20

78% (s.c.), 70% (oral)

ACR 50

62% (s.c.), 59% (oral)

ACR 70

41% (s.c.), 33% (oral)

Note

Switched patients achieving ACR 20 23% (15 mg MTX s.c. => 20 mg MTX s.c.), 30% (15 mg oral = 15 mg s.c.)

Adverse events

Any adverse event 66% (s.c.), 62% (oral) At least a moderate adverse event 41% (s.c.), 41% (oral) Adverse event possibly related to study drug 53% (s.c.), 48% (oral) Serious adverse event 5.7% (s.c.), 4.3% (oral) Adverse event leading to withdrawal 9.3% (s.c.), 4.3% (oral) Abdominal pain 8.8% (s.c.), 10.6% (oral) Diarrhoea 2.6% (s.c.), 6.9% (oral) Dyspepsia 6.7% (s.c.), 5.9% (oral) Loss of appetite 7.3% (s.c.), 3.2% (oral) Nausea 16.6% (s.c.), 12.2% (oral) Stomatitis 3.1% (s.c.), 3.7% (oral) Vomiting 3.6% (s.c.), 3.2% (oral) Increased alanine aminotransferase 1.6% (s.c.), 4.3% (oral) Bronchitis 2.1% (s.c.), 3.7% (oral) Headache 2.1% (s.c.), 4.3% (oral) Nasopharyngitis 4.7% (s.c.), 5.3% (oral)

Rheumatoid Arthritis: Sulfasalazine

Trial

Sulfasalazine in Early Rheumatoid Arthritis

Substance

2 g Sulfasalazine/day (n = 53) Placebo (n = 52) Concomitant medication: No systemic steroids Previous Medication: No SSZ

Result

Sulfasalazine was effective in early RA patients

Patients

105 early non-responsive RA patients No evidence of bone erosions Disease duration < 12 months

Authors

The Australian Multicentre Clinical Trial Group

Publication

J of Rheumatology. 1992; 19:1672–1677

Follow up

6 months

Note

New erosions 15% (SSZ), 29% (placebo) Change of: ESR -12.8% (SSZ), +2.7% (placebo) Pain -13.4% (SSZ), -5.1% (placebo) Morning stiffness -1.1% (SSZ), -0.7% (placebo) Ritchie index -5.3% (SSZ), -7.6% (placebo) Tender and swollen joint count -10.4% (SSZ), -7.6% (placebo)

Adverse events

Liver abnormalities n = 3 (SSZ), n = 0 (placebo) Rash n = 5 (SSZ), n = 1 (placebo) GI disturbance n = 3 (SSZ), n = 2 (placebo) Others (rupture Baker’s cyst, fever, mouth ulcers, depression) n = 3 (SSZ), n = 1 (placebo)

69

70

Rheumatoid Arthritis: Sulfasalazine

Trial

Sulfasalazine in early rheumatoid arthritis. A 48-week double-blind, prospective, placebo-controlled study

Substance

500 mg Sulfasalazine/day (increased weekly to 2 g/day, n = 37) Placebo (n = 40) Concomitant medication: Steroid injections were permitted Prednisolone £ 7.5 mg/day was permitted NSAIDs were permitted Previous Medication: No DMARDs Stable doses of NSAIDs ³ 2 weeks

Result

Treatment of RA sulfasalazine was effective and onset of effect was rapid. Sulfasalazine retarded the development of joint erosions, but did not induce remission

Patients

80 RA patients Disease duration £ 12 months Min. 2 out of: DMARD naive ESR ³ 20 mm/h ³ 6 arthritic joints Morning stiffness ³ 45 min

Authors

Hannonen P, Möttönen T, Hakola M, Oka M

Publication

Arthritis Rheum. 1993 Nov;36(11):1501–1509

Follow up

48 weeks

Note

Change of: Ritchie articular index -1.69 (RF neg., placebo), 0.24 (RF pos, placebo), -5.46 (RF neg., SSZ), -1.68 (RF pos, SSZ) Swollen joint count -0.23 (RF neg., placebo), 0.76 (RF pos, placebo), -4.39 (RF neg., SSZ), -1.77 (RF pos, SSZ) Physician’s assessment -0.15 (RF neg., placebo), -0.08 (RF pos, placebo), -0.69 (RF neg., SSZ), 0.00 (RF pos, SSZ) Patient’s global assessment –0.08 (RF neg., placebo), –0.04 (RF pos, placebo), -0.92 (RF neg., SSZ), -0.23 (RF pos, SSZ) Erosion score change +2.5 (SSZ), +4.4 (placebo) Joint space narrowing score +1.0 (SSZ), +2.7 (placebo) Total score +3.5 (SSZ), +7.1 (placebo)

Rheumatoid Arthritis: Sulfasalazine vs. Gold

Trial

Sulfasalazine has a better efficacy/toxicity profile than auranofin–evidence from a 5 year prospective, randomized trial

Substance

500 mg Sulfasalazine/day (increased to 40 mg/kg/day, n = 100) Auranofin (6–9 mg/day, n = 100) Concomitant medication: Steroid injections were permitted Prednisolone £ 7.5 mg/day was permitted NSAIDs were permitted Previous Medication: No DMARDs Stable doses of NSAIDs ³ 2 weeks

Result

Sulfasalazine therapy was more likely to be continued for 5 years than auranofin, suggesting better tolerability and/or efficacy of Sulfasalazine

Patients

200 patients with active RA Despite immunosuppressive therapy

Authors

McEntegart A, Porter D, Capell HA, Thomson EA

Publication

J Rheumatol. 1996 Nov;23(11):1887–1890

Follow up

5 years

Note

Percentage continuing treatment 31% (SSZ) 15% (auranofin) Change of: Articular index -7 (SSZ), -8.5 (auranofin) Duration of morning stiffness (min) -75 (SSZ), -60 (auranofin) Pain Score -7 (SSZ), -6.5 (auranofin) ESR (mm/h) -16.5 (SSZ), -17 (auranofin) CRP (mg/l) -21 (SSZ), -22 (auranofin) Ritchie articular index -5 (SSZ), -1 (auranofin) Morning stiffness (min) -45 (SSZ), 0 (auranofin)

Adverse events

Leucopenia n = 6 (SSZ), n = 3 (auranofin) Thrombocytopenia n = 0 (SSZ), n = 1 (auranofin) Rash n = 9 (SSZ), n = 11 (auranofin) Diarrhoea n = 2 (SSZ), n = 26 (auranofin) Mouth ulcers n = 3 (SSZ), n = 4 (auranofin) Nausea/vomiting n = 7 (SSZ), n = 1 (auranofin) Proteinuria n = 0 (SSZ), n = 3 (auranofin) Abnormal lung function tests n = 2 (SSZ), n = 0 (auranofin) Central nervous system n = 1 (SSZ), n = 1 (auranofin) Pulmonary fibrosis n = 0 (SSZ), n = 1 (auranofin) Other n = 3 (SSZ), n = 5 (auranofin)

71

72

Rheumatoid Arthritis: Sulfasalazine

Trial

Treating rheumatoid arthritis early with disease modifying drugs reduces joint damage: a randomised double-blind trial of sulphasalazine vs. diclofenac sodium

Substance

2 g sulfasalazine/day (n = 59) 100 mg diclofenac/day (n = 54) Concomitant medication: No systemic or intraarticular corticosteroids Paracetamol was permitted Dextropropoxyphene was permitted Hihydrocodein was permitted No other NSAIDs

Result

Clinical signs and symptoms of RA were equally reduced by sulphasalazine and diclofenac. Treatment with sulfasalazine significantly reduced the extent of radiological progression in active RA

Authors

Choy EH, Scott DL, Kingsley GH, Williams P, Wojtulewski J, Papasavvas G, Henderson E, Macfarlane D, Erhardt C, Young A, Plant MJ, Panay GS

Publication

Clin Exp Rheumatol. 2002 May-Jun;20(3):351–358

Patients

111 patients with RA Disease duration < 12 months ³ 6 tender joints ³ 6 swollen joints DAS 28 ³ 3

Follow up

1 year

Note

New erosions n = 2/patient (Sulfasalazine), n = 7.5/patient (Diclofenac) Patients with new erosions 44% (Sulfasalazine), 38% (Diclofenac)

Adverse events

Gastrointestinal 44% (SSZ), 32% (Diclofenac) Nausea 25.8% (SSZ), 7.5% (Diclofenac) Anemia 0 (SSZ), 3.8% (Diclofenac) Myocardial infarction 1.7% (SSZ), 0 (Diclofenac) Herpes zoster 1.7% (SSZ), 0 (Diclofenac) Prostatic cancer 0% (SSZ), 1.9% (Diclofenac)

Rheumatoid Arthritis: Tacrolimus

Trial

Efficacy of Tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with Methotrexate: a six-month, double-blind, randomized, dose-ranging study

Substance

1 mg tacrolimus (n = 69) 3 mg tacrolimus (n = 64) 5 mg tacrolimus (n = 64) Placebo (n = 71)

73

Concomitant medication: Prednisone £ 10 mg/day NSAIDs were permitted Previous medication: DMARDs were discontinued ³ 4 weeks Result

Treatment of active RA patients with tacrolimus led to a reduction of disease activity with an optimal dose of 1 to 3 mg daily

Patients

268 patients with RA who were resistant MTX (³ 15 mg/week)

Authors

Furst DE, Saag K, Fleischmann MR, Sherrer Y, Block JA, Schnitzer T, Rutstein J, Baldassare A, Kaine J, Calabrese L, Dietz F, Sack M, Senter RG, Wiesenhutter C, Schiff M, Stein CM, Satoi Y, Matsumoto A, Caldwell J, Harris RE, Moreland LW, Hurd E, Yocum D, Stamler DA

Publication

Arthritis Rheum. 2002 Aug;46(8):2020–2028

ACR 20

15.5% (placebo), 29.0 % (1 mg), 34.4% (3 mg), 50% (5 mg)

ACR 50

1.4% (placebo), 14.5% (1 mg), 17.2% (3 mg), 14.1% (5 mg)

Note

Change of: Tender joint count -1.0 (placebo), –6.3 (1 mg), -8.0 (3 mg), -12.9 (5 mg) Swollen joint count -1.9 (placebo), -3.8 (1 mg Tacrolimus), -5.4 (3 mg), -6.8 (5 mg) Pain (VAS 0–100), -5.5 mm (placebo), -11.0 mm (1 mg), -16.0 mm (3 mg), -24 mm (5 mg) Patient’s global assessment -3 (placebo), -11.0 (1 mg), -13 (3 mg), -21 (5 mg) Physician’s global assessment -11 (placebo), -14 (1 mg Tacrolimus), -19 (3 mg), -28 (5 mg) HAQ change 0 (placebo), -0.1 (1 mg), -0.3 (3 mg), -0.4 (5 mg) ESR +5 mm/h (placebo), -4 mm/h (1 mg), -5 mm/h (3 mg), -11 mm/h (5 mg) CRP +0.5 mg/L (placebo), -0.3 mg/dL (1 mg), -0.8 mg/dL (3 mg), -1.7 mg/dL (5 mg)

74

Adverse events

Rheumatoid Arthritis: Tacrolimus

Creatinine elevation ³ 40% increased in a dose-dependent manner. Discontinuation for creatinine elevation 3.1% (3 mg), 10.9% (5 mg) Cardiovascular 15.5% (placebo), 15.9% (1 mg), 18.8% (3 mg), 17.2% (5 mg) Digestive 35.2% (placebo), 49.3% (1 mg), 57.8% (3 mg), 57.8% (5 mg) Diarrhoea 11.3% (placebo), 11.6% (1 mg), 5.6% (3 mg), 28.1% (5 mg) Dyspepsia 7% (placebo), 17.4% (1 mg), 20.3% (3 mg), 9.4% (5 mg) Nausea 5.6% (placebo), 15.9 (1 mg), 18.8% (3 mg), 14.1% (5 mg) Hematologic 1.4% (placebo), 7.2% (1 mg), 0% (3 mg), 6.3% (5 mg) Metabolic 4.2% (placebo), 5.8% (1 mg), 10.9% (3 mg), 14.1% (5 mg) Musculoskeletal 11.3% (placebo), 13.0% (1 mg), 15.6% (3 mg), 7.8% (5 mg) Nervous system 22.5% (placebo), 26.1% (1 mg), 23.4% (3 mg), 48.4% (5 mg) Anxiety 1.4% (placebo), 1.4% (1 mg), 1.6% (3 mg), 10.9% (5 mg) Headache 11.3% (placebo), 10.1% (1 mg), 20.3% (3 mg), 15.6% (5 mg) Tremor 0% (placebo), 4.3% (1 mg), 3.1% (3 mg), 21.9% (5 mg) Respiratory 15.5% (placebo), 26.1% (1 mg Tacrolimus), 20.3% (3 mg), 12.5% (5 mg) Skin 16.9% (placebo), 17.4% (1 mg), 7.8% (3 mg), 10.9% (5 mg) Special senses 8.5% (placebo), 4.3% (1 mg), 4.7% (3 mg), 9.4% (5 mg) Uro-genital 4.2% (placebo), 11.6% (1 mg), 21.9% (3 mg Tacrolimus) 20.3% (5 mg) Urinary tract infection 1.4% (placebo), 0% (1 mg), 12.5% (3 mg), 9.4% (5 mg) GU symptoms 0% (placebo), 0% (1 mg), 6.3% (3 mg), 6.3% (5 mg) GU signs 1.4% (placebo), 5.7% (1 mg), 4.8% (3 mg), 4.8% (5 mg)

Rheumatoid Arthritis: Tacrolimus

Trial

Efficacy and safety of Tacrolimus in patients with rheumatoid arthritis: a double-blind trial

Substance

Tacrolimus 2 mg (n = 154) Tacrolimus 3 mg (n = 153) Placebo (n = 157)

75

Concomitant medication: Prednisone £ 10 mg/day (or equivalent) NSAIDs were permitted Previous medication: Resistant or intolerant to DMARDs ³ 4–12 weeks Result

2 mg/day and 3 mg/day tacrolimus was an efficacious and safe monotherapy for active RA patients. Treatment with 3 mg tacrolimus resulted in generally better ACR response rates

Patients

464 RA patients ³ 10/68 tender and 7/66 swollen joints Despite DMARD treatment

Authors

Yocum DE, Furst DE, Kaine JL, Baldassare AR, Stevenson JT, Borton MA, Mengle-Gaw LJ, Schwartz BD, Wisemandle W, Mekki QA; Tcrolimus Rheumatoid Arthritis Study Group

Publication

Arthritis Rheum. 2003 Dec;48(12):3328–3337

Follow up

6 months

ACR 20

13.4% (placebo), 21.4% (tacrolimus 2 mg), 32.0% (tacrolimus 3 mg)

ACR 50

4.5% (placebo), 11.7% (tacrolimus 2 mg), 11.8% (tacrolimus 3 mg)

ACR 70

0.6% (placebo), 5.2% (tacrolimus 2 mg), 3.3% (tacrolimus 3 mg)

Note

Change of: Tender joint count -1.86 (placebo), -3.09 (tacrolimus 2 mg), -7.25 (tacrolimus 3 mg) Swollen joint score -1.47 (placebo), -4.02 (tacrolimus 2 mg), -5.3 (tacrolimus 3 mg) Pain (VAS) -2.13 (placebo), -11.28 (tacrolimus 2 mg), -10.62 (tacrolimus 3 mg) Physician’s global assessment -8.98 (placebo), -15.84 (tacrolimus 2 mg), -18.19 (tacrolimus 3 mg) Patient’s global assessment +2.48 (placebo), -7.25 (tacrolimus 2 mg), -6.55 (tacrolimus 3 mg) HAQ +0.09 (placebo), -0.13 (tacrolimus 2 mg), -0.04 (tacrolimus 3 mg) ESR +2.64 mm/h (placebo), -4.31 mm/h (tacrolimus 2 mg), -8.59 mm/h (tacrolimus 3 mg) CRP -0.05 mg/dL (placebo), -0.75 mg/dL (tacrolimus 2 mg), -0.64 mg/dL (tacrolimus 3 mg)

Adverse events

Serum creatinine levels increased by ³ 40%: 20% (tacrolimus 2 mg/day), 29% (tacrolimus 3 mg/day) Serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients

76

Rheumatoid Arthritis: Tacrolimus

Trial

Efficacy and safety of Tacrolimus (FK506), in treatment of rheumatoid arthritis: a randomized, double-blind, placebo controlled dose-finding study

Substance

1.5 mg Tacrolimus/day (68 patients) 3 mg Tacrolimus/day (70 patients) Placebo (74 patients) Concomitant medication: Prednisolone £ 5 mg/day (or equivalent) NSAIDs were permitted No other DMARDs Previous medication: Resistant or intolerant to DMARDs ³ 6 months

Result

Tacrolimus was effective in patients with DMARD-resistant RA. The optimal dosage appeared to be 3 mg/day

Patients

212 RA patients DMARD-resistant for min 1/2 year ESR > 30 mm/h CRP 1 mg/l ³ 6 tender joints ³ 3 swollen joints

Authors

Kondo H, Abe T, Hashimoto H, Uchida S, Irimajiri S, Hara M, Sugawara S

Publication

J Rheumatol. 2004 Feb;31(2):243–251

Follow up

16 weeks

ACR 20

48.3% (tacrolimus 3 mg), 24.6% (tacrolimus 1.5 mg), 14.1% (placebo)

ACR 50

12.1% (tacrolimus 3 mg), 10.5% (tacrolimus 1.5 mg), 6.3% (placebo)

Note

Change of: Tender joints -0.4 (placebo), -3.3 (tacrolimus 1.5 mg), -5.3 (tacrolimus 3 mg) Swollen joints -1.3 (placebo), -3.6 (tacrolimus 1.5 mg), -4.2 (tacrolimus 3 mg) CRP 0.36 mg/dL (placebo), -0.36 mg/dL (tacrolimus 1.5 mg), -1.77 mg/dL (tacrolimus 3 mg) ESR +7.1 (placebo), -0.9 mm/h (tacrolimus 1.5 mg), -14.7 mm/h (tacrolimus 3 mg) Pain (VAS) +2.6 cm (placebo), -8.9 cm (tacrolimus 1.5 mg), -15.0 cm (tacrolimus 3 mg) Patients’ global assess. +3.1 (placebo), -9.8 (tacrolimus 1.5 mg), -20.4 (tacrolimus 3 mg) Physicians global assess. -3.7 (placebo), -15.8 (tacrolimus 1.5 mg), -29.6 (tacrolimus 3 mg)

Rheumatoid Arthritis: Tacrolimus

Adverse events

Cardiovascular 1.5% (placebo), 1.6% (tacrolimus 1.5 mg), 0% (tacrolimus 3 mg) Gastrointestinal 9.0% (placebo), 4.8% (tacrolimus 1.5 mg), 11.1% (tacrolimus 3 mg) Heart rate/rhythm 0% (placebo), 1.6% (tacrolimus 1.5 mg), 3.2% (tacrolimus 3 mg) Hematologic 17.9% (placebo), 8.1% (tacrolimus 1.5 mg), 3.2% (tacrolimus 3 mg) Liver/bilary 9.0% (placebo), 9.7% (tacrolimus 1.5 mg), 4.8% (tacrolimus 3 mg) Metabolic/nutritional 10.4% (placebo), 16.1% (tacrolimus 1.5 mg), 22.2% (tacrolimus 3 mg) Musculosceletal 1.5% (placebo), 1.6% (tacrolimus 1.5 mg), 0% (tacrolimus 3 mg) Nervous system 4.5% (placebo), 0% (tacrolimus 1.5 mg), 3.2% (tacrolimus 3 mg) Platelets, bleeding, clotting 0% (placebo), 3.2% (tacrolimus 1.5 mg), 0% (tacrolimus 3 mg) Psychiatric 1.5% (placebo), 1.6% (tacrolimus 1.5 mg), 0% (tacrolimus 3 mg) Resistance mechanisms 7.5% (placebo), 3.2% (tacrolimus 1.5 mg), 1.6% (tacrolimus 3 mg) Respiratory 4.5% (placebo), 1.6% (tacrolimus 1.5 mg), 0% (tacrolimus 3 mg) Skin 11.9% (placebo), 8.1% (tacrolimus 1.5 mg), 4.8% (tacrolimus 3 mg) Reproductive 0% (placebo), 3.2% (tacrolimus 1.5 mg), 1.6% (tacrolimus 3 mg) Urinary 13.4% (placebo), 25.8% (tacrolimus 1.5 mg), 25.4% (tacrolimus 3 mg) Vascular 3.0% (placebo), 0% (tacrolimus 1.5 mg), 0% (tacrolimus 3 mg)

77

78

Rheumatoid Arthritis: Tacrolimus

Trial

Safety of Tacrolimus in patients with rheumatoid arthritis: long-term experience

Substance

Tacrolimus 3 mg Concomitant medication: No oral corticosteroids Intra- and periarticular steroid injections were permitted without restriction No NSAIDs No DMARDs £ 2 weeks Previous medication: Resistant or intolerant to DMARDs ³ 4–12 weeks

Result

Tacrolimus was safe, well-tolerated and provided clinical benefit over a period of min. 12 months

Patients

896 patients Disease duration > 6 months Failed MTX

Authors

Yocum DE, Furst DE, Bensen WG, Burch FX, Borton MA, Mengle-Gaw LJ, Schwartz BD, Wisememandle W, Mekki QA; Tacrolimus RA Study Group

Publication

Rheumatology (Oxford). 2004 Aug;43(8):992–999. Epub 2004 Mar 10

Follow up

12 months

ACR 20

38.4%

ACR 50

18.6%

ACR 70

9%

Note

Change of: Tender joint count -52.1% Swollen joint score -50% Pain (VAS) -22% Physician’s global assessment -44% Patient’s global assessment -25.3% HAQ -21.7% ESR -17.2% CRP -18.1% 16.2% withdrew from the study for adverse events 12.5% withdrew for lack of efficacy

Rheumatoid Arthritis: Tacrolimus

Adverse events

Any adverse event 59% Flu syndrome 4.7% Diarrhoea 14.6% Headache 8.7% Nausea 10.3% Abdominal pain 7.9% Dyspepsia 7.6% Tremor 9.0% Accidental injury <2% Hypertension 5.4% Asthenia 4.4% Increased creatinine 6.8% Rash 3.6% Dizziness 3.0% Vomiting 3.3% Back pain <2% Sinusitis <2% Urinary tract infection <2% Pharyngitis <2% Cramps 2.3% Pneumonia 0.6% Hyperglycaemia 0.3% Gastroenteritis 0.2% Pancreatitis 0.2% Diabetes mellitus 0.2% 8.4% having creatinine levels exceeding the normal range 20.3% had a ³ 30% increase from baseline in creatinine

79

80

Rheumatoid Arthritis: Early DMARD therapy

VERA-Trial

Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis VERA: Very early rheumatoid arthritis

Substance

The choice of DMARD was left to the rheumatologists’ discretion: Therapy at baseline: SSZ n = 9 (VERA), n = 8 (LERA) MTX n = 5 (VERA), n = 8 (LERA) Chloroquine n = 5 (VERA), n = 4 (LERA) MTX + Chloroquine n = 1 (VERA), n = 0 (LERA) Therapy at 3 0: SSZ n = 6 (VERA), n = 4 (LERA) MTX n = 8 (VERA), n = 6 (LERA) Chloroquine n = 4 (VERA), n = 2 (LERA) MTX + Chloroquine n = 1 (VERA), n = 1 (LERA) MTX + CsA n = 0 (VERA), n = 1 (LERA) MTX + SSZ n = 1 (VERA), n = 1 (LERA) Lef n = 0 (VERA), n = 3 (LERA)

Result

Begin of treatment within the first 3 months of the disease was more effective than later onset of treatment

Patients

20 very early RA (VERA) patients with median disease duration of 3 months 20 late early RA (LERA) patients with median disease duration of 12 months until first DMARD initiation

Authors

Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS

Publication

Rheumatology (Oxford). 2004 Jul;43(7):906–914. Epub 2004 Apr 27

Follow up

36 months

ACR 20

65% (VERA), 20% (LERA)

ACR 50

50% (VERA), 15% (LERA)

ACR 70

35% (VERA), 0% (LERA)

Note

Change of: DAS28 -2.8 (VERA), -1.7 (LERA) HAQ -0.7 (VERA), -0.4 (LERA) Pain (VAS 0–100), -40.4 (VERA), -24.9 (LERA) Patient’s global assessment -35.8 (VERA), -24.2 (LERA) Physician’s global assessment -38.0 (VERA), -19.5 (LERA) Swollen joint count change -7.5 (VERA), -4.8 (LERA) Tender joint count -8.0 (VERA), -4.5 (LERA) ESR change -30 mm/h (VERA), -20 mm/h (LERA) CRP -22.9 mg/l (VERA), -10.2 mg/l (LERA) Larsen scores showed a statistically significant retardation of progression in the VERA compared with the LERA

Rheumatoid Arthritis: Ciclosporin + Chloroquine

Trial

Combination therapy in recent onset rheumatoid arthritis: A randomized double-blind trial of the addition of low dose Ciclosporin to patients treated with low dose Chloroquine

Substance

16 week pre-entry phase (all patients): 300 mg chloroquine/day 1st month 200 mg chloroquine/day 2nd month 100 mg chloroquine/day 3rd month Randomized trial (24 week): Ciclosporin 1.25 mg/kg/day (n = 29) Ciclosporin 2.5 mg/kg/day (n = 30) Concomitant medication: Adequate contraception NSAIDs were permitted Chloroquine was continued Previous medication: No previous DMARDs No oral corticosteroids

Result

Treatment of early RA patients with ciclosporin in combination with chloroquine was moderately effective Renal function was impaired

Patients

88 early RA patients with active disease Suboptimal response after 16 weeks of pre-entry phase + ³ 3 of the following: ³ 5 swollen joints CRP ³ 30 mg/l Ritchie articular index ³ 15 Morning stiffness ³ 30 min. ESR ³ 28 mm/h

Authors

van den Borne B, Landewé R, Ghoei The H, Rietveld J, Zwinderman A, Bruyn G, Breedveld F, Dijkmans B

Publication

J Rheumatology. 1998;25:1493–1498

Follow up

42 weeks

81

82

Note

Rheumatoid Arthritis: Ciclosporin + Chloroquine

Meeting the preliminary ACR response criteria 28% (placebo), 34% (1.25 mg/kg CsA), 50% (2.5 mg/kg CsA) Study Completers meeting the preliminary ACR response criteria 26% (placebo), 41% (1.25 mg/kg CsA), 55% (2.5 mg/kg CsA) Discontinued because of inefficiency n = 2 (placebo), n = 4 (1.25 mg/kg CsA), n = 4 (2.5 mg/kg CsA) Change of (week 24 of randomized phase): Tender joint count -2.2 (placebo), -2.2 (1.25 mg/kg CsA), -5.0 (2.5 mg/kg CsA) Swollen joint count -3.5 (placebo), -2.1 (1.25 mg/kg CsA), -3.1 (2.5 mg/kg CsA) Pain assessment (VAS 0–10) -1.5 (placebo), -0.8 (1.25 mg/kg CsA), -1.7 (2.5 mg/kg CsA) D-HAQ -0.19 (placebo), -0.04 (1.25 mg/kg CsA), -0.27 (2.5 mg/kg CsA) CRP (mg/l) -14 (placebo), 0 (1.25 mg/kg CsA), -9 (2.5 mg/kg CsA) Physician’s global assessment -0.2 (placebo), -0.1 (1.25 mg/kg CsA), -0.2 (2.5 mg/kg CsA) Patient’s global assessment -0.1 (placebo), 0 (1.25 mg/kg CsA), -0.3 (2.5 mg/kg CsA)

Adverse events

Discontinued because of adverse events n = 0 (placebo), n = 3 (1.25 mg/kg CsA), n = 4 (2.5 mg/kg CsA) Gastrointestinal complaints events n = 7 (placebo), n = 5 (1.25 mg/kg CsA), n = 8 (2.5 mg/kg CsA) Temporary increase in serum creatinine ³ 30% n = 1 (placebo), n = 3 (1.25 mg/kg CsA), n = 11 (2.5 mg/kg CsA) Serum creatinine increase in the CsA group

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine

Trial

Safety and efficacy of Hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with Methotrexate and Hydroxychloroquine

Substance

1st part (24 weeks): 7.5 mg MTX/week (increased by 2.5 to 15 mg) + 2 × 200 mg Hydroxychloroquine 2nd part (36 weeks): Patients with a moderate or better response were continued with MTX (n = 40) HCQ (n = 41) MTX + HCQ (n = 40) Concomitant medication: Prednisone £ 7.5 mg/day (or equivalent) NSAIDs were permitted No DMARDs £ 2 weeks Analgetics were permitted No ketoprofen No DMARDs

Result

Combination of hydroxychloroquine and methotrexate was effective and well tolerated in RA patients. After withdrawal of methotrexate the response was prolonged for 24 weeks

Patients

141 RA patients Dsease duration > 6 months Functional class II/III Unsatisfactory relief from min. 1 NSAID

Authors

Clegg D, Dietz F, Duffey J, Wilkens RF, Hurd E, Germain BF, Wall B, Wallace DJ, Bell CL, Sleckman J

Publication

J Rheumatology. 1997;24:1896–1902

Follow up

60 weeks

Note

Time to flair 285 days (HCQ), 62 days (MTX), 90 days (combination)

Adverse events

Headache n = 9 (HCQ + MTX), n = 3 (HCQ), n = 4 (MTX) Diarrhoea n = 5 (HCQ + MTX), n = 4 (HCQ), n = 0 (MTX) Dyspepsia n = 4 (HCQ + MTX), n = 3 (HCQ), n = 2 (MTX) Nausea n = 4 (HCQ + MTX), n = 1 (HCQ), n = 4 (MTX) Respiratory system disturbances n = 7 (HCQ + MTX), n = 6 (HCQ) n = 7 (MTX) Pharyngitis n = 4 (HCQ + MTX), n = 2 (HCQ), n = 3 (MTX) Nervous system disturbances n = 4 (HCQ + MTX), n = 4 (HCQ), n = 5 (MTX) Skin disturbances n = 3 (HCQ + MTX), n = 4 (HCQ), n = 6 (MTX) Uro-genital system disturbances n = 5 (HCQ + MTX), n = 1 (HCQ), n = 3 (MTX) Eye and nose disturbances n = 2 (HCQ + MTX), n = 4 (HCQ), n = 2 (MTX)

83

84

Rheumatoid Arthritis: Methotrexate + Doxycycline

Trial

Treatment of early sero-positive rheumatoid arthritis: Doxycycline plus Methotrexate versus Methotrexate alone

Substance

2 × 100 mg Doxycycline/day + MTX (high-dose doxycycline group, n =24) 2 × 20 mg of Doxycycline + MTX (low-dose doxycycline group, n = 18) Placebo + MTX (placebo group, n = 24) Concomitant medication: 7.5 mg MTX/week Titrated up every 3 months to max. 17.5 mg/week Prednisone £ 7.5 mg/day (or equivalent) Previous medication: No DMARDs No intraarticular injections £ 4 weeks

Result

Therapy with MTX plus doxycycline was superior to treatment with MTX alone in sero-positive RA. The therapeutic responses to low-dose and high-dose doxycycline were similar

Patients

66 patients with sero-positive RA Disease duration > 6 weeks and <1 year Not previously treated with DMARDs Rheumatoid factor positive

Authors

O’Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, Blakely KM, Hausch R, Leff RD, RAIN network: Rheumatoid Arthritis Investigational Network

Publication

Arthritis Rheum. 2006 Feb;54(2):621–627

ACR 20

63% (Doxy 20 mg), 61% (Doxy 200 mg), 33% (placebo)

ACR 50

42% (Doxy 20 mg), 39% (Doxy 200 mg), 13% (placebo)

ACR 70

21% (Doxy 20 mg), 28% (Doxy 200 mg), 8% (placebo)

Note

Change of: Tender joint count -9.0 (Doxy), -7.7 (placebo) Swollen joint count -8.9 (Doxy), -8.1 (placebo) ESR (mm/h) -14.6 (Doxy), -13.1 (placebo) HAQ score -0.47 (Doxy), -0.28 (placebo) Physician global assessment of disease activity (0–10 VAS) -2.67 (Doxy), -1.78 (placebo) Patient global assessment of disease activity (0–10 VAS) -2.18 (Doxy), -1.16 (placebo) Patient assessment of pain (0–10 VAS) -1.68 (Doxy), -0.85 (placebo) Morning stiffness, minutes -108 (Doxy), -27 (placebo) Fatigue (0–10 VAS) -1.4 (Doxy), -0.5 (placebo)

Adverse events

High-dose Doxycycline group Increased alanine aminotransferase (ALT) level n = 1 myocardial infarction n = 1 Photosensitivity rash n = 2 Low-dose Doxycycline group: increased ALT levels n = 2 Placebo group: Multiple medical problems n = 1 Rash n = 1

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

Trial

Combination of Methotrexate and Sulfasalazine vs. Methotrexate alone: a randomized open clinical trial in rheumatoid arthritis patients resistant to Sulfasalazine therapy

Substance

2 g Sulfasalazine/day + 7.5 mg MTX/week (n = 22) 7.5 mg MTX/week (n = 18) MTX dose was increased to 15 mg/week if needed Concomitant medication: 7.5 mg MTX/week After week 16 titrated up every 3 months to max. 17.5 mg/week No oral corticosteroids 1 local injection with corticosteroids was permitted NSAIDs were permitted Previous medication: No MTX

Result

The efficacy of the combination of methotrexate and sulfasalazine was superior to methotrexate monotherapy. The toxicities of both therapies was similar

Patients

40 RA patients Current SSZ treatment for min. 6 months DAS ³ 3.0 No previous MTX treatment

Authors

Haagsma CJ, van Riel PL, de Rooij DJ, Vree TB, Russel FJ, van’t Hof MA, van de Putte LB

Publication

Br J Rheumatol. 1994 Nov;33(11):1049–1055

Follow up

24 weeks

Note

Change of: DAS -1.0 (MTX), -2.6 (MTX + SSZ) Swollen joint count -3.7 (MTX), -13.1 (MTX + SSZ) Ritchie articular index -6.1 (MTX), -14.6 (MTX + SSZ) Tender joint count -7.8 (MTX), -19.9 (MTX + SSZ) VAS general health (mm) -4 (MTX), –26 (MTX + SSZ) VAS Pain (mm) -14 (MTX), -30 (MTX + SSZ) Morning stiffness (min) -21 (MTX), -75 (MTX + SSZ) Grip strength right hand (kPa) +4.8 (MTX), +12.1 (MTX + SSZ) Grip strength left hand (kPa) +3.9 (MTX), +17.4 (MTX + SSZ) ESR (mm/h) -11.7 (MTX), -20.8 (MTX + SSZ)

Adverse events

Gastrointestinal n = 5 (MTX), n = 3 (MTX + SSZ) Increase of transaminases n = 6 (MTX), n = 6 (MTX + SSZ) Central nervous system n = 2 (MTX), n = 1 (MTX + SSZ) Leucopoenia n = 0 (MTX), n = 1 (MTX + SSZ) Hair loss n = 1 (MTX), n = 1 (MTX + SSZ) Stomatitis n = 1 (MTX), n = 0 (MTX + SSZ)

85

86

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

COBRA-Trial

Randomised comparison of combined step-down prednisolone, Methotrexate and Sulfasalazine with Sulfasalazine alone in early rheumatoid arthritis COBRA: Combinatietherapie bij Rheumatoide Arthrits

Substance

Combination MTX + SSZ (n = 77) 500 mg Sulphasalazine/day (increased to 2 g/day over 3 weeks) + 7.5 mg Methotrexate/week Sulphasalazine alone (n = 79) Concomitant medication: 7.5 mg MTX/week Titrated up every 3 months to max. 17.5 mg/week 60 mg Prednisolone/day Tapered in 6 weekly steps to 7.5 mg/day NSAIDs were permitted Previous medication: NSAID pre treatment was permitted No DMARDs No Corticosteroids

Result

The combined-therapy of methotrexate and sulfasalazine was more effective than sulfasalazine monotherapy. The effect persisted for up to a year after corticosteroids were stopped

Patients

155 patients with early RA Disease duration < 2a Min. 6 inflamed joints

Authors

Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S

Publication

Lancet. 1997 Aug 2;350(9074):309–318

Follow up

56 weeks

Note

Change of (week 56): Tender joint count -10 (Combined), -9 (SSZ) Grip strength (kPa) +18 (Combined), +13 (SSZ) ESR -31 (Combined), -24 (SSZ) VAS -27 (Combined), -20 (SSZ) Swollen joint count -7 (Combined), -5 (SSZ) HAQ –0.8 (Combined), 0.6 (SSZ) Pain score (VAS) -23 (Combined), -25 (SSZ) Patient’s global assessment (VAS) -14 (Combined), -21 (SSZ) Swollen joint count -7 (Combined), -5 (SSZ) Change of (week 80): Erosion score +4 (Combined), +7 (SSZ) Narrowing score +2 (Combined), +2 (SSZ) Erosion score +4 (Combined), +12 (SSZ)

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

Trial

Combination of Sulfasalazine and Methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52-week clinical trial.

Substance

500 mg sulfasalazine/day (increased to max. 3,000 mg/day, n = 34) 7.5 mg methotrexate/week (increased to max. 15 mg/week, n = 35) Combination MTX + SSZ (n = 36) Concomitant medication: NSAIDs were permitted No oral corticosteroids Previous medication: NSAID pre treatment was permitted No DMARDs

Result

Combination therapy of sulfasalazine and methotrexate was tendentially superior to sulfasalazine or methotrexate monotherapy. The results of sulfasalazine and methotrexate monotherapy were similar. Nausea occurred more often in the combination group

Patients

105 patients with active, early rheumatoid arthritis Not treated with disease-modifying anti-rheumatic drugs previously Rheumatoid factor and/or HLA DR1/4 positive

Authors

Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB

Publication

Br J Rheumatol. 1997 Oct;36(10):1082–1088

Follow up

52 weeks

Note

Change of: Disease Activity Score (DAS) -1.8 (SSZ), -2.0 (MTX), -2.3 (SSZ + MTX) Ritchie articular index -9.2 (SSZ), -9.5 (MTX), -10.6 (SSZ + MTX) Swollen joint count -9.2 (SSZ), -12.4 (MTX), -14.3 (SSZ + MTX) Erythrocyte sedimentation rate -17 mm/h (SSZ), -21 mm/h (MTX), -28 mm/h (SSZ + MTX) No. of painful joints -12.5 (SSZ), -15.2 (MTX), -16.9 (SSZ + MTX) VAS general health (mm) -15.4 (SSZ), -21.3 (MTX), -20.6(SSZ + MTX) VAS pain (mm) -25.2 (SSZ), -25.1 (MTX), -25.1 (SSZ + MTX) Grip strength (kPa) +16 (SSZ), +16 (MTX), +21 (SSZ + MTX) HAQ score -0.32 (SSZ), -0.46 (MTX), -0.51 (SSZ + MTX) ESR (mm) -17 (SSZ), -21 (MTX), -28 (SSZ + MTX)

87

88

Adverse events

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

Nausea n = 10 (SSZ), n = 9 (MTX), n = 23 (SSZ + MTX) Abdominal pain/discomfort n = 9 (SSZ), n = 7 (MTX), n = 13 (SSZ + MTX) Stomatitis n = 1 (SSZ), n = 2 (MTX), n = 2 (SSZ + MTX) Pyrosis n = 2 (SSZ), n = 3 (MTX), n = 5 (SSZ + MTX) Increase in transaminases >2x normal n = 4 (SSZ), n = 5 (MTX), n = 2 (SSZ + MTX) Haematological n = 1 (SSZ), n = 1 (MTX), n = 0 (SSZ + MTX) Flu-like symptoms/upper respiratory tract infection n = 6 (SSZ), n = 7 (MTX), n = 10 (SSZ + MTX) Central nervous system dizziness n = 6 (SSZ), n = 3 (MTX), n = 4 (SSZ + MTX) Headache n = 6 (SSZ), n = 4 (MTX), n = 4 (SSZ + MTX) Neuropathy n = 1 (SSZ), n = 0 (MTX), n = 1 (SSZ + MTX) Dyspnoea n = 2 (SSZ), n = 0 (MTX), n = 2 (SSZ + MTX) Rash n = 5 (SSZ), n = 2 (MTX), n = 0 (SSZ + MTX)

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

89

Trial

Combination therapy in early rheumatoid arthritis: a randomised, controlled, double-blind 52 week clinical trial of sulphasalazine and Methotrexate compared with the single components

Substance

7.5 mg MTX/week (n = 69), raised to 15 mg/week 1 g SSZ/day (n = 68), raised to 3 g/day, if needed MTX + SSZ (n = 68) Concomitant medication: No information provided Previous medication: NSAID pre treatment was permitted No DMARDs No Corticosteroids

Result

In early RA patients an early initiated DMARD therapy seemed to be of benefit without clinically relevant superiority of the combination therapy with methotrexate and sulfasalazine. The tolerability of the three treatment modalities seemed acceptable

Patients

209 early, active rheumatoid arthritis patients Not treated with DMARDS £ 1 year duration Disease Activity Score > 3.0 Rheumatoid factor and/or HLA DR 1 or 4 positive

Authors

Dougados M, Combe B, Cantagrel A, Goupille P, Olive P, Schattenkirchner M, Meusser S, Paimela L, Rau R, Zeidler H, Leirisalo-Repo M, Peldan K

Publication

Ann Rheum Dis. 1999 Apr;58(4):220–225

Follow up

52 weeks

90

Note

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

EULAR good responders 34% (SSZ), 38% (MTX), 38% (SSZ + MTX) ACR criteria responders 59% (SSZ), 59% (MTX), 65% (SSZ + MTX) Change of: DAS -1.15 (SSZ), -0.87 (MTX), -1.26 (SSZ + MTX) Mean changes in erosion score: +2.4 (SSZ), +2.4 (MTX), +1.9 (SSZ + MTX) Narrowing score: +2.3 (SSZ), +2.1 (MTX), +1.6 (SSZ + MTX) Total damage score: +4.6 (SSZ), +4.5 (MTX), +3.5 (SSZ + MTX) Patient’s global assessment -0.9 (SSZ), -0.9 (MTX), -0.8 (SSZ + MTX) Physician’s global assessment -0.7 (SSZ), -0.7 (MTX), -0.6 (SSZ + MTX) Ritchie articular index -7.1 (SSZ), -4.2 (MTX), -9.4 (SSZ + MTX) Swollen joints -4.5 (SSZ), -3.9 (MTX), -4.5 (SSZ + MTX) HAQ -0.74 (SSZ), -0.73 (MTX), -0.70 (SSZ + MTX) Morning stiffness (min) -46 (SSZ), -53 (MTX), -55 (SSZ + MTX) ESR (mm/h) -30 (SSZ), -24 (MTX), -25 (SSZ + MTX) CRP (mg/l) –8 (SSZ), -16 (MTX), -17 (SSZ + MTX) Erosion score +2.38 (SSZ), +2.38 (MTX), +1.85 (SSZ + MTX) Narrowing score +2.26 (SSZ), +2.12 (MTX), +1.61 (SSZ + MTX) Total damage score +4.64 (SSZ), +4.50 (MTX), +3.46 (SSZ + MTX)

Adverse events

Nausea 32% (SSZ), 23% (MTX), 49% (SSZ + MTX) Headache 9% (SSZ), 4% (MTX), 12% (SSZ + MTX) Vertigo 6% (SSZ), 1% (MTX), 3% (SSZ + MTX) Epigastralgia 9% (SSZ), 6% (MTX), 13% (SSZ + MTX) AST 0% (SSZ), 0% (MTX), 3% (SSZ + MTX) ALT 0% (SSZ), 1% (MTX), 9% (SSZ + MTX) Leucopenia 10% (SSZ), 1% (MTX), 9% (SSZ + MTX)

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

COBRA-Trial

COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention COBRA: Combinatietherapie Bij Reumatoide Artritis

Substance

Combination (COBRA, n = 74) 2 g Sulphasalazine/day + 7.5 mg Methotrexate/week (tapered and stopped after week 40) Sulphasalazine monotherapy (n = 74) Concomitant medication: 60 mg Prednisolone/day, tapered in 6 weeks to 7.5 mg/day 1 mg Folic acid/day 500 mg Calcium/day 400 IU 25-Hydroxyvitamin D/day Previous medication: No DMARDs No Corticosteroids

Result

Combination treatment of early RA patients with high-dose corticosteroids resulted in sustained suppression of the rate of radiologic progression, independent of subsequent antirheumatic therapy

Patients

148 patients with early RA, active RA ³ 6 inflamed joints ³ 9 tender joint count Morning stiffness ³ 45 min ESR ³ 28 mm/h Disease duration < 2a

Authors

Landewé RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, van Denderen JC, Westedt ML, Peeters AJ, Dijkmans BA, Jacobs P, Boonen A, van der Heijde DM, van der Linden S

Publication

Arthritis Rheum. 2002 Feb;46(2):347–356

Follow up

5 years

Note

End of follow up: DAS28 4.3 (SSZ), 3.7 (Cobra) Still on DMARD therapy 96% (SSZ), 96% (Cobra) Still on corticosteroids 13% (SSZ), 18% (Cobra) Change of: Sharp Score +8.6 (SSZ), +5.6 (Cobra) Functional ability +0.01(SSZ), +0.01 (Cobra)

91

92

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

MASCOT-Trial

Combination therapy with Sulfasalazine and Methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to Sulfasalazine: results from the double-blind placebo-controlled MASCOT: Methotrexate and Sulfasalazine Combination Trial

Substance

Phase 1: 500 mg SSZ/day (increase to 40 mg/kg/day, max. 4 g/day) Phase 2 (if DAS ³ 2.4): Continue SSZ+ 7.5 mg MTX/week (increased to max. 25 mg/week, n = 56) Continue SSZ + Placebo-MTX (n = 55) Or Placebo-SSZ + 7.5 mg MTX/week (increased to max. 25 mg/week, n = 54) Concomitant medication: Steroids £ 7.5 mg/day Prochlorperazine as antiemetic Folic acid 3 day after MTX NSAIDs were continued Intraarticular or intramuscular corticosteroid were permitted (not within 1 month) Previous medication: No MTX or SSZ

Result

Combination of sulfasalazine and methotrexate was more effective than monotherapy in RA patients with a suboptimal response to sulfasalazine. There was no increase in toxicity

Patients

687 RA patients Sulfasalazine for 6 months Active disease DAS > 2.4

Authors

Capell HA, Madhok R, Porter DR, Munro RA, McInnes IB, Hunter JA, Steven M, Zoma A, Morrison E, Sambrook M, Wui Poon F, Hampson R, McDonald F, Tierney A, Henderson N, Ford I

Publication

Ann Rheum Dis. 2007 Feb;66(2):235–241. Epub 2006 Aug 22

Rheumatoid Arthritis: Methotrexate + Sulfasalazine

Follow up

18 months

ACR 20

After phase 1: 77% After phase 2: 48% (combination), 32% (SSZ), 33% (MTX)

ACR 50

After phase 1: 47% After phase 2: 25% (combination), 10% (SSZ), 7% (MTX)

ACR 70

After phase 1: 18% After phase 2: 13% (combination), 7% (SSZ), 4% (MTX)

Note

28% patients had a DAS <2.4 18% were eligible but did not wish to enter phase II 19% stopped SSZ because of reversible adverse events 24% entered phase II EULAR good response 18% (combination), 3% (SSZ), 2% (MTX) EULAR remission 10% (combination), 2% (SSZ), 1% (MTX) Change of: DAS -0.67 (combination), -0.3 (SSZ), -0.26 (MTX) HAQ -0.5 (combination), -0.25 (SSZ), -0.19 (MTX) Ritchie articular index -4 (combination), -3 (SSZ), 0 (MTX) Swollen joint count -3 (combination), -3 (SSZ), -2 (MTX) Pain score change -8 (combination), 0 (SSZ), 0 (MTX) Patient’s global assessment -11.5 (combination), 0 (SSZ), -7 (MTX) Physician’s global assessment -12.5 (combination), -4 (SSZ), -5 (MTX) ESR 0 (combination), 0 (SSZ), +1 (MTX) CRP 0 (combination), 0 (SSZ), 0 (MTX)

93

94

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Trial

Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group

Substance

2.5 mg/kg ciclosporin/day (increased by 0.5 mg/kg/day to max. 5 mg/kg/day, n = 48) Placebo (group 2; n = 44) Cross over to receive ciclosporin + methotrexate Concomitant medication: MTX £ 15 mg/week was continued Prednisone £ 10 mg/day was continued NSAIDs were continued Previous medication: MTX £ 15 mg/week Prednisone £ 10 mg/day NSAIDs were permitted DMARDs

Result

Patients with severe rheumatoid arthritis despite methotrexate had clinically important improvement after combination therapy with ciclosporine and methotrexate. Side effects were not substantially increased

Patients

92 RA patients With a partial response to MTX (max. 15 mg/week) Prednisolone (max 10 mg/day) Min. 6 inflamed joints

Authors

Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G, McKendry R, Tesser J, Baker P, Wells G

Publication

N Engl J Med. 1995 Jul 20;333(3):137–141

Follow up

24 weeks

Note

Withdrawal: Lack of efficacy n = 1 (CsA), n = 3 (placebo) Adverse reaction n = 9 (CsA), n = 5 (placebo) Intercurrent illness n = 3 (CsA), n = 1 (placebo) Refusal to continue n = 2 (CsA), n = 2 (placebo) Protocol violation n = 1 (CsA), n = 0 (placebo) Death n = 2 (CsA), n = 0 (placebo) Other n = 1 (CsA), n = 1 (placebo) Change of (month 6): No. of tender joints -7.5 (CsA), -2.7 (placebo) No. of swollen joints -5.7 (CsA), -1.9 (placebo) Global assessment by physician -0.76 (CsA), -0.19 (placebo) Global assessment by patient -0.64 (CsA), -0.04 (placebo) Pain -12.1 (CsA), -2.6 (placebo) Degree of disability -0.25 (CsA), 0.03 (placebo) Erythrocyte sedimentation rate (mm/h) +4.2 (CsA), -4.8 (placebo)

Adverse events

Death n = 2 (CsA), n = 0 (placebo) Serum creatinine concentrations +0.14 mg/dL (CsA), 0.05 mg/dL (placebo)

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Title

Combination treatment of severe rheumatoid arthritis with Ciclosporin and Methotrexate for forty-eight weeks: an open-label extension study. The Methotrexate-Ciclosporin Combination Study Group

Substance

Ciclosporin + methotrexate for 24 weeks (group 1; n = 48) Placebo + methotrexate (group 2; n = 44) Cross over to receive ciclosporin + methotrexate Concomitant medication: MTX £ 15 mg/week was continued Prednisone £ 10 mg/day was continued NSAIDs were continued Previous medication: MTX £ 15 mg/w Prednisone £ 10 mg/d NSAIDs were permitted

Result

RA patients treated with the combination of ciclosporin and methotrexate for 48 weeks improved. An increase of serious adverse effects was not observed

Patients

92 RA patients With a partial response to MTX (max. 15 mg/week) Prednisolone (max 10 mg/day)

Authors

Stein CM, Pincus T, Yocum D, Tugwell P, Wells G, Gluck O, Kraag G, Torley H, Tesser J, McKendry R, Brooks RH

Publication

Arthritis Rheum. 1997 Oct;40(10):1843–1851

Follow up

48 weeks

Note

Change of: Tender joint count -9.8 (CsA + MTX), -9.8 (MTX) Swollen joint count -6.9 (CsA + MTX), -6.3 (MTX) Physicians global assessment -1.0 (CsA + MTX), -0.8 (MTX) Patients global assessment -0.7 (CsA + MTX), -0.5 (MTX) Pain VAS -14.2 (CsA + MTX), -12.8 (MTX) Modified HAQ Score -0.3 (CsA + MTX), +0.1 (MTX) ESR +4.3 (CsA + MTX), -2.2 (MTX)

Adverse events

Nausea 4% (CsA + MTX), 30% (MTX) Diarrhoea 6% (CsA + MTX), 14% (MTX) Mouth ulcers 4% (CsA + MTX), 9% (MTX) Paresthesia 4% (CsA + MTX), 9% (MTX) 30% creatinine increase 36% (CsA + MTX), 16% (MTX) Hypertrichosis 2% (CsA + MTX), 9% (MTX) Breast tenderness 0% (CsA + MTX), 5% (MTX) Hypertension 16% (CsA + MTX), 23% (MTX)

95

96

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Trial

Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with Methotrexate, Ciclosporin A, and intraarticular corticosteroids compared with Sulfasalazine alone

Substance

Combination therapy 1.5 mg/kg/day ciclosporin A (increased to max. 4.2 mg/kg/day) + 7.5 mg MTX/week (increased by 2.5 mg, max. 20 mg/week, n = 40) 500 mg/day SSZ (increased to 2 g/day every week, n = 42) Concomitant medication: No oral corticosteroids Folic acid, 5 mg 2 days/week NSAIDs were continued No diclophenac Methylprednisolone injections: Maximum i.a. dose of 160 mg at a single visit: 10 mg for each small joint 20 mg for each wrist and ankle 40 mg for each knee If No ACR 20% improvement after 3 months Intramuscular injection of 120 mg methylprednisolone Previous medication: No immunosuppressive or cytotoxic drugs No DMARDs No corticosteroids

Result

Combination therapy of poor-prognosis RA patients with methotrexate and ciclosporin A led to more rapid disease suppression but did not result in significantly better ACR response or remission rates

Patients

82 consecutive patients presenting with new, untreated RA Disease duration £ 12 months Min 3 out of: C-reactive protein > 20 mg/L Rheumatoid factor positivity Presence of the conserved sequence of DRbeta in the third allelic hypervariable region Abnormal findings on the HAQ (raw score): 4–11 (1 point) or >11 (2 points) Female sex

Authors

Proudman SM, Conaghan PG, Richardson C, Griffiths B, Green MJ, McGonagle D, Wakefield RJ, Reece RJ, Miles S, Adebajo A, Gough A, Helliwell P, Martin M, Huston G, Pease C, Veale DJ, Isaacs J, van der Heijde DM, Emery P

Publication

Arthritis Rheum. 2000 Aug;43(8):1809–1819

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Follow up

48 weeks

ACR 20

58% (SSZ), 45%(MTX + CsA)

Note

Median cumulative steroid dose 85 mg (SSZ), 230 mg (MTX + CsA) Change of: Swollen joint count -8.3 (SSZ), -13.6 (MTX + CsA) Tender joint count -9.5 (SSZ), -13.4 (MTX + CsA) CRP (mg/l) -23.6 (SSZ), -30.3 (MTX + CsA) ESR (mm/h) -15.0 (SSZ), -15.3 (MTX + CsA) HAQ score -0.6 (SSZ), -0.6 (MTX + CsA) Pain score (VAS) -24 (SSZ), -19 (MTX + CsA) Patient’s global assessment (VAS) -26 (SSZ), -22 (MTX + CsA) DAS 28 -1.9 (SSZ), -2.2 (MTX + CsA) Erosion score +1.75 (SSZ), +0.75 (MTX + CsA) Joint space narrowing +0.5 (SSZ), +0.5 (MTX + CsA) Damage score +3.0 (SSZ), +2.0 (MTX + CsA)

Adverse events

Elevated transaminase levels n = 0 (MTX + CsA), n = 1 (SSZ) Neutropenia n = 0 (MTX + CsA), n = 1 (SSZ) Erythema multiforme n = 0 (MTX + CsA), n = 1 (SSZ) Hypersensitivity reaction n = 0 (MTX + CsA), n = 1 (SSZ) Thrombo-embolic cerebrovascular accident n = 1 (MTX + CsA), n = 0 (SSZ) MTX pneumonitis n = 2 (MTX + CsA), n = 0 (SSZ) Hypertension n = 9 (MTX + CsA), n = 0 (SSZ) Gastrointestinal symptoms n =25 (MTX + CsA), n = 31 (SSZ) Headache n = 11 (MTX + CsA), n = 7 (SSZ) Rash n = 2 (MTX + CsA), n = 8 (SSZ) Hypertrichosis n = 7 (MTX + CsA), n = 0 (SSZ)

97

98

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Trial

Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of Ciclosporin and Methotrexate with Methotrexate alone

Substance

Combination therapy (n = 30): 3 mg/kg CsA/day (increased to 4 mg/kg/day) + 10–15 mg MTX/week (n = 30, increased to 20 mg/week) MTX arm (n = 31): 10–15 mg MTX/week (increased to 20 mg/week) Concomitant medication: Adequate contraceptive method Prednisone £ 10 mg/day No corticosteroid injections Previous medication: No immunosuppressive, cytotoxic medicaments No DMARD No Prednisone > 10 mg/day

Result

Ciclosporin and methotrexate combination therapy led to a significantly lower rate of radiographic progression in patients with early RA

Authors

Marchesoni A, Battafarano N, Arreghini M, Panni B, Gallazzi M, Tosi S

Publication

Rheumatology (Oxford). 2003 Dec;42(12):1545–1549. Epub 2003 Jun 16

Patients

61 consecutive patients with untreated RA Disease duration £ 2 years ESR ³ 30 mm/h (women) ³ 20 mm/h (men) Morning stiffness ³ 45 min

Follow up

12 months

ACR 20

53% (CsA + MTX), 61% (MTX)

ACR 50

50% (CsA + MTX), 42% (MTX)

ACR 70

47% (CsA + MTX), 19% (MTX)

Note

Change of: Damage score 1.93 (CsA + MTX), 7.47 (MTX) Eroded joint score 0.29 (CsA + MTX), 1.37 (MTX) Erosion score 0.75 (CsA + MTX), 3.9 (MTX) Narrowing score 1.18 (CsA + MTX), 3.57 (MTX)

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Trial

Ciclosporin A monotherapy versus Ciclosporin A and Methotrexate combination therapy in patients with early rheumatoid arthritis: a double-blind randomised placebo-controlled trial

Substance

2.5 mg/kg CsA/day (n = 60, increased to max. 5 mg/kg/day in 16 weeks) 7.5 mg MTX/week + CsA (n = 60, increased to 15 mg/week at week 16)

99

Concomitant medication: NSAIDs at stable doses Adequate contraceptive method Prednisone £ 10 mg/day No corticosteroid injections Previous medication: No immunosuppressive, cytotoxic medicaments No CsA or MTX £ 1 DMARD ³ 3 months Result

Neither combination therapy with ciclosporin A and methotrexate nor ciclosporin A monotherapy was very effective in inducing clinical remission of recent onset RA patients. Combination therapy was better at slowing radiological progression

Patients

60 active RA patients ³ 6 swollen joints (out of 66) ³ 6 tender joints (out of 68) ESR ³ 28 mm/h, and/or CRP ³ 20 mg/L Global assessor’s score of disease activity (ranging 1–5) of ³ 4

Authors

Gerards AH, Landewé RB, Prins AP, Bruyn GA, Goei Thé HS, Laan RF, Dijkmans BA

Publication

Ann Rheum Dis. 2003 Apr;62(4):291–296

Follow up

48 weeks

ACR 20

47% (monotherapy), 57% (combination)

ACR 50

25% (monotherapy), 48% (combination)

ACR 70

12% (monotherapy), 20% (combination)

Note

Median Larsen 10 (CsA), 4 (MTX + CsA) Change of (after 24 weeks): Swollen joint count -12 (CsA + MTX), -8 (CsA) Tender joint count -13 (CsA + MTX), -13 (CsA) ESR -15 mm/h (CsA + MTX), -5 mm/h (CsA) CRP -15 mg/L (CsA + MTX), -19 mg/L (CsA) HAQ -0.9 (CsA + MTX), -0.87 (CsA) VAS for pain -2.0 cm (CsA + MTX), -2.3 cm (CsA)

Adverse events

>30% raised serum creatinine 78.3% (CsA + MTX), 70% (CsA) A period with hypertension 54% (CsA + MTX), 54% (CsA) Gastric intestinal complaints 46% (CsA + MTX), 46% (CsA) Hypertrichosis 21.7% (CsA + MTX), 31.7% (CsA) Headache 18.3% (CsA + MTX), 21.7% (CsA) Raised serum potassium 16.6% (CsA + MTX), 6.6% (CsA) Liver enzyme disturbances 11.7% (CsA + MTX), 11.7% (CsA) Paresthesia 10% (CsA + MTX), 11.7% (CsA) Gingivitis 8.3% (CsA + MTX), 13.3% (CsA) Fluid retention 8.3% (CsA + MTX), 5% (CsA) Tremor 6.6% (CsA + MTX), 3.3% (CsA) Metrorrhagia 5% (CsA + MTX), 1.6% (CsA) Fatigue 1.6% (CsA + MTX), 5% (CsA)

100

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Trial

An open, randomized comparison study of Ciclosporin A, Ciclosporin A + Methotrexate and Ciclosporin A + Hydroxychloroquine in the treatment of early severe rheumatoid arthritis

Substance

3 mg/kg/day CSA + 7.5 10 mg MTX/day (n = 34) 3 mg/kg/day CSA + 400 mg/day HCQ (n = 35) 3 mg/kg/day CSA alone (n = 36) Concomitant medication: NSAIDs at stable doses Prednisone £ 10 mg/day Previous medication: No immunosuppressive, cytotoxic medicaments No DMARDs

Result

Combination therapy with ciclosporin A and methotrexate was more effective than the respective monotherapies in improving clinical signs and symptoms of the disease and inhibiting radiographic progression in RA patients

Patients

105 active RA patients Disease duration £ 36 months ³ 6 swollen and tender joints C-reactive protein >2.0 mg/dL Rheumatoid factor positivity Presence ³ 1 articular erosion according to the Larsen–Dale score

Authors

Sarzi-Puttini P, D’Ingianna E, Fumagalli M, Scarpellini M, Fiorini T, Chérié-Lignière EL, Panni B, Fiorentini F, Corbelli V, Beyene NB, Mastaglio C, Severi C, Locati M, Cazzola M, Menozzi G, Monti G, Saccardo F, Alfieri G, Atzeni F

Publication

Rheumatol Int. 2005 Jan;25(1):15–22. Epub 2003 Oct 7

Follow up

12 months

ACR 20

45.7% (CSA), 54.2% (CSA + HCQ), 75% (CSA + MTX)

ACR 50

17.4% (CSA), 20.0% (CSA + HCQ), 59.3% (CSA + MTX)

ACR 70

8.5% (CSA), 11.4% (CSA + HCQ), 28.1% (CSA + MTX)

Note

Larsen-Dale damage score +2.76 (CSA), +2.97 (CSA + HCQ), +0.97 (CSA + MTX) Larsen-Dale erosion score +1.21 (CSA), +1.00 (CSA + HCQ), +0.30 (CSA + MTX)

Rheumatoid Arthritis: Methotrexate + Ciclosporin

Adverse events

GI system disorders n = 9 (CSA), n = 10 (CSA + HCQ), n = 11 (CSA + MTX) Neurologic disturbances n = 2 (CSA), n = 2 (CSA + HCQ), n = 2 (CSA + MTX) Mucocutaneous alterations n = 4 (CSA), n = 3 (CSA + HCQ), n = 4 (CSA + MTX) Hypertension n = 6 (CSA), n = 7 (CSA + HCQ), n = 5 (CSA + MTX) Cardiovascular disturbances n = 1 (CSA), n = 1 (CSA + HCQ), n = 0 (CSA + MTX) Infections n = 1 (CSA), n = 0 (CSA + HCQ), n = 0 (CSA + MTX) Liver dysfunctions n = 0 (CSA), n = 2 (CSA + HCQ), n = 5 (CSA + MTX) Kidney dysfunctions n = 4 (CSA), n = 4 (CSA + HCQ), n = 2 (CSA + MTX) No. of side effects n = 27 (CSA), n = 29 (CSA + HCQ), n = 28 (CSA + MTX) No. of patients with side effects n = 18 (CSA), n = 23 (CSA + HCQ), n = 22 (CSA + MTX) No. of withdrawal n = 5 (CSA), n = 6 (CSA + HCQ), n = 5 (CSA + MTX) Inefficacy n = 3 (CSA), n = 2 (CSA + HCQ), n = 0 (CSA + MTX) Non compliance n = 0 (CSA), n = 0 (CSA + HCQ), n = 1 (CSA + MTX) Adverse reactions n = 2 (CSA), n = 4 (CSA + HCQ), n = 4 (CSA + MTX)

101

102

Rheumatoid Arthritis: Methotrexate + Ciclosporin

CIMESTRA Trial

Combination treatment with Methotrexate, Ciclosporin, and intraarticular Betamethasone compared with Methotrexate and intraarticular Betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study CIMESTRA: Ciclosporin, Methotrexate, Steroid in RA

Substance

MTX 7.5 mg/week (increased by 2.5 mg every 4 weeks to max. 20 mg/week) + ciclosporin 2.5 mg/kg (n = 80) MTX + placebo (n = 80) Concomitant medication: No oral glucocorticoids At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 mL per visit) Previous medication: No DMARDs

Result

Combination treatment with methotrexate and intraarticular glucocorticoids stopped the progression of erosions in patients with early active RA. Addition of ciclosporin improved the ACR20 responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the two study groups

Patients

Early RA Patients (n = 160) Active disease of < 6 months’ duration ³ 2 swollen joints at baseline Not treated with glucocorticoids in the preceding 4 weeks No previous use of DMARDs

Authors

Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T, Andersen LS, Hansen I, Skjødt H, Pedersen JK, Lauridsen UB, Svendsen A, Tarp U, Pødenphant J, Hansen G, Lindegaard H, de Carvalho A, Østergaard M, Hørslev-Petersen K; CIMESTRA Study Group

Publication

Arthritis Rheum. 2006 May;54(5):1401–1409

Follow up

52 weeks

ACR20

85% (MTX + CsA), 68% (MTX)

Note

ACR remission criteria were met in 35% (MTX + CsA), 28% (MTX) Progression in the Larsen score -0.2 (MTX + CsA), 0.4 (MTX) ACR-N (median) 80.0% (MTX + CsA), 54.5% (MTX)

Adverse events

Dyspepsia 23% (MTX + CsA), 20% (MTX) Hypertrichosis 33% (MTX + CsA), 8% (MTX) Constipation 4% (MTX + CsA), 11% (MTX) Insomnia 5% (MTX + CsA), 11% (MTX) Antihypertensive agent added 21% (MTX + CsA), 11% (MTX) Decrease of serum albumin 8% (MTX + CsA), 11% (MTX) Increase of serum creatinine increase 19% (MTX + CsA), 6% (MTX)

Rheumatoid Arthritis: Methotrexate + Ciclosporin

103

CIMESTRATrial 2 year follow up

Aggressive combination therapy with intraarticular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study CIMESTRA: Ciclosporin, Methotrexate, Steroid in RA

Substance

MTX 7.5 mg/week (increased by 2.5 mg every 4 weeks to max. 20 mg/ week) + ciclosporin 2.5 mg/kg (n = 80) MTX + placebo (n = 80) Concomitant medication: No oral glucocorticoids At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 mL per visit) Previous medication: No DMARDs At week 68: Hydroxychloroquine 200 mg daily was added From week 76–104: Ciclosporin or placebo were tapered to zero

Result

Continuous methotrexate and intraarticular corticosteroid treatment led to an excellent clinical response and disease control at 2 years. Addition of ciclosporin during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome

Patients

160 patients with early RA Disease duration < 6 months

Authors

Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Hansen I, Andersen LS, Tarp U, Svendsen A, Pedersen JK, Skjødt H, Lauridsen UB, Ellingsen T, Hansen GV, Lindegaard H, Vestergaard A, Jurik AG, Østergaard M, Hørslev-Petersen K; CIMESTRA study group

Publication

Ann Rheum Dis. 2008 Jun;67(6):815–822. Epub 2007 Sep 18

Follow up

2 years

ACR 20

88% (MTX + CsA), 73% (MTX)

ACR 50

79%(MTX + CsA), 62% (MTX)

ACR 70

59% (MTX + CsA), 54% (MTX)

104

Note

Rheumatoid Arthritis: Methotrexate + Ciclosporin

EULAR remission 51% (CsA + MTX), 50% (MTX) ACR remission 41% (CsA + MTX), 35% (MTX) Change of: Total Sharp-van der Heijde scores +1.42 (MTX + CsA), +2.03 (MTX) Erosion score +1.08 (MTX + CsA), +1.46 (MTX) Joint space narrowing +0.34 (MTX + CsA), +0.56 (MTX) No. of tender joints (0–40) -14 (CsA + MTX), -13 (MTX) No. of swollen joints (0–40) -12 (CsA + MTX), -11 (MTX) Doctor’s global assessment (0–100 mm VAS) -52 (CsA + MTX), -58 (MTX) Patient’s assessment of pain (0–100 mm VAS) -38 (CsA + MTX), -38 (MTX) Patient’s global assessment (0–100 mm VAS) -38 (CsA + MTX), -43 (MTX) Serum CRP (mg/l) -14 (CsA + MTX), -12 (MTX) ESR (mm/h) -18 (CsA + MTX), -17 (MTX) DAS28 – ESR -3.4 (CsA + MTX), -3.5 (MTX) HAQ score, range (0–3) -1.0 (CsA + MTX), -0.8 (MTX)

Adverse events

Dyspepsia 10% (MTX + CsA), 6% (MTX) Hypertrichosis 10% (MTX + CsA), 6% (MTX) Sleeplesness 3% (MTX + CsA), 10% (MTX) >10% decrease of serum albumin 4% (MTX + CsA), 13% (CsA) >30% decrease of serum creatinine 14% (MTX + CsA), 4% (CsA)

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

FIN-RACo Trial Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group FIN-RACo: Finish RA Cohort Substance

Combination (n = 97): 2 × 500 mg SSZ/day (increased to 2 g/day if needed) + 7.5 mg MTX/week (increased to 15 mg/day if needed) + 300 mg HCQ/d + 5 mg prednisolone/d If one or several components had to be discontinued: SSZ or HCQ => auranofin (3–6 mg daily) Methotrexate => azathioprine (2 mg/kg daily) Other DMARDs could also be used as substitutes Single drug therapy (n = 51): Started with 2 g sulfasalazine/(increased to 3 g/day if needed) Change to 7.5–15 mg methotrexate/d Change to other DMARDs Concomitant medication: Oral prednisolone 5 mg/day (increased to 7.5 mg/day if needed) Adequate contraception NSAIDs were permitted Intraarticular glucocorticoid injections were permitted Folic acid was permitted At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum four joints or 4 mL per visit) Previous medication: No DMARDs No oral glucocorticoids £ 2 weeks

Result

Combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine was better than single treatment in induction of remission in early RA in this cohort study. Combination treatment was not more hazardous

Patients

199 patients were randomly assigned to two treatment groups Never received DMARDs Symptom duration < 2 years, and Presence of active disease: ³ 3 swollen joints + ³ 3 of the following 4 features: Erythrocyte sedimentation rate ³ 28 mm/h C-reactive protein level > 19 mg/l Morning stiffness > 29 min > 5 swollen joints > 10 tender joints

105

106

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

Authors

Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, Korpela M, Laasonen L, Julkunen H, Luukkainen R, Vuori K, Paimela L, Blåfield H, Hakala M, Ilva K, Yli-Kerttula U, Puolakka K, Järvinen P, Hakola M, Piirainen H, Ahonen J, Pälvimäki I, Forsberg S, Koota K, Friman C

Publication

Lancet. 1999 May 8;353(9164):1568–1573

Follow up

24 months

ACR 20

78% (combination), 84% (monotherapy)

ACR 50

69% (combination), 57% (monotherapy)

Note

Remission 24.7% (combination), 11.2% (Single), after 1 year Remission 37.11% (combination), 18.3% (Single), after 2 years Change of (2 years): ESR –23 mm/h (combination), –19 mm/h (Single) Number of swollen joints –10 mm/h (combination), –10 mm/h (Single) Number of tender joints –13 mm/h (combination), –14 mm/h (Single) Patient’s overall assessment –28 mm/h (combination), –25 mm/h (Single) Physician’s overall assessment –28 mm/h (combination), –29 mm/h (Single) HAQ –0.6 mm/h (combination), –0.6 mm/h (Single)

Adverse events

Gastrointestinal 30% (combination), 31% (monotherapy) Mucocutaneous 24% (combination), 16% (monotherapy) Respiratory 14% (combination), 14% (monotherapy) Central nervous system 12% (combination), 9% (monotherapy) Alanine aminotransferase increase 11% (combination), 23% (monotherapy) Urogenital 8% (combination), 10% (monotherapy) Haematological 8% (combination), 7% (monotherapy)

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

Trial

Treatment of rheumatoid arthritis with Methotrexate and Hydroxychloroquine, Methotrexate and Sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial

Substance

MTX, SSZ, HCQ (n = 58) MTX, HCQ (n = 58) MTX, SSZ (n = 55)

107

Dosages employed: 7.5 mg MTX/week, increased by 2.5 mg every month to max. 17.5 mg/week 2 × 500 mg SSZ/day, increased to 2 × 1.000 mg/day at 6 months 2 × 200 mg HCQ/day Concomitant medication: £ 10 mg of prednisone (or its equivalent)/d NSAIDs were permitted £ 2 joint injections within the 2-year trial (£ 1 injection per joint) Previous medication: MTX was permitted No DMARD combination therapy Result

The triple combination of hydroxychloroquine, methotrexate and sulfasalazine was well tolerated, and more effective than double combination of methotrexate and sulfasalazine or methotrexate and hydroxychloroquine

Patients

171 RA-patients Disease duration > 6 months Active disease, with at least 3 of the following 4 features: ESR > 28 mm/h Duration of morning stiffness ³ 45 min ³ 8 tender joints ³ 3 swollen joints

Authors

O’Dell JR, Leff R, Paulsen G, Haire C, Mallek J, Eckhoff PJ, Fernandez A, Blakely K, Wees S, Stoner J, Hadley S, Felt J, Palmer W, Waytz P, Churchill M, Klassen L, Moore G

Publication

Arthritis Rheum. 2002 May;46(5):1164–1170

Follow up

24 month

ACR 20

78% (MTX, SSZ, HCQ), 60% (MTX, HCQ), 49% (MTX, SSZ)

ACR 50

55% (MTX, SSZ, HCQ), 40% (MTX, HCQ), 29% (MTX, SSZ)

ACR 70

26% (MTX, SSZ, HCQ), 16% (MTX, HCQ), 18% (MTX, SSZ)

108

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

Note

Change of: Tender joint count (max. 38), –10 (MTX + HCQ), –14 (MTX + HCQ + SSZ), –10.2 (MTX + SSZ) Swollen joint count (max. 38) –14 (MTX + HCQ), –17 (MTX + HCQ + SSZ), –13 (MTX + SSZ) Pain (0–10) –1.8 (MTX + HCQ), –2.7 (MTX + HCQ + SSZ), –1.8 (MTX + SSZ) Patient’s global assessment –2.1 (MTX + HCQ), –2.5 (MTX + HCQ + SSZ), –1.5 (MTX + SSZ) Physician’s global assessment –2.7 (MTX + HCQ), –3.2 (MTX + HCQ + SSZ), –2.3 (MTX + SSZ) ESR –3.7 mm/h (MTX + HCQ), –13.0 mm/h (MTX + HCQ + SSZ), –6.8 mm/h (MTX + SSZ) Morning stiffness –59.2 min (MTX + HCQ), –109.3 min (MTX + HCQ + SSZ), –53.2 (MTX + SSZ)

Adverse events

MTX + SSZ: Headaches n = 1 Rash n = 1 Pneumonia n = 1 Gastrointestinal distress n = 2 MTX + HCQ group: Weight loss n = 1 Gastrointestinal distress n = 1 HCQ-related changes in the eye n = 1 Myocardial infarction n = 1 Lobar pneumonia n = 1 MTX + SSZ + HCQ: Gastrointestinal distress n = 1 Transient changes on liver function studies n = 1 Mild neutropenia n = 1 Non-Hodgkin’s lymphoma n = 1

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

TICORA-Trial

Effect of a treatment strategy of Tight Control for Rheumatoid Arthritis (the TICORA study): a single blind randomised controlled trial TICORA: Tight Control for Rheumatoid Arthritis

Substance

Escalation protocol of base line therapy: 1. 40 mg/kg SSZ 2. 4 0 mg/kg SSZ +7.5 mg MTX/week + 200–400 mg hydroxychloroquine 3. Triple therapy with monthly increasing MTX dose (max 25 mg/week) 4. Triple therapy with increasing dose of SSZ (max 5 g/day) 5. Addition of prednisolone 7.5 mg/day 6. Change triple therapy 2–5 mg/day CsA, 25 mg/week MTX 7. Change to other DMARDs Intensive management (n = 55): Monthly visits to the same rheumatologist Routine care (n = 55): Monthly visits to two rheumatologist of the same department and one trainee under supervision Concomitant medication: Injection of corticosteroids into max. 3 joints Total dose max. 120 mg triamcinolone/visit No repeated injections into the same joint £ 3 months Previous medication: No prior DMARDs combination therapy

Result

Disease activity, radiographic disease progression, physical function, and quality of life of RA patients improved subsequent to intensive outpatient management, at no additional cost

Patients

111 RA patients with active disease Disease activity score of ³ 2.4

Authors

Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, Kincaid W, Porter D

Publication

Lancet. 2004 Jul 17–23;364(9430):263–269

Follow up

18 months

109

110

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

ACR20

91% (intensive care), 64% (routine care)

ACR 50

84% (intensive care), 40% (routine care)

ACR 70

71% (intensive care), 18% (routine care)

Note

EULAR good response 82% (intensive care), 44% (routine care) EULAR remission 65% (intensive care), 16% (routine care) Change of: Disease activity score –3.5 (intensive care), –1.9 (routine care) Joint swelling count –11 (intensive care), –8 (routine care) Joint tenderness count –20 (intensive care), –12 (routine care) Patient global assessment –51 (intensive care), –21 (routine care) Assessor global assessment –58 (intensive care), –34 (routine care) Pain score –45 (intensive care), –20 (routine care) Erythrocyte sedimentation rate –30 (intensive care), –12 (routine care) C–reactive protein –30 (intensive care), –14 (routine care) Health assessment questionnaire –0.97 (intensive care), –0.47 (routine care) Erosion score +0.5 (intensive care), +3 (routine care) Joint space narrowing +3.25 (intensive care), +4.5 (routine care) Total Sharp score +4.5 ((intensive care), +8.5 (routine care)

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

111

Fin-RACo-Trial Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study FIN-RACO: Finish RA Cohort Substance

Combination (n = 97): 2 × 500 mg SSZ/day (increased to 2 g/day if needed) + 7.5 mg MTX/week (increased to 15 mg/day if needed) + 300 mg HCQ/day + 5 mg Prednisolone/day If one or several components had to be discontinued: SSZ or HCQ => auranofin (3–6 mg daily) Methotrexate => azathioprine (2 mg/kg daily) Other DMARDs could also be used as substitutes Single drug therapy (n = 51): Started with 2 g sulfasalazine/(increased to 3 g/day if needed) Change to 7.5–15 mg methotrexate/d Change to other DMARDs Concomitant medication: Oral prednisolone 5 mg/day (increased to 7.5 mg/day if needed) Adequate contraception NSAIDs were permitted Intraarticular glucocorticoid injections were permitted Folic acid was permitted At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum four joints or 4 mL per visit) Previous medication: No DMARDs No oral glucocorticoids £ 2 weeks

Result

Aggressive initial treatment with methotrexate, sulfasalazine, and hydroxychloroquine for the first 2 years limited the peripheral joint damage for at least 5 years in early RA patients

Authors

Korpela M, Laasonen L, Hannonen P, Kautiainen H, Leirisalo-Repo M, Hakala M, Paimela L, Blåfield H, Puolakka K, Möttönen T; FIN-RACo Trial Group

Publication

Arthritis Rheum. 2004 Jul;50(7):2072–2081

112

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

Follow up

5 years

Patients

195 patients with early, clinically active RA ³ 3 swollen joints ³ 3 tender joints ESR > 28 mm CRP > 19 mg/l Morning stiffness > 29 min Symptom duration: 6 months – 2 years

DAS28

Baseline 5.33 (combination DMARD), 5.67 (single DMARD) At 2 years 2 (combination DMARD), 3.13 (single DMARD) At 5 years 2.3 (combination DMARD), 2.8 (single DMARD)

Remission

Remission at 2 years 40% (combination DMARD), 18% (single DMARD) Remission at 5 years 28% (combination DMARD), 22% (single DMARD)

DAS28/12 Months

Larsen radiologic damage scores at baseline 0 (combination DMARD), 2 (single DMARD) 2 years 4 (combination DMARD), 12 (single DMARD) 5 years 11 (combination DMARD), 24 (single DMARD)

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

Trial

Tight control and intensified COBRA combination treatment in early rheumatoid arthritis: 90% remission in a pilot trial

Substance

Sulfasalazine (2 g/day) + 10 mg methotrexate/week + 400 mg hydroxychloroquine/d + 60 mg prednisoloneday(tapered in 6 weekly steps to 7.5 mg/day) Concomitant medication: No additional information

Result

intensified and tightly controlled COBRA treatment was uniquely effective in early RA patients

Patients

21 early RA patients Disease duration £ 36 months Active disease defined by DAS28 > 3.2

Authors

van Tuyl LH, Lems WF, Voskuyl AE, Kerstens PJ, Garnero P, Dijkmans BA, Boers M

Publication

Ann Rheum Dis. 2008 Nov;67(11):1574–1577. Epub 2008 Jul 14

Follow up

40 weeks

ACR 20

100%

ACR 50

95%

ACR 70

71%

ACR 90

43%

Note

Remission (DAS28 < 2.6) after 8 weeks, 57% Remission after 21 weeks, 76% Remission after 40 weeks 90%

113

114

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

Trial

Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies

Substance

Step-up therapy (n = 47): 2 × 500 mg sulfasalazine/day monotherapy (increased to 40 mg/kg/day) + 7.5 mg methotrexate/week after 3 months (increased by 2.5–5 mg every 4 weeks, max. 25 mg/week) + 200 mg hydroxychloroquine/day after 3 months (increase to 400 mg/d) Parallel triple therapy (n = 49, initiated at once): 2 × 500 mg sulfasalazine/day (increased to 40 mg/kg/day) + 7.5 mg methotrexate/week (increased by 2.5–5 mg every 4 weeks, max. 25 mg/week) + 200 mg hydroxychloroquine/day (increase to 400 mg/d) DAS28 ³ 3.2, the dosage of DMARDs was increased Concomitant medication: Swollen joints were injected with triamcinolone (max. 80 mg/ month) Prednisolone/day was permitted n = 1 (step-up), n = 2 (triple group) Previous medication: No DMARDs (other than HCQ)

Result

Highly effective control of disease activity was achieved using conventional DMARDs as part of an intensive disease management strategy. Within this setting, step-up therapy was at least as effective as parallel triple therapy

Patients

96 early RA patients Symptom duration of £ 5 years DAS 28 of > 5.1

Authors

Saunders SA, Capell HA, Stirling A, Vallance R, Kincaid W, McMahon AD, Porter DR

Publication

Arthritis Rheum. 2008 May;58(5):1310–1317

Follow up

12 months

ACR 20

77% (step-up), 76% (parallel triple therapy)

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

ACR 50

60% (step-up), 51% (parallel triple therapy)

ACR 70

30% (step-up), 20% (parallel triple therapy)

Note

EULAR remission 45% (step-up) 33% (triple therapy) EULAR good response 60% (step-up) 41% (triple therapy)

115

Change of: DAS28 score –4.0 (step–up), –3.3 (triple group) Swollen joint count (range 0–28) –12 (step–up), –11 (triple group) Tender joint count (range 0–28) –15 (step–up), –12 (triple group) Pain score (range 0–100-mm VAS) –42 (step–up), –43 (triple group) Patient’s global assessment (0–100-mm VAS) –51 (step–up), –52 (triple group) Physician’s global assessment (range 1–5) –1.7 (step–up), –1.4 (triple group) CRP (mg/l) –43 (step–up), –26 (triple group) ESR (mm/h) –27 (step–up), –17 (triple group) HAQ score (range 0–3) –0.9 (step–up), –0.8 (triple group) SF–12 health survey score +10 (step–up), +9 (triple group) Erosion score +1.1 (step–up), +1.7 (triple group) Joint space narrowing score +4.9 (step–up), +4.8 (triple group) Total Sharp score +6.0 (step-up), +6.6 (triple group) Adverse events

Gastrointestinal n = 48 (step-up), n = 52 (triple therapy) Abnormal liver function tests n = 6 (step-up), n = 5 (triple therapy) Infective n = 27 (step-up), n = 29 (triple therapy) Mucocutaneous n = 16 (step-up), n = 19 (triple therapy) Hematologic n = 8 (step-up), n = 8 (triple therapy) Neurologic n = 13 (step-up), n = 6 (triple therapy) Other n = 17 (step-up), n = 22 (triple therapy)

116

Rheumatoid Arthritis: Methotrexate + Hydroxychloroquine + Sulfasalazine

FinRACo Trial The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: The eleven-year results of the Finnish rheumatoid arthritis combination therapy trial. FIN-RACo trial group FIN-RACo: Finish RA Cohort Substance

Combination (n = 97): 2 × 500 mg SSZ/day (increased to 2 g/day if needed) + 7.5 mg MTX/week (increased to 15 mg/day if needed) + 300 mg HCQ/day + 5 mg prednisolone/day If one or several components had to be discontinued: SSZ or HCQ => auranofin (3–6 mg daily) Methotrexate => azathioprine (2 mg/kg daily) Other DMARDs could also be used as substitutes Single drug therapy (n = 51): Started with 2 g sulfasalazine/ (increased to 3 g/day if needed) Change to 7.5–15 mg methotrexate/d Change to other DMARDs Concomitant medication: Oral prednisolone 5 mg/day (increased to 7.5 mg/day if needed) Adequate contraception NSAIDs were permitted Intraarticular glucocorticoid injections were permitted Folic acid was permitted At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum four joints or 4 mL per visit) Previous medication: No DMARDs No oral glucocorticoids £ 2 weeks

Result

Initial therapy with a combination of DMARDs in early RA was superior to an initial single-DMARD therapy in the induction of remission

Patients

195 patients with early, clinically active RA Min. 3 swollen joints Min. 3 tender joints ESR > 28 mm CRP > 19 mg/l Morning stiffness > 29 min

Authors

Rantalaiho V, Korpela M, Hannonen P, Kautiainen H, Järvenpää S, Leirisalo-Repo M, Hakala M, Puolakka K, Julkunen H, Luosujärvi R, Möttönen T; FIN-RACo Trial Group

Publication

Arthritis Rheum. 2009 Apr 29;60(5):1222–1231

Follow up

11 years

Note

HAQ score = 0: 56% (combination), 43% (single-DMARD) Modified minimal disease activity 63% (combination), 43% (single DMARD) ACR remission 37% (combination), 19% (single DMARD)

Rheumatoid Arthritis: Methotrexate + Leflunomide

117

Trial

Concomitant Leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of Methotrexate. A randomized, double-blind, placebo-controlled trial

Substance

10–20 mg MTX/week + Placebo (n = 133) 10 mg leflunomide/day (after 3 × 100 mg loading dose, n = 130) Dose was increased to 20 mg/day leflunomide/day if needed Concomitant medication: 1 mg folate acid Previous medication: No DMARDs No prednisolone > 10 mg/day £ 30 days prior study entry

Result

Disease activity improved more if patients with active rheumatoid arthritis were treated with leflunomide and methotrexate than with methotrexate alone

Patients

263 RA patients with active disease Despite MTX (10–20 mg/week) > 9 tender joints > 6 swollen joints > 45 min morning stiffness ESR > 28 mm/h

Authors

Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM

Publication

Ann Intern Med. 2002 Nov 5;137(9):726–733

Follow up

24 weeks

ACR 20

19.5% (MTX), 46.2% (Lef + MTX)

ACR 50

6.0% (MTX), 26.2% (Lef + MTX)

ACR 70

2.3% (MTX), 10.0% (Lef + MTX)

Note

Discontinuation rates 23.1% (Lef + MTX), 24.8% (MTX) Change of: HAQ -0.42 (Lef + MTX), -0.09 (MTX) SF-36 physical component scores +6.8 (Lef + MTX), +0.3 (MTX) SF-36 mental component score +3.0 (Lef + MTX), +1.2 (MTX)

Adverse events

Diarrhoea 25.4% (LEF + MTX) 13.5% (MTX) Upper respiratory tract infection 22.3% (LEF + MTX), 24.1% (MTX) Nausea 16.2% (LEF + MTX), 11.3% (MTX) Headache 10.0% (LEF + MTX), 8.3% (MTX) Rash 7.7% (LEF + MTX), 8.3% (MTX) Dizziness 7.7% (LEF + MTX), 5.3% (MTX) Alopecia 6.2% (LEF + MTX), 3.8% (MTX)

118

Rheumatoid Arthritis: Methotrexate + Leflunomide

Trial

Combination Leflunomide and Methotrexate (MTX), therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial

Substance

10–20 mg MTX/week + Placebo (n = 133) MTX + 10 mg leflunomide/day (after 3 × 100 mg loading dose, n = 130) Dose was increased to 20 mg/day leflunomide/day if needed Placebo treated patients could be switched to leflunomide after 24 weeks Concomitant medication: 1 mg folate acid Previous medication: No DMARDs No prednisolone > 10 mg/day £ 30 days prior study entry

Result

The sustained effect of leflunomide and MTX was maintained at 48 weeks. Adverse events decreased in patients who switched to leflunomide without a loading dose

Patients

Patients on an active dose of MTX (10–20 mg/week) Active disease: ³ 9 tender joints ³ 6 swollen joints ³ 45 min morning stiffness ESR ³ 28 mm/h

Authors

Kremer J, Genovese M, Cannon GW, Caldwell J, Cush J, Furst DE, Luggen M, Keystone E, Bathon J, Kavanaugh A, Ruderman E, Coleman P, Curtis D, Kopp E, Kantor S, Weisman M, Waltuck J, Lindsley HB, Markenson J, Crawford B, Fernando I, Simpson K, Strand V

Publication

J Rheumatol. 2004 Aug;31(8):1521–1531

Follow up

24 weeks + 24 weeks open extension

ACR 20

57.3% (Placebo => LEF), 55.2% (Lef + MTX)

ACR 50

28.1% (Placebo => LEF), 35.4% (Lef + MTX)

ACR 70

11.5% (Placebo => LEF), 16.7% (Lef + MTX)

Rheumatoid Arthritis: Methotrexate + Leflunomide

Note

Change of: Tender joint count -14.1 (MTX, Placebo => Lef), -15.9 (Lef + MTX) Swollen joint count -9.7 (MTX, Placebo => Lef), -8.8 (Lef + MTX) Patient’s global assessment -20.9 (MTX, Placebo => Lef), -22 (Lef + MTX) Physician’s global assessment -29.3 (MTX, Placebo => Lef), -33.7 (Lef + MTX) Pain intensity (VAS), -26.9 (MTX, Placebo => Lef), -27.2 (Lef + MTX) HAQ -0.33 (MTX, Placebo => Lef), -0.54 (Lef + MTX) ESR -4.5 mm (MTX, Placebo => Lef), -2.1 mm (Lef + MTX) CRP -8.7 mg/l (MTX, Placebo => Lef), -13.7 mg/l (Lef + MTX) Rheumatoid factor -82.6 mU/l (MTX, Placebo => Lef), -47.4 mU/l (Lef + MTX) SF-36 physical component scores +6.6 (MTX, Placebo => Lef), +8.5 (Lef + MTX) SF-36 mental component score +1.5 (MTX, Placebo => Lef), +4.2 (Lef + MTX)

Adverse events

Diarrhoea 16.7% (Lef after placebo), 3.1% (MTX + Lef) Nausea 4.2% (Lef after placebo), 3.1% (MTX + Lef) Gastroenteritis 2.1% (Lef after placebo), 2.1% (MTX + Lef) Dyspepsia 4.2% (Lef after placebo), 2.1% (MTX + Lef) Gastrointestinal disorder 1% (Lef after placebo), 0% (MTX + Lef) Liver function test abnormal 1% (Lef after placebo), 2.1% (MTX + Lef) Vomiting 1% (Lef after placebo), 0% (MTX + Lef) Infections 10.4% (Lef after placebo), 4.2% (MTX + Lef) Accidental injury 3.1% (Lef after placebo), 3.1% (MTX + Lef) Abdominal pain 5.2% (Lef after placebo), 0% (MTX + Lef) Upper respiratory infection 11.5% (Lef after placebo), 14.6% (MTX + Lef), Sinusitis 5.2% (Lef after placebo), 6.3% (MTX + Lef) Bronchitis 5.2% (Lef after placebo), 3.1% (MTX + Lef) Pneumonia 3.1% (Lef after placebo), 5.2% (MTX + Lef) Urinary tract infection 6.3% (Lef after placebo), 2.1% (MTX + Lef) Headache 1.0% (Lef after placebo), 3.1% (MTX + Lef) Rash 6.3% (Lef after placebo), 7.3% (MTX + Lef) Alopecia 8.3% (Lef after placebo), 1% (MTX + Lef) Hypertension 3.1% (Lef after placebo), 2.1% (MTX + Lef)

119

120

Rheumatoid Arthritis: Methotrexate + Azathioprine

Trial

Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial

Substance

5 mg MTX/week (after 8 weeks 15 mg/week, n = 67) 50 mg azathioprine/day (after 8 weeks 150 mg/week, n = 73) Combination MTX + azathioprine (n = 69) Concomitant medication: No information was provided Previous medication: Inadequate response to 750 mg injectable gold or Inadequate response 6 mg auranofin or Inadequate response 500 mg D-penicillamine NSAIDs discontinued ³ 1 month

Result

Both combination therapy and methotrexate monotherapy were superior to therapy with azathioprine in active RA

Patients

212 RA patients Disease duration > 6 months ³ 9 swollen joints ESR ³ 28 mm/h Morning stiffness ³ 45 min

Authors

Willkens RF, Urowitz MB, Stablein DM, McKendry RJ Jr, Berger RG, Box JH, Fiechtner JJ, Fudman EJ, Hudson NP, Marks CR, et al

Publication

Arthritis Rheum. 1992 Aug;35(8):849–856

Follow up

24 weeks

Note

Response rate: Painful/tender joint count 61% (MTX + Aza), 44% (Aza), 55% (MTX) Swollen joint count 58% (MTX + Aza), 44% (Aza), 66% (MTX) Change of (all patients, median): Morning stiffness (min) -13 (MTX + Aza), 0 (Aza), -30 (MTX) Onset of fatigue (h) 0 (MTX + Aza), -1 (Aza), 0 (MTX) 50 m walking time (sec) 0 (MTX + Aza), 0 (Aza), -1 (MTX) Mean grip strength (mmHg) +5 (MTX + Aza), +3 (Aza), +5 (MTX) Number of subcutaneous nodules 0 (MTX + Aza), 0 (Aza), 0 (MTX) Patient’s global assessment -17 (MTX + Aza), 0 (Aza), -17 (MTX) Physician’s global assessment -21 (MTX + Aza), -6 (Aza), -20 (MTX) Tender joint count -8 (MTX + Aza), -1 (Aza), -7 (MTX) Swollen joint count -6 (MTX + Aza), -2 (Aza), -6 (MTX)

Adverse events

Leading to discontinuation n = 16 (MTX + Aza), n = 22 (Aza), n = 3 (MTX)

Rheumatoid Arthritis: Methotrexate + Azathioprine

Trial

Radiological and clinical results of long-term treatment of rheumatoid arthritis with Methotrexate and Azathioprine

Substance

7.5 mg MTX/week (after 8 weeks 15 mg/week, n = 33) 100 mg azathioprine/day (after 8 weeks 150 mg/week, n = 31) Concomitant medication: Prednisone £ 10 mg/day was permitted Previous medication: DMARDs were permitted

Result

Drug continuation after 4 years of follow-up was better for methotrexate than for azathioprine. In an intention-to-treat analysis the beneficial effect of methotrexate on radiologic progression compared with azathioprine was sustained after 2 years of follow-up

Patients

64 RA patients

Authors

Kerstens PJ, Boerbooms AM, Jeurissen ME, de Graaf R, Mulder J, van de Putte LB

Publication

J Rheumatol. 2000 May;27(5):1148–1155

Follow up

4 years

Note

Change of: Ritchie articular index –10.7 (Aza) –13.6 (MTX) Tender joint count –9.7 (Aza) –17.0 (MTX) Swollen joint count –6.7 (Aza) –10.3 (MTX) Pain (VAS 0–100) –15.2 (Aza) –20.7 (MTX) General health (VAS) –1.0 (Aza) –12.1 (MTX) Morning stiffness (min) –44 (Aza) –38 (MTX) Grip strength right (mmHg) +2 (Aza) +31 (MTX) Grip strength left (mmHg) +11 (Aza) +41 (MTX) ESR (mm/h) –19.1 (Aza) –26.6 (MTX) CRP (mg/l) –15.7 (Aza) –16.8 (MTX) DAS –1.52 (Aza) –2.14 (MTX) Radiological erosion score +5.0 (Aza) +5.9 (MTX) Total radiological score +12.6 (Aza) +12.2 (MTX)

Adverse events

Mouth ulcers n = 3 (Aza), n = 12 (MTX) Nausea, vomiting, pain n = 19 (Aza), n = 13 (MTX) Peptic ulcers n = 3 (Aza), n = 0 (MTX) Diarrhoea n = 1 (Aza), n = 0 (MTX) Elevated liver enzymes n = 7 (Aza), n = 21 (MTX) Leucopoenia n = 4 (Aza), n = 1 (MTX) Thrombopenia n = 3 (Aza), n = 4 (MTX) Pancytopenia n = 1 (Aza), n = 0 (MTX) Dermatitis n = 3 (Aza), n = 2 (MTX) Fever n = 3 (Aza), n = 2 (MTX) Central nervous system disorders n = 3 (Aza), n = 3 (MTX) Nodulitis/Vasculitis n = 0 (Aza), n = 5 (MTX) Infections n = 3 (Aza), n = 7 (MTX)

121

122

Rheumatoid Arthritis: Methotrexate + Azathioprine

Trial

Comparison of Azathioprine, Methotrexate, and the combination of the two in the treatment of rheumatoid arthritis. A forty-eight-week controlled clinical trial with radiologic outcome assessment

Substance

5–15 mg methotrexate/week (n = 67) 50–150 mg azathioprine/day (n = 73) 5 mg MTX/week + 50 mg AZA/day (n = 69) Concomitant medication: No information provided Previous medication: DMARDs discontinued ³ 1 month Corticosteroids discontinued ³ 1 month

Result

combination therapy of azathioprine and methotrexate was not more effective than the single substances. It was not associated with more toxicity than treatment with single agents. There was a trend toward decreased radiologic progression in patients treated with methotrexate

Patients

209 patients with active RA ³ 6 swollen joints ³ 6 tender joints + ³ 2 out of: ESR > 27 mm/h Morning stiffness > 45 min. ³ 9 tender and swollen joints

Authors

Willkens RF, Sharp JT, Stablein D, Marks C, Wortmann R

Publication

Arthritis Rheum. 1995 Dec;38(12):1799–1806

Follow up

48 weeks

Note

³ 30% Response in: Tender joint count 42% (MTX + AZA), 33% (AZA), 43% (MTX) Swollen joint count 43% (MTX + AZA), 27% (AZA), 51% (MTX) Patient global assessment 38% (MTX + AZA), 30% (AZA), 48% (MTX) Physician’s global assessment 43% (MTX + AZA), 30% (AZA), 49% (MTX)

Adverse events

Total n = 83 (Aza + MTX), n = 37 (Aza), n = 40 (MTX) Serious adverse events n = 11 (Aza + MTX), n = 4 (Aza), n = 3 (MTX) Abdominal pain n = 17 Abnormal liver function tests n = 13 Mouth ulcers n = 10 Rash n = 9 Leucopenia n = 6 Dizziness n = 5 Occurrence was not differentiated by the groups analyzed

Rheumatoid Arthritis: Gold + Methotrexate

METGO-Trial

A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination Methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study METGO: Methotrexate and intramuscular gold

Substance

10 mg i.m. aurothioglucose/week (increased to 50 mg/week, n = 27) Placebo (n = 38)

123

Concomitant medication: Background MTX ³ 15 mg/week Prednisone £ 10 mg/d Folic acid was permitted NSAIDs at stable doses were permitted 6 injections (max. 40 mg/injection of methylprednisolone, or the equivalent) Previous medication: MTX at stable dose ³ 4 weeks HCQ was permitted if stable ³ 3 months No other DMARDs Result

Addition of i.m. gold in RA patients with a suboptimal response to methotrexate lead to a significant clinical improvement. Adverse events were minor, and i.m. gold-related adverse events led to discontinuation in only 11%

Patients

RA patients with a suboptimal response to MTX ³ 5 tender joints ³ 4 swollen joints ESR ³ 25 mm/h Morning stiffness ³ 45 min

Authors

Lehman AJ, Esdaile JM, Klinkhoff AV, Grant E, Fitzgerald A, Canvin J; METGO Study Group

Publication

Arthritis Rheum. 2005 May;52(5):1360–1370

Follow up

48 weeks

ACR 20

61% (gold), 30% (placebo)

ACR 50

26% (gold), 4% (placebo)

ACR 70

21% (gold), 0% (placebo)

Note

Change of: No. of tender joints –47 (gold + MTX), –14 (MTX) No. of swollen joints, –43 (gold + MTX), –22 (MTX) ESR –31 mm/h (gold + MTX), +8 mm/h (MTX) HAQ physical function score –39 (gold + MTX), –25 (MTX) Pain severity (0–100) –11 (gold + MTX), +4 (MTX) Patient’s assessment of disease severity –21 (gold + MTX), –11 (MTX) Physician’s assessment of dis. severity –49 (gold + MTX), –16 (MTX)

Adverse events

Mucocutaneous 45% (gold + MTX), 7% (MTX) Rash 24% (gold + MTX), 7% (MTX) Pruritus 26% (gold + MTX), 7% (MTX) Mouth ulcers 16% (gold + MTX), 0% (MTX) Proteinuria 11% (gold + MTX), 4% (MTX) Leucopoenia 5% (gold + MTX), 4% (MTX) Metallic taste 3% (gold + MTX ld), 0% (MTX) Tea coloured urine 3% (gold + MTX), 4% (MTX) Lump on buttocks 0% (gold + MTX), 4% (MTX) Abdominal pain 0% (gold + MTX), 4% (MTX) Dysgeusia 3% (gold + MTX), 0% (MTX)

124

Rheumatoid Arthritis: Gold + Hydroxychloroquine

Trial

Combination therapy with gold and Hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo controlled study

Substance

10 mg sodium aurothiomalate test injection Followed by 50 mg injections/week + 200 mg hydroxychloroquine (n = 52) Placebo (n = 49) Concomitant medication: No corticosteroids NSAIDs at stable doses were permitted Previous medication: No DMARDs £ 3 months

Result

Combination therapy with gold and hydroxychloroquine was superior to a single substance therapy

Patients

101 consecutive RA patients Disease duration < 5 a Morning stiffness > 30 min

Authors

Scott DL, Dawes PT, Tunn PD, Fowler PD, Shafforth MF, Fisher J, Clarke S, Collins M, Jones P, Popert AJ, Bacon PA

Publication

Br J Rheumatol. 1989;28:128–133

Follow up

12 months

Note

Change of: Larsen Score 31.2 => 47.2 (gold + HCQ), 30.5 => 50.8 (gold) Pain 42.8 => 19.7 (gold + HCQ), 39.1 => 21.9 (gold) ESR 51.7 => 19.3 (gold + HCQ), 54.8 => 27.8 (gold) CRP 39.9 => 9.4 (gold + HCQ), 46.6 => 20.5 (gold) Ritchie articular index 15.9 => 4.8 (gold + HCQ), 15.2 => 6.7 (gold)

Adverse events

Skin n = 10 (gold + HCQ), n = 4 (gold) Mouth ulcers n = 1 (gold + HCQ), n = 1 (gold) Renal n = 4 (gold + HCQ), n = 2 (gold) Thrombopenia n = 1 (gold + HCQ), n = 2 (gold) Ophthalmic n = 1 (gold + HCQ), n = 1 (gold) Hepatitis n = 1 (gold + HCQ), n = 0 (gold)

Rheumatoid Arthritis: Gold + Hydroxychloroquine

125

Trial

Combination therapy in rheumatoid arthritis-no benefit of addition of Hydroxychloroquine to patients with a suboptimal response to intramuscular gold therapy

Substance

400 mg hydroxychloroquine (n = 72) Placebo (n = 70) Added to i.m. gold therapy Concomitant medication: No corticosteroids No other DMARDs NSAIDs at stable doses were permitted Previous medication: No DMARDs £ 3 months

Result

Combination of gold and hydroxychloroquine did not differ from gold monotherapy

Patients

190 RA patients with suboptimal response to i.m. Gold

Authors

Porter DR, Capell HA, Hunter J

Publication

J Rheumatol. 1993 Apr;20(4):645–649

Follow up

6 months

Note

Change of: ESR (mm/h) –37 (gold + HCQ), –21 (gold) CRP (mg/l) –16 (gold + HCQ), –27 (gold) Grip strength left (mmHg) +26 (gold + HCQ), +6 (gold) Grip strength right (mmHg) +24 (gold + HCQ), +6 (gold) HAQ 0 (gold + HCQ), –0.12 (gold) Pain (VAS) –9 (gold + HCQ), –3 (gold)

Adverse events

Loss of effect 1.3% (gold + HCQ), 5.7% (gold) Rash 4.1% (gold + HCQ), 5.7% (gold) Mouth ulcers 1.3% (gold + HCQ), 1.4% (gold) Thrombocytopenia 2.6% (gold + HCQ), 0% (gold) Proteinuria 5.4% (gold + HCQ), 7.1% (gold) Diarrhoea 1.3% (gold + HCQ), 0% (gold) Ophthalmological 8.2% (gold + HCQ), 1.4% (gold) Headache 0% (gold + HCQ), 4.2% (gold) Nausea 1.3% (gold + HCQ), 8.5% (gold)

126

Rheumatoid Arthritis: Abatacept

Trial

Co-stimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y 85 days after the first infusion

Substance

0.5 mg CTLA-4Ig/kg (n = 26) 2 mg CTLA-4Ig/kg (n = 32) 10 mg CTLA-4Ig/kg (n = 32) 0.5 mg LEA29Y/kg (n = 32) 2 mg LEA29Y/kg (n = 29) 10 mg LEA29Y/kg (n = 31) Placebo (n = 32) Concomitant medication: Low-dose corticosteroids (£ 10 mg/day) NSAIDs were continued DMARDs were discontinued Previous medication: Discontinue any DMARD or etanercept treatment from 28 days ³ 1 DMARD treatment without success

Result

Both co-stimulatory blocking molecules CTLA-4Ig and LEA29Y demonstrated efficacy in the treatment of RA as compared with placebo

Patients

214 patients with RA ³ 10 swollen joints ³ 12 tender joints ESR ³ 28 mm/h Morning stiffness of ³ 45 min

Authors

Moreland LW, Alten R, Van den Bosch F, Appelboom T, Leon M, Emery P, Cohen S, Luggen M, Shergy W, Nuamah I, Becker JC

Publication

Arthritis Rheum. 2002 Jun;46(6):1470–1479

Follow up

169 days

Rheumatoid Arthritis: Abatacept

127

Note

Tender joint count –29.3% (placebo), –26.1% (CTLA-4Ig, 0.5 mg/kg), –49.0% (CTLA-4Ig, 2 mg/kg), –54.6% (CTLA-4Ig, 10 mg/kg), –40.8% (LEA29Y, 0.5 mg/kg), –43.5% (LEA29Y, 2 mg/kg), –47.8% (LEA29Y, 10 mg/kg) Swollen joint count –32.1% (placebo), –15.4% (CTLA-4Ig, 0.5 mg/kg), –41.6% (CTLA-4Ig, 2 mg/kg), –40.7% (CTLA-4Ig, 10 mg/kg), –32.6% (LEA29Y, 0.5 mg/kg), –40.7% (LEA29Y, 2 mg/kg), –61.3% (LEA29Y, 10 mg/kg) Pain score (1–5) –4.6% (placebo), –5.1% (CTLA-4Ig, 0.5 mg/kg), –25.6% (CTLA-4Ig, 2 mg/kg), –28.1% (CTLA-4Ig, 10 mg/kg), –15.0% (LEA29Y, 0.5 mg/kg), –15.2% (LEA29Y, 2 mg/kg), –23.7% (LEA29Y, 10 mg/kg) Patient global assessment (1–5) –3.3% (placebo), –8.0% (CTLA-4Ig, 0.5 mg/kg), –24.3% (CTLA-4Ig, 2 mg/kg), –30.9% (CTLA-4Ig, 10 mg/kg), –10.8% (LEA29Y, 0.5 mg/kg), –20.6% (LEA29Y, 2 mg/kg), –30.6% (LEA29Y, 10 mg/kg) Physician global assessment (1–5) –14.4% (placebo), –10.5% (CTLA-4Ig, 0.5 mg/kg), –25.7% (CTLA-4Ig, 2 mg/kg), 28.2% (CTLA-4Ig, 10 mg/kg), –20.3% (LEA29Y, 0.5 mg/kg), –22.3% (LEA29Y, 2 mg/kg), 31.8% (LEA29Y, 10 mg/kg) Function score (1–4) –5.1% (placebo), –0.7% (CTLA-4Ig, 0.5 mg/kg), –11.8% (CTLA-4Ig, 2 mg/kg), –20.3% (CTLA-4Ig, 10 mg/kg), –8.8% (LEA29Y, 0.5 mg/kg), –18.3% (LEA29Y, 2 mg/kg), –24.5% (LEA29Y, 10 mg/kg) CRP (mg/dL) –0.7% (placebo), 0.0% (CTLA-4Ig, 0.5 mg/kg), –13.7% (CTLA-4Ig, 2 mg/kg), –54.6% (CTLA-4Ig, 10 mg/kg), +10.0% (LEA29Y, 0.5 mg/kg), –46.6% (LEA29Y, 2 mg/kg), –71.4% (LEA29Y, 10 mg/kg) ESR (mm/h) +8.3% (placebo), –11.1% (CTLA-4Ig, 0.5 mg/kg), –25.0% (CTLA-4Ig, 2 mg/kg), –18.3% (CTLA-4Ig, 10 mg/kg), –13.0% (LEA29Y, 0.5 mg/kg), –23.5% (LEA29Y, 2 mg/kg), –41.7% (LEA29Y, 10 mg/kg) Morning stiffness (minutes) +3.0% (placebo), –13.0% (CTLA-4Ig, 0.5 mg/kg), 40.5% (CTLA-4Ig, 2 mg/kg), –42.9% (CTLA-4Ig, 10 mg/kg), –29.2% (LEA29Y, 0.5 mg/kg), –63.3% (LEA29Y, 0.5 mg/kg), –51.4% (LEA29Y, 10 mg/kg)

Adverse events

Total with adverse events 75.0% (placebo), 81.1% (CTLA-4Ig), 82.6% (LEA29Y) Discontinuation due to adverse events 0% (placebo), 4.4% (CTLA-4Ig), 1.1% (LEA29Y) Most frequent adverse events Headache 3.1% (placebo), 8.9% (CTLA-4Ig), 5.4% (LEA29Y) Nausea/vomiting 6.3% (placebo), 5.6% (CTLA-4Ig), 5.4% (LEA29Y) Fatigue 3.1% (placebo), 4.4% (CTLA-4Ig), 7.6% (LEA29Y) Arthritis 9.4% (placebo), 4.4% (CTLA-4Ig), 4.3% (LEA29Y) Hypotension 6.3% (placebo), 3.3% (CTLA-4Ig), 1.1% (LEA29Y) Serious adverse events 12.5% (placebo), 4.4% (CTLA-4Ig), 4.3% (LEA29Y) Serious adverse events related to study drug 0% (placebo), 0% (CTLA-4Ig), 0.0% (LEA29Y)

128

Rheumatoid Arthritis: Abatacept

Trial

Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig

Substance

2 mg/kg of CTLA4Ig (n = 105) 10 mg/kg of CTLA4Ig (n = 115 patients) Placebo (n = 119 patients) Concomitant medication: 10–30 mg methotrexate/day background therapy ³ 6 months Low-dose corticosteroids £ 10 mg/day were permitted NSAIDs were continued Previous medication: Discontinue IFX or Lef were discontinued ³ 60 days other DMARD were discontinued ³ 28 days

Result

Combination treatment of RA patients with methotrexate and CTLA4Ig significantly improved the signs and symptoms of RA and the health-related quality of life

Patients

³ 10 swollen joints ³ 12 tender joints C-reactive protein ³1 mg/dL Pre-treated with methotrexate (10 to 30 mg weekly) ³ 6 months Stable low-dose corticosteroids (£10 mg per day), and NSAIDs

Authors

Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Nuamah IF, Williams GR, Becker JC, Hagerty DT, Moreland LW

Publication

N Engl J Med. 2003 Nov 13;349(20):1907–1915

Follow up

6 months

ACR 20

35.3% (placebo), 41.9% (Aba 2 mg/kg), 60% (Aba 10 mg/kg)

ACR 50

11.8% (placebo), 22.9% (Aba 2 mg/kg), 36.5% (Aba 10 mg/kg)

ACR 70

1.7% (placebo), 10.5% (Aba 2 mg/kg), 16.5% (Aba 10 mg/kg)

Rheumatoid Arthritis: Abatacept

Note

Change of: Tender joints -32.1% (placebo), -43.3% (Aba 2 mg/kg), –59.9% (Aba 10 mg/kg) Swollen joints –33.4% (placebo), –45.1% (Aba 2 mg/kg), –54.9% (Aba 10 mg/kg) Pain 8.4% (placebo), –22.7% (Aba 2 mg/kg), –46.4% (Aba 10 mg/kg) Physical function –14.1% (placebo), –17.3% (Aba 2 mg/kg), 41.5% (Aba 10 mg/kg) Patient’s global assessment –17.6% (placebo), –9.6% (Aba 2 mg/kg), –40.8% (Aba 10 mg/kg) Physician’s global assessment –25.6% (placebo), –38.6% (Aba 2 mg/kg), –52.0% (Aba 10 mg/kg) C-reactive protein level 23.6% (placebo), –16.2% (Aba 2 mg/kg), –31.5% (Aba 10 mg/kg)

Adverse events

Death 0% (placebo), 0% (Aba 2 mg/kg), 0% (Aba 10 mg/kg) Total 10.1% (placebo), 11.4% (Aba 10 mg/kg), 2.6% (Aba 10 mg/kg) Related to study drug 0.8% (placebo), 3.8% (Aba 10 mg/kg), 0% (Aba 10 mg/kg) Headache 12.6% (placebo), 14.3% (Aba 2 mg/kg), 10.4% (Aba 10 mg/kg) Upper respiratory tract infection 10.1% (placebo), 12.4% (Aba 2 mg/kg), 13.0% (Aba 10 mg/kg) Musculoskeletal pain 12.6% (placebo), 14.3% (Aba 2 mg/kg), 7.0% (Aba 10 mg/kg) Nausea and vomiting 11.8% (placebo), 6.7% (Aba 2 mg/kg), 13.9% (Aba 10 mg/kg) Fatigue 10.9% (placebo), 9.5% (Aba 2 mg/kg), 5.2% (Aba 10 mg/kg) Cough 8.4% (placebo), 5.7% (Aba 2 mg/kg), 10.4% (Aba 10 mg/kg) Diarrhoea 5.9% (placebo), 6.7% (Aba 2 mg/kg), 9.6% (Aba 10 mg/kg) Pharyngitis 5.9% (placebo), 4.8% (Aba 2 mg/kg), 10.4% (Aba 10 mg/kg)

129

130

Rheumatoid Arthritis: Abatacept

ATTAIN-Trial

Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition ATTAIN: Abatacept Trial in Treatment of Anti-TNF INadequate

Substance

Abatacept (60 kg => 500 mg, 60–100 kg => 750 mg, > 100 kg => 1000 mg days 0 – 15 – 29, every 4 weeks thereafter, n = 258) Placebo (n = 133) Patients discontinued anti-TNF-alpha therapy before randomization Concomitant medication: Oral corticosteroids £ 10 mg/d DMARDs were continued Previous medication: Patients with stable DMARD or anakinra ³ 3 months

Result

Abatacept had significant clinical and functional benefits in patients with an inadequate response to anti-TNF-alpha therapy

Patients

393 Patients with active rheumatoid arthritis Inadequate response to anti-TNF-alpha therapy ³ 10 swollen joints ³ 12 tender joints CRP ³ 1 mg/dL

Authors

Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M

Publication

N Engl J Med. 2005 Sep 15;353(11):1114–1123

ACR 20

50.4% (abatacept), 19.5% (placebo)

ACR 50

20.3% (abatacept), 3.8% (placebo)

ACR 70

10.2% (abatacept), 1.5% (placebo)

Note

DAS < 3.2 17.1% (abatacept), 3.1% (placebo) DAS < 2.6 10.0% (abatacept), 0.8% (placebo) ³ 0.3 Decrease in HAQ 47.3% (abatacept), 23.3% (placebo)

Adverse events

Death 0.4% (abatacept), 0% (placebo) Serious infections 2.3% (abatacept), 2.3% (placebo) Headache 12.4% (abatacept), 5.3% (placebo) Nasopharyngitis 7.8% (abatacept), 6.0% (placebo) Nausea 6.6% (abatacept), 6.8% (placebo) Sinusitis 6.2% (abatacept), 3.8% (placebo) Upper respiratory infections 5.8% (abatacept), 7.5% (placebo) Diarrhoea 5.8% (abatacept), 5.3% (placebo) Bronchitis 5.8% (abatacept), 4.5% (placebo) Back pain 5.0% (abatacept), 5.3% (placebo)

Rheumatoid Arthritis: Abatacept

Trial

Treatment of rheumatoid arthritis with the selective co-stimulation modulator Abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial

Substance

10 mg/kg abatacept (n = 115, days 1–15–30, every 30 days thereafter) 2 mg/kg abatacept (n = 105) Placebo (n = 119)

131

Concomitant medication: 10–30 mg MTX/week stable ³ 6 months Corticosteroids £10 mg/day Addition of another DMARD (hydroxychloroquine, sulfasalazine, gold, or azathioprine) was permitted Previous medication: MTX ³ 6 months Other DMARDs were permitted Result

Abatacept treatment in patients with RA active despite MTX treatment was associated with significant reductions in disease activity and improvements in physical function. These effects were maintained over the course of 12 months. Abatacept was also well tolerated and safe

Patients

339 RA patients Functional classes I, II, or III ³ 10 swollen joints ³ 12 tender joints CRP ³ 1 mg/dL

Authors

Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W, Steinfeld S, Tindall E, Becker JC, Li T, Nuamah IF, Aranda R, Moreland LW

Publication

Arthritis Rheum. 2005 Aug;52(8):2263–2271

Follow up

12 months

ACR 20

62.6% (Aba), 36.1% (placebo)

ACR 50

41.7% (Aba), 20.2% (placebo)

ACR 70

20.9% (Aba), 7.6% (placebo)

132

Note

Rheumatoid Arthritis: Abatacept

Modified Health Assessment Questionnaire 49.6% (Aba), 27.7% (placebo) DAS 28 <2.6 34.8% (Aba), 10.1% (placebo) Change of: Tender joint count -30.0% (placebo), -43.6% (2 mg/kg/Aba), –66.4% (10 mg/kg/Aba) Swollen joint count -36.2% (placebo), -46.4% (2 mg/kg/Aba), 59.7% (10 mg/kg/Aba) Pain -12.6% (placebo), -26.2% (2 mg/kg/Aba), -44.9% (10 mg/kg/Aba) Patient’s global assessment (0–100-mm VAS) -2.0% (placebo), -16.0% (2 mg/kg/Aba), -41.0% (10 mg/kg/Aba) Physician’s global assessment (VAS 0–100-mm) -24.1% (placebo), -37.9% (2 mg/kg/Aba), -53.5% (10 mg/kg/Aba) M-HAQ -10.3% (placebo), -22.9% (2 mg/kg/Aba), -42.3% (10 mg/kg/Aba) CRP +31.3% (placebo), -11.0% (2 mg/kg/Aba), -27.6% (10 mg/kg/Aba)

Adverse events

Death n = 0 (placebo), n = 1 (2 mg/kg/Aba), n = 0 (10 mg/kg/Aba) Nasopharyngitis 9.2% (placebo), 18.1% (2 mg/kg/Aba), 14.8% (10 mg/kg/Aba) Headache 15.1% (placebo), 16.2% (2 mg/kg/Aba), 14.8% (10 mg/kg/Aba) Nausea 14.3% (placebo), 11.4% (2 mg/kg/Aba), 13.9% (10 mg/kg/Aba) Cough 12.6% (placebo), 9.5% (2 mg/kg/Aba), 13.0% (10 mg/kg/Aba) Diarrhoea 7.6% (placebo), 9.5% (2 mg/kg/Aba), 11.3% (10 mg/kg/Aba) Upper respiratory tract infection 7.6% (placebo), 9.5% (2 mg/kg/Aba), 11.3% (10 mg/kg/Aba) Dyspepsia 5.9% (placebo), 11.4% (2 mg/kg/Aba), 8.7% (10 mg /kg/Aba) Malignancies n = 3 (placebo), n = 0 (2 mg/kg/Aba), n = 4 (10 mg/kg/Aba)

Rheumatoid Arthritis: Abatacept

AIM-Trial

Effects of Abatacept in patients with resistant-resistant active rheumatoid arthritis: a randomized trial AIM: Abatacept in inadequate responders to MTX

Substance

Abatacept, approximately 10 mg/kg/month (n = 433) < 60 kg => 500 mg abatacept 60 to 100 kg => 750 mg abatacept > 100 kg => 1000 mg abatacept days 1, 15, and 29 and then every 28 days Placebo (n = 218) Concomitant medication: 15 mg MTX/week stable ³ 3 months prior randomization No other DMARDs £ 28 days Prednisone £ 10 mg/day £ 25 days prior randomization NSAIDs were permitted Between 6 and 12 months: Adjustment in methotrexate dose Addition of 1 other DMARD Adjustment in corticosteroid dose equal to 10 mg of prednisone or less Previous medication: MTX ³ 6 months Other DMARDs were permitted

Result

Treatment with abatacept of RA patients with an inadequate response to methotrexate reduced disease activity

Patients

652 patients with active rheumatoid arthritis Despite methotrexate treatment Disease duration ³ 1 year Min. 10 swollen joints Min. 12 tender joints CRP min 10 mg/l

Authors

Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Li T, Ge Z, Becker JC, Westhovens R

Publication

Ann Intern Med. 2006 Jun 20;144(12):865–876

Follow up

1 year

ACR 20

6-months: 67.9% (abatacept + MTX), 39.7% (MTX) 1 year: 73.1% (abatacept + MTX), 39.7% (MTX)

ACR 50

6-months: 39.9% (abatacept + MTX), 16.8% (MTX) 1 year: 48.3% (abatacept + MTX), 18.2% (MTX)

ACR 70

6-months: 19.8% (abatacept + MTX), 6.5% (MTX) 1 year: 28.8% (abatacept + MTX), 6.1% (MTX)

Note

6 months DAS28 £ 3.2 30.1% (abatacept + MTX), 10.0% (MTX) 1 year DAS28 £ 3.2 42.5% (abatacept + MTX), 9.9% (MTX) Change of: Physical function +63.7% (abatacept + MTX), +39.3% (MTX) Erosion score 0.0 (abatacept + MTX), +0.27 (MTX) joint-space narrowing 0.0 (abatacept + MTX), 0.0 (MTX)

133

134

Adverse event

Rheumatoid Arthritis: Abatacept

Death 0.2% (abatacept + MTX), 0.5% (MTX) Headache 17.6% (abatacept + MTX), 11.9% (MTX) Nasopharyngitis 15.2% (abatacept + MTX), 11.4% (MTX) Nausea 12.0% (abatacept + MTX), 11.0% (MTX) Diarrhoea 10.9% (abatacept + MTX), 9.6% (MTX) Upper respiratory infections 10.9% (abatacept + MTX), 9.6% (MTX) Dizziness 9.2% (abatacept + MTX), 7.3% (MTX) Back pain 9.2% (abatacept + MTX), 5.5% (MTX) Influenza 7.2% (abatacept + MTX), 5.5% (MTX) Cough 6.7% (abatacept + MTX), 5.9% (MTX) Dyspepsia 6.2% (abatacept + MTX), 4.6% (MTX) Pharyngitis 6.0% (abatacept + MTX), 4.6% (MTX) Hypertension 5.5% (abatacept + MTX), 1.4% (MTX) Fatigue 5.3% (abatacept + MTX), 6.8% (MTX) Urinary tract infection 5.1% (abatacept + MTX), 5.0% (MTX) Upper abdominal pain 4.4% (abatacept + MTX), 5.9% (MTX) Sinusitis 4.2% (abatacept + MTX), 6.8% (MTX) Bronchitis 4.2% (abatacept + MTX), 5.5% (MTX) Mucosceletal disorders 4.6% (abatacept + MTX), 4.6% (MTX) Infections 3.9% (abatacept + MTX), 2.3% (MTX) Nervous system disorders 1.4% (abatacept + MTX), 1.8% (MTX) Cardiac disorders 0.9% (abatacept + MTX), 0.9% (MTX) Neoplasm 0.9% (abatacept + MTX), 0.9% (MTX) Serious infections 2.5% (abatacept + MTX), 0.9% (MTX)

Rheumatoid Arthritis: Abatacept

Trial

Safety of the selective co-stimulation modulator Abatacept in rheumatoid arthritis patients receiving background biologic and non-biologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study

Substance

Abatacept approximately 10 mg/kg (n = 959) < 60 kg => 500 mg abatacept 60 to 100 kg => 750 mg abatacept > 100 kg => 1000 mg abatacept Administered day 1 – 15 – 29, every 4 weeks thereafter Placebo (n = 482)

135

Concomitant medication: Background DMARDs £ 28 days Corticosteroids £ 10 mg/day £ 25 days prior randomization NSAIDs were permitted at stable dosage Between 6 and 12 months: Adjustment in methotrexate dose Addition of 1 other DMARD Adjustment in corticosteroid dose equal to 10 mg of prednisone or less Previous medication: Biologics DMARDs Result

Abatacept in combination with other DMARDs improved physical function and physician- and patient-reported disease outcomes and was well tolerated. Abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events

Patients

1441 Patients with active rheumatoid arthritis Despite receiving background DMARDs and/or biologic therapy ³ 1 DMARDs Assessment of disease activity (VAS 0–100 mm) ³ 20 mm RA functional class I – IV

Authors

Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E

Publication

Arthritis Rheum. 2006 Sep;54(9):2807–2816

Follow up Adverse events

1 year Death nonbiol. background therapy 0.6% (Aba), 1.0% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Total adverse events nonbiol. background therapy 89.7% (Aba), 86.1% (placebo), biol. background therapy 95.1% (Aba), 89.1% (placebo) Related adverse events nonbiol. background therapy 55.3% (Aba), 48.6% (placebo), biol. background therapy 59.2% (Aba), 56.3% (placebo) Discontinuations due to adverse events nonbiol. background therapy 5.0% (Aba), 4.3% (placebo), biol. background therapy 8.7% (Aba), 3.1% (placebo) Total serious adverse events nonbiol. background therapy 11.7% (Aba), 12.2% (placebo), biol. background therapy 22.3% (Aba), 12.5% (placebo) Related serious adverse events nonbiol. background therapy 2.1% (Aba), 2.4% (placebo), biol. background therapy 4.9% (Aba), 4.7% (placebo) Discontinuations due to serious adverse events nonbiol. background therapy 2.1% (Aba), 1.2% (placebo), biol. background therapy 4.9% (Aba), 3.1% (placebo)

136

Rheumatoid Arthritis: Abatacept Serious infections nonbiol. background therapy 2.6% (Aba), 1.7% (placebo), biol. background therapy 5.8% (Aba), 1.6% (placebo) Total neoplasms nonbiol. background therapy 3.2% (Aba), 3.8% (placebo), biol. background therapy 6.8% (Aba), 1.6% (placebo) Uterine leiomyoma nonbiol. background therapy 0.5% (Aba), 0.2% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Fibroadenoma of breast nonbiol. background therapy 0.5% (Aba), 0% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Basal cell carcinoma nonbiol. background therapy 0.4% (Aba), 0.7% (placebo), biol. background therapy 1.9% (Aba), 0% (placebo) Infections nonbiol. background therapy 54.9% (Aba), 53.6% (placebo), biol. background therapy 65.0% (Aba), 57.8% (placebo) Gastrointestinal disorders nonbiol. background therapy 40.9% (Aba), 35.4% (placebo), biol. background therapy 38.8% (Aba), 31.3% (placebo) Nervous system disorders nonbiol. background therapy 35.5% (Aba), 28.9% (placebo), biol. background therapy 27.2% (Aba), 31.3% (placebo) Musculoskeletal and connective tissue disorder nonbiol. background therapy 26.8% (Aba), 26.8% (placebo), biol. background therapy 27.2% (Aba), 21.3% (placebo) Serious infections nonbiol. background therapy 2.6% (Aba), 1.7% (placebo), biol. background therapy 5.8% (Aba), 1.6% (placebo) Respiratory nonbiol. background therapy 1.1% (Aba), 1.0% (placebo), biol. background therapy 2.9% (Aba), 1.6% (placebo) Dermatologic nonbiol. background therapy 0.6% (Aba), 0.2% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Urinary nonbiol. background therapy 0.5% (Aba), 0.2% (placebo), biol. background therapy 1.9% (Aba), 0% (placebo) Gastrointestinal nonbiol. background therapy 0.2% (Aba), 0.2% (placebo), biol. background therapy 1.0% (Aba), 0% (placebo) Gynaecologic nonbiol. background therapy 0% (Aba), 0.2% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Opportunistic nonbiol. background therapy 0% (Aba), 0.5% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Pneumocystis pneumoniae nonbiol. background therapy 0% (Aba), 0.2% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Candidiasis nonbiol. background therapy 0% (Aba), 0.2% (placebo), biol. background therapy 0% (Aba), 0% (placebo) Other nonbiol. background therapy 0.4% (Aba), 0% (placebo), biol. background therapy 1% (Aba), 0% (placebo)

Rheumatoid Arthritis: Abatacept

137

ATTAIN-Trial

Efficacy and safety of the selective co-stimulation modulator Abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy ATTAIN: Abatacept Trial in Treatment of Anti-TNF INadequate

Substance

Open label extension with Abatacept ~10 mg/kg after 6 months of: Abatacept (60 kg => 500 mg, 60–100 kg => 750 mg, > 100 kg => 1000 mg days 0 – 15 – 29, every 4 weeks thereafter, n = 258) Placebo (n = 133) Patients discontinued anti-TNF-alpha therapy before randomization Concomitant medication: Oral corticosteroids £ 10 mg/d DMARDs were continued Previous medication: Patients with stable DMARD or anakinra ³ 3 months

Result

Improvements in clinical symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the second year in this population with difficult-to-treat disease

Patients

317 Patients with active rheumatoid arthritis Inadequate response to anti-TNF-alpha therapy ³ 10 swollen joints ³ 12 tender joints CRP ³ 1 mg/dL

Authors

Genovese MC, Schiff M, Luggen M, Becker JC, Aranda R, Teng J, Li T, Schmidely N, Le Bars M, Dougados M

Publication

Ann Rheum Dis. 2008 Apr;67(4):547–554. Epub 2007 Oct 5

Follow up

24-month

ACR 20

56.2% (primary non responders to Aba), 51.5% (primary non responders to Placebo), 75.0% (primary responders to Aba)

ACR 50

33.2% (primary non responders to Aba), 32.3% (primary non responders to Placebo), 45.8% (primary responders to Aba)

ACR 70

16.1% (primary non responders to Aba), 13.1% (primary non responders to Placebo), 22.6% (primary responders to Aba)

Note

HAQ DI responders 65.6% DAS28 (CRP) -2.66 (all patients) Low disease activity score (£ 3.2) 32.0% (all patients) DAS28 (CRP) remission (< 2.6) 20.3% (all patients)

Adverse events

Patients with AEs 92.2% AEs 308.7/100 patient-years Discontinuations due to AEs 7.0% Patients with SAEs 28.9% SAEs 23.4/100 patient-years Discontinuations due to SAEs 5.0% Patients with infections 65.5% Infections 89.4/100 patient-years Patients with serious infections 7.0% Serious infections 5.0/100 patient-years Death 0.6%

138

Rheumatoid Arthritis: Abatacept

AIM-Trial

Results of a two-year follow-up study of patients with rheumatoid arthritis who received a combination of Abatacept and Methotrexate AIM: Abatacept in inadequate responders to MTX

Substance

10 mg/kg abatacept + MTX (n = 376) < 60 kg => 500 mg abatacept 60 to 100 kg => 750 mg abatacept > 100 kg => 1000 mg abatacept Administered day 1 – 15 – 29, every 4 weeks thereafter Placebo (n = 160) + MTX Concomitant medication: 15 mg MTX/week stable ³ 3 months prior randomization Adjustments to background DMARDs was permitted Prednisone £ 10 mg/day £ 25 days prior randomization NSAIDs were permitted Between 6 and 12 months: Adjustment in methotrexate dose Addition of 1 other DMARD Adjustment in corticosteroid dose equal to 10 mg of prednisone or less Previous medication: MTX ³ 6 months Other DMARDs were permitted

Result

The improvements in signs, symptoms, and physical function observed after 1 year of abatacept treatment were maintained through the second year of treatment. Radiographic progression was further inhibited in the second year compared with the first year. This suggests an increasing effect of abatacept on the inhibition of structural damage in year 2

Patients

536 RA patients with active disease Despite treatment with MTX ³ 10 swollen joints ³ 12 tender joints CRP > 1 mg/dL > 6 months

Authors

Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, Szechiński J, Li T, Teng J, Becker JC, Westhovens R

Publication

Arthritis Rheum. 2008 Apr;58(4):953–963

Rheumatoid Arthritis: Abatacept

Follow up

1 year double blind study + 1 year open label extension

ACR 20

80.3% (Aba =>Aba), 78.1% (Placebo => Aba)

ACR 50

55.6% (Aba =>Aba), 58.1% (Placebo => Aba)

ACR 70

34.3% (Aba =>Aba), 31.9% (Placebo => Aba)

Note

DAS28 < 2.6: 30.9% (Aba => Aba) DAS28-CRP < 2.6: 30.9% (Aba => Aba) HAQ DI –0.73 (both groups) SF-36 7.3 versus 7.2 Low disease activity 56.1% (Aba => Aba), 78.1% (Placebo => Aba) Total radiological score from baseline was +1.1 (1st year) 1.6 (2nd year)

Adverse events

No. of SAEs 16.3/100 patient-years Discontinuations due to SAEs 4.0% Patients with infections 67.3% No. of infections 77.6/100 patient-years Patients with serious infections 7.2% No. of serious infections/100 patient-years 4.3% Death 0.5% Malignancy n = 14 New developing autoimmune diseases: Psoriasis n = 7 Vasculitis n = 3 Keratoconjunctivitis n = 2 Sicca symptoms n = 2 Cutaneous vasculitis n = 1 Erythema nodosum n = 1 Sjögren’s syndrome n = 1 Systemic lupus erythematosus n = 1

139

140

Rheumatoid Arthritis: Abatacept

AIM-Trial

Abatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial AIM: Abatacept in inadequate responders to MTX

Substance

10 mg/kg BW abatacept + MTX (n = 376) < 60 kg => 500 mg abatacept 60 to 100 kg => 750 mg abatacept > 100 kg => 1000 mg abatacept Administered day 1 – 15 – 29, every 4 weeks thereafter Placebo (n = 160) + MTX Concomitant medication: 15 mg MTX/week stable ³ 3 months prior randomization Adjustments to background DMARDs was permitted Prednisone £ 10 mg/day £ 25 days prior randomization NSAIDs were permitted Between 6 and 12 months: Adjustment in methotrexate dose Addition of 1 other DMARD Adjustment in corticosteroid dose equal to 10 mg of prednisone or less Previous medication: MTX ³ 6 months Other DMARDs were permitted

Result

Progression of structural damage was inhibited by abatacept. The mean change in radiographic progression in patients treated with abatacept for 2 years was significantly lower in the second year versus the first year, suggesting that abatacept may have an increasing disease-modifying effect on structural damage over time

Patients

536 RA patients with active disease Despite treatment with MTX ³ 10 swollen joints ³ 12 tender joints CRP > 1 mg/dL Disease duration > 12 months

Authors

Genant HK, Peterfy CG, Westhovens R, Becker JC, Aranda R, Vratsanos G, Teng J, Kremer JM

Publication

Ann Rheum Dis. 2008 Aug;67(8):1084–1989. Epub 2007 Dec 17

Follow up

2 years

Rheumatoid Arthritis: Abatacept

Note

Genant-modified Sharp score 1.55 (abatacept), 3.17 (placebo) Erosion score 0.84 (abatacept), 1.69 (placebo) Joint space narrowing score 0.71 (abatacept), 1.48 (placebo)

Adverse events

Death 0.2% (Aba), 0.5% (placebo) Headache 17.6% (Aba), 11.9% (placebo) Nasopharyngitis 15.2% (Aba), 11.4% (placebo) Nausea 12% (Aba), 11% (placebo) Diarrhoea 10.9% (Aba), 9.6% (placebo) Upper respiratory tract infection 10.9% (Aba), 9.6% (placebo) Dizziness 9.2% (Aba), 7.3% (placebo) Back pain 9.2% (Aba), 5.5% (placebo) Influenza 7.2% (Aba), 5.5% (placebo) Cough 6.7% (Aba), 5.9% (placebo) Dyspepsia 6.2% (Aba), 4.6% (placebo) Pharyngitis 6.0% (Aba), 4.6% (placebo) Hypertension 5.5% (Aba), 1.4% (placebo) Fatigue 5.3% (Aba), 6.8% (placebo) Urinary tract infection 5.1% (Aba), 5.0% (placebo) Upper abdominal pain 4.4% (Aba), 5.9% (placebo) Sinusitis 4.2% (Aba), 6.8% (placebo) Bronchitis 4.2% (Aba), 5.5% (placebo)

141

142

Rheumatoid Arthritis: Abatacept

ATTEST-Trial

Efficacy and safety of Abatacept or Infliximab versus placebo in ATTEST: a phase III, multicenter, randomized, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to Methotrexate ATTEST: A Trial for Tolerability, Efficacy and Safety in Treating rheumatoid arthritis

Substance

Abatacept (~10 mg/kg every 4 weeks, n = 156) Infliximab (3 mg/kg every 8 weeks, n = 165) Placebo (every 4 weeks, n = 110) Concomitant medication: MTX > 15 mg/week for >3 months prior to randomisation No other DMARDs £ 28 days Prednisone £ 10 mg/day £ 25 days prior randomization NSAIDs were permitted Between days 198–365: Dose modification was permitted for MTX (£25 mg weekly) Oral corticosteroids (£10 mg prednisone or equivalent daily) Hydroxychloroquine, sulfasalazine, gold, or azathioprine were permitted Previous medication: MTX ³ 3 months No prior anti–TNF or abatacept application

Result

Abatacept and infliximab demonstrated similar efficacy. Infections were more frequent with infliximab

Patients

Patients with rheumatoid arthritis Inadequate response to methotrexate ³ 10 swollen joints ³ 12 tender joints CRP ³ 1 mg/dL

Authors

Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, Saldate C, Li T, Aranda R, Becker JC, Lin C, Cornet PL, Dougados M

Publication

Ann Rheum Dis. 2008 Aug;67(8):1096–1103. Epub 2007 Nov 29

Follow up

1 year

Rheumatoid Arthritis: Abatacept

ACR 20

72.4 (abatacept), 55.8% (infliximab)

ACR 50

45.5 (abatacept), 36.4% (infliximab)

ACR 70

26.3 (abatacept), 20.6% (infliximab)

DAS28/6Mo

–2.53 (abatacept), -1.48 (placebo), -2.25 (infliximab)

Note

DAS28 -2.88 (abatacept), -2.25 (infliximab) Good EULAR response 32% (abatacept), 18.5% (infliximab) Low disease activity 35.3% (abatacept), 22.4% (infliximab) Remission 18.7% (abatacept), 12.2% (infliximab)

Adverse events

Hypotension n = 0 (abatacept), n = 8 (infliximab) Headache n = 2 (abatacept), n = 7 (infliximab) Nausea n = 3 (abatacept), n = 7 (infliximab) Flushing n = 1 (abatacept), n = 5 (infliximab) Dyspnoea n = 0 (abatacept), n = 5 (infliximab) Urticaria n = 0 (abatacept), n = 8 (infliximab) Pruritus n = 0 (abatacept), n = 5 (infliximab) Dizziness n = 1 (abatacept), n = 4 (infliximab) Serious infection n = 3 (abatacept), n = 14 (infliximab)

143

144

Rheumatoid Arthritis: Abatacept

AGREE-Trial

Clinical efficacy and safety of Abatacept in naïve-naive patients with early rheumatoid arthritis and poor prognostic factors AGREE: Ababacept study to gauge remission and joint damage in early erosive rheumatoid arthritis

Substance

Abatacept (~10 mg/kg, n = 256) plus MTX Placebo plus MTX (n = 253) Concomitant medication: MTX 7.5 mg/week, increased to 15 mg/week (week 4), 20 mg (week 8) Prednisone £ 10 mg/day 2 corticosteroid pulses > 10 mg were permitted After 6 months a 2nd DMARD was permitted NSAIDs were permitted Previous medication: MTX £ 10 mg/week £ 3 weeks

Result

Combination therapy with abatacept and methotrexate of MTX-naïve early RA patients with poor prognostic factors significantly resulted in better clinical and radiographic efficacy compared with methotrexate alone, and had a comparable, favourable safety profile

Patients

509 patients with RA Disease duration £ 2 years MTX-naïve Seropositive for rheumatoid factor (RF) pos Anti-cyclic citrullinated protein (CCP) pos ³ 12 tender joints ³ 10 swollen joints CRP ³ 0.45 mg/dL Radiographic evidence of bone erosion of the hands/wrists/feet

Authors

Westhovens R, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, Gomez-Reino J, Grassi W, Haraoui B, Shergy W, Park SH, Genant H, Peterfy C, Becker JC, Covucci A, Helfrick R, Bathon J

Publication

Ann Rheum Dis. 2009 Dec;68(12):1870–1877. Epub 2009 Jan 5

Rheumatoid Arthritis: Abatacept

Follow up

1 year

ACR 50

57.4% (abatacept), 42.3% (MTX)

ACR 70

42.6% (abatacept), 27.3% (MTX)

ACR 90

16.4% (abatacept), 6.7% (MTX)

Note

CRP-DAS remission 41.4% (abatacept), 23.3% (MTX) Change of: Total Sharp score +0.63 (abatacept), +1.06 (MTX) Erosion score +0.46 (abatacept), +0.89 (MTX) Joint space narrowing +0.13 (abatacept), +0.17 (MTX) HAQ-DI 0.0 (abatacept), -0.76 (MTX)

Adverse events

Serious AEs 7.8% (abatacept), 7.9% (MTX) Serious infections 2.0% (abatacept), 2.0% (MTX) Autoimmune disorders 2.3% (abatacept), 2.0% (MTX) Acute infusion reactions 6.3% (abatacept), 2.0% (MTX) Malignancies 0.4% (abatacept), 0% (MTX) Death 0.8% (abatacept), 1.6% (MTX)

145

146

Rheumatoid Arthritis: Abatacept

Trial

Safety and efficacy of the selective co-stimulation modulator Abatacept in patients with rheumatoid arthritis receiving background Methotrexate: a 5-year extended phase IIB study

Substance

Patients were enrolled to 10 mg abatacept After 1 year of: 10 mg/kg abatacept (n = 115, days 1-15–30, every 30 days thereafter) 2 mg/kg abatacept (n = 105) Placebo (n = 119) Concomitant medication: 10–30 mg MTX/week stable ³ 6 months Corticosteroids £10 mg/day Addition of another DMARD (hydroxychloroquine, sulfasalazine, gold, or azathioprine) was permitted Previous medication: MTX ³ 6 months Other DMARDs were permitted

Result

Efficacy, safety, and tolerability of abatacept were maintained and demonstrated consistent over 5 years of treatment, with relatively high retention rates

Patients

219 RA patients entered the long-term extension After completing the double-blind period (n = 235) N =130 (59.4%), were continuing at Year 5

Authors

Westhovens R, Kremer JM, Moreland LW, Emery P, Russell AS, Li T, Aranda R, Becker JC, Qi K, Dougados M

Publication

J Rheumatol. 2009 Apr;36(4):736–742. Epub 2009 Feb 27

Follow up

5 years

ACR 20

77.1% (abatacept second line), 82.7% (abatacept first line)

ACR 50

53.0% (abatacept second line), 65.4% (abatacept first line)

ACR 70

28.9% (abatacept second line), 40.4% (abatacept first line)

Rheumatoid Arthritis: Abatacept

147

Note

Low Disease Activity State 48.2% (year 1), 58.5% (year 5) Disease Activity Score-28-defined remission 25.3% (year 1), 45.3% (year 5)

Adverse events

Malignancies 1.5/100 patient years Non melanoma skin cancers n = 10 Solid tumors n = 7 Squamous cell carcinoma n = 3 Small-cell lung cancer n = 1 Squamous cell carcinoma of the skin n = 1 Bladder cancer n = 1 Breast cancer n = 1 Ovarian cancer n = 1 Lung adenocarcinoma n = 1 Metastatic lung cancer n = 1 Malignant lung neoplasm n = 1 Cutaneous vasculitis n = 2 Infections and serious infections 94.2 and 2.1/100 patient-years Nasopharyngitis; 12.6/100 patient-years Upper respiratory tract infection 8.4/100 patient-years Cough 8.3/100 patient-years Headache 8.8/100 patient-years Nausea 5.2/100 patient-years Diarrhea 6.9/100 patient-years

148

Rheumatoid Arthritis: Abatacept

ARRIVE-Trial

The 6-month safety and efficacy of Abatacept in patients with rheumatoid arthritis who underwent a washout after anti-TNF therapy or were directly switched to Abatacept: the ARRIVE trial ARRIVE (Abatacept Researched in RA patients with an Inadequate anti-TNF response to Validate Effectiveness)

Substance

~10 mg/kg abatacept after washout (n = 449) Direct switch (n = 597) Administered on days 1-15–29, every 4 weeks thereafter Concomitant medication: DMARDs continued at stable dose Glucocorticosteroids at stable doses Previous medication: Biological therapy

Result

Abatacept over 6 months demonstrated acceptable safety and tolerability, and clinically meaningful efficacy in patients with an inadequate response to anti-TNF therapy. The outcome was similar with a washout of abatacept or direct-switching from anti-TNF therapy to abatacept

Patients

1046 active RA patients Inadequate response to anti-TNF therapy for ³ 3 months DAS28 (CRP) ³ 5.1 ‘Washout’ patients discontinued anti-TNF therapy ³ 2 months pre-screening; ‘direct-switch’ patients began abatacept (~10 mg/kg), at their next scheduled anti-TNF therapy dose

Authors

Schiff MH, Pritchard C, Huffstutter JE, Rodriguez-Valverde V, Durez P, Zhou X, Li T, Bahrt K, Kelly S, Le Bars M, Genovese MC

Publication

Ann Rheum Dis. 2009 Nov;68(11):1708–1714. Epub 2008 Dec 15

Follow up

6 months

Note

DAS28 (CRP) reduction ³ 1.2 59.5 (washout), 53.6% (direct switch) Low disease activity state 22.5 (washout), 22.3% (direct switch) DAS28-defined remission 12.0 (washout), 13.7% (direct switch) HAQ-DI ³ 0.22 improvement; 46.3 (washout), 47.1% (direct switch) Overall, 22.4% of patients achieved LDAS and 13.0% achieved remission

Adverse events

Total serious infections 2.7% (washout), 2.2% (direct switch) Pneumonia 0.0% (washout), 0.7% (direct switch) Bronchitis 0.4% (washout), 0.2% (direct switch) Lobar pneumonia 0.4 (washout), 0.2% (direct switch) Autoimmune disorders 0.9% (washout), 1.5% (direct switch) Total neoplasms 1.8% (washout), 1.2% (direct switch) Total malignancies 0.9% (washout), 0.3% (direct switch) Basal cell carcinoma 0.0% (washout), 0.3% (direct switch) Breast cancer 0.4% (washout), 0.0% (direct switch) Lung adenocarcinoma 0.2% (washout), 0.0% (direct switch) Uterine cancer 0.2% (washout), 0.0% (direct switch)

Rheumatoid Arthritis: Abatacept

149

ADJUSTTrial

The impact of T-cell co-stimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept ADJUST Abatacept Study to Determine the effectiveness in preventing the development of rheumatic arthritis in patients with undifferentiated inflammatory arthritis and to Evaluate safety and tolerability

Substance

~10 mg/kg abatacept (n = 28) Placebo (n = 28) On days 1, 15, 29, 57, 85, 113, 141 and 169 Concomitant medication: DMARDs continued at stable dose £ 10 mg prednisone/d NSAIDs were permitted Previous medication: No DMARDs No biologic therapy

Result

Progression of undifferentiated or very early RA in some patients is delayed by abatacept treatment. Radiographic and MRI progression was inhibited. This was maintained for 6 months after therapy cessation

Patients

56 anti-CCP2-positive patients with undifferentiated arthritis Clinical synovitis of ³ 2 joints Meeting ³ 1 and £ 3 ACR criteria Symptom duration < 18 months

Authors

Emery P, Durez P, Dougados M, Legerton CW, Becker JC, Vratsanos G, Genant HK, Peterfy CG, Mitra P, Overfield S, Qi K, Westhovens R

Publication

Ann Rheum Dis. 2009 Nov 23. [Epub ahead of print]

Follow up

12 months

Note

Change of: Anti-CCP level (U/mL) -6.5 (Aba), +149.5 (placebo) Rheumatoid factor (U/mL) -40.7 (Aba), -7.8 (placebo) Patients developed RA 46% (Aba), 67% (placebo) DAS defined remission 6 months 71.4% (Aba), 35.0% (placebo) 12 months 47.4% (Aba), 38.5% (placebo) Genant-modified Sharp radiographic score: Total score +0.01 (Aba), +1.11 (placebo) Erosion score +0.01 (Aba), +0.86 (placebo) Joint space narrowing 0 (Aba), +0.26 (placebo) MRI scores: MRI erosion score 0 (Aba), +5.0 (placebo) MRI osteitis score 0.2 (Aba), +6.7 (placebo) MRI synovitis score 0.2 (Aba), +2.3 (placebo)

Adverse events

Total AEs 64.3% (Aba), 71.4% (placebo) Discontinuations due to AEs 3.6% (Aba), 3.6% (placebo) SAEs 3.6% (Aba), 71.4% (placebo) Infections 35.7% (Aba), 39.3% (placebo) Malignancies 3.6% (Aba), 0% (placebo) Death 0% (Aba), 0% (placebo)

150

Rheumatoid Arthritis: Etanercept + Abatacept

Trial

Selective co-stimulation modulation using Abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial

Substance

Abatacept 2 mg/kg (n = 85) day 1, 15, 30, and every 4 weeks Placebo (n = 36) Concomitant medication: Both added to etanercept 2 × 25 mg/week DMARDs stopped ³ 28 days before randomisation Corticosteroids £ 10 mg/day NSAIDs were permitted Addition of HCQ, SSZ, Lef or MTX was allowed after 6 All patients entering the long term extension were switched to receive abatacept 10 mg/kg Previous medication: DMARDs Etanercept

Result

The combination of abatacept and etanercept was associated with an increase in serious adverse events. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment

Patients

121 RA patients Rheumatoid arthritis functional class I, II or III Etanercept 2 × 25 mg/week for ³ 3 months and ³ 8 swollen joints ³10 tender joints CRP ³ 2 mg/dL

Authors

Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, Chen D, Becker JC

Publication

Ann Rheum Dis. 2007 Feb;66(2):228–234. Epub 2006 Aug 25

Follow up

6 months + 1.5 years open label extension

ACR 20

48.2% (Aba + ETN), 30.6% (ETN); all after 1 year

ACR 50

28.2% (Aba + ETN), 16.7% (ETN); all after 1 year

ACR 70

9.4% (Aba + ETN), 5.6% (ETN); all after 1 year

Note

Change Baseline to 1 year Tender joints -11.6 (Aba + ETN), -8.8 (ETN) Swollen joints -7.8 (Aba + ETN), -4.4 (ETN) Patient assessment of pain -22.0 (Aba + ETN), -6.1 (ETN) Patient assessment of function (mHAQ) -0.3 (Aba + ETN), -0.2 (ETN) Patient assessment of disease activity -18.2 (Aba + ETN), -7.1 (ETN) Physician assessment of disease activity -25.7 (Aba + ETN), -18.2 (ETN) CRP -0.6 (Aba + ETN), -0.9 (ETN) Change 1 year to 2 years Tender joints -4.2 (Aba + ETN), -3.0 (ETN) Swollen joints -4.4 (Aba + ETN), -4.2 (ETN) Patient assessment of pain -5.3 (Aba + ETN), +2.8 (ETN) Patient assessment of function (mHAQ) -0.1 (Aba + ETN), 0.0 (ETN) Patient assessment of disease activity -4.1 (Aba + ETN), +1.6 (ETN) Physician assessment of disease activity -7.6 (Aba + ETN), -0.6 (ETN) CRP -0.2 (Aba + ETN), -0.4 (ETN)

Rheumatoid Arthritis: Etanercept + Abatacept

Adverse events

151

Death 0% (Aba + ETN), 0% (ETN), 1.3% (Open label 10 mg/kg Aba) Total AEs 92.9% (Aba + ETN), 88.9% (ETN), 97.5% (Open label 10 mg/kg Aba) Rheumatoid arthritis 43.5% (Aba + ETN), 36.1% (ETN), 30.0% (Open label 10 mg/kg Aba) Urinary tract infection 23.5% (Aba + ETN), 13.9% (ETN), 28.8% (Open label 10 mg/kg Aba) Headache 23.5% (Aba + ETN), 13.9% (ETN), 12.5% (Open label 10 mg/kg Aba) Fatigue 16.5% (Aba + ETN), 16.7% (ETN), 17.5% (Open label 10 mg/kg Aba) Sinusitis 16.5% (Aba + ETN), 8.3% (ETN), 22.5% (Open label 10 mg/kg Aba) Nausea 15.3% (Aba + ETN), 2.8% (ETN), 15.0% (Open label 10 mg/kg Aba) Arthralgia 15.3% (Aba + ETN), 8.3% (ETN), 6.3% (Open label 10 mg/kg Aba) Dizziness 15.3% (Aba + ETN), 5.6% (ETN), 10.0% (Open label 10 mg/kg Aba) Diarrhoea 14.1% (Aba + ETN), 5.6% (ETN), 16.3% (Open label 10 mg/kg Aba) Cough 12.9% (Aba + ETN), 8.3% (ETN), 13.8% (Open label 10 mg/kg Aba) Rash 12.9% (Aba + ETN), 8.3% (ETN), 12.5% (Open label 10 mg/kg Aba) Discontinuations due to AEs 11.8% (Aba + ETN), 2.8% (ETN), 10.0% (Open label 10 mg/kg Aba) Related AEs 62.4% (Aba + ETN), 47.2% (ETN), 65.0% (Open label 10 mg/kg Aba) SAEs 16.5% (Aba + ETN), 2.8% (ETN), 32.5% (Open label 10 mg/kg Aba) Musculoskeletal and connective tissue disorders 1.2% (Aba + ETN), 0% (ETN), 11.3% (Open label 10 mg/kg Aba) Vascular disorders 0% (Aba + ETN), 1.2% (ETN), 7.5% (Open label 10 mg/kg Aba) Malignancies 0% (Aba + ETN), 0% (ETN), 3.8% (Open label 10 mg/kg Aba) Gastrointestinal disorders 0% (Aba + ETN), 0% (ETN), 3.8% (Open label 10 mg/kg Aba) Infections and infestations 3.5% (Aba + ETN), 0% (ETN), 1.3% (Open label 10 mg/kg Aba) Nervous system disorders 2.4% (Aba + ETN), 0% (ETN), 1.3% (Open label 10 mg/kg Aba) Respiratory, thoracic and mediastinal disorders 35.3% (Aba + ETN), 9.4% (ETN), 40.0% (Open label 10 mg/kg Aba) Related SAEs 5.9% (Aba + ETN), 0% (ETN), 3.8% (Open label 10 mg/kg Aba) Serious infections 3.5% (Aba + ETN), 0% (ETN), 1.3% (Open label 10 mg/kg Aba)

152

Rheumatoid Arthritis: Adalimumab

ArmadaTrial

Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant Methotrexate: the ARMADA trial. Anti–Tumor Necrosis Factor Research Study Program of the Monoclonal Antibody adalimumab (D2E7), in Rheumatoid Arthritis ARMADA: Anti–Tumor Necrosis Factor Research Study Program of the Monoclonal Antibody adalimumab in Rheumatoid Arthritis

Substance

Adalimumab 20 mg/2 weeks (n = 69) Adalimumab 40 mg/2 weeks (n = 67) Adalimumab 80 mg/2 weeks (n = 73) Placebo (n = 62) Concomitant medication: 12.5–25 mg MTX/week was continued All other DMARDs were discontinued Prednisone £ 10 mg/day Folic acid or leucovorin was permitted No highpotency opioid analgesics (e.g., methadone, hydromorphone, or morphine) NSAIDs were permitted Previous medication: 12.5–25 mg MTX/week £6 months ³ 1 DMARD besides MTX £ 4 DMARDs

Result

Combination of adalimumab and methotrexate was superior to methotrexate monotherapy in inducing a rapid and sustained improvement of disease

Patients

271 RA patients Inadequate response to DMARDs ³ 9 tender joints ³ 6 swollen joints (of 66 joints)

Authors

Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK

Publication

Arthritis Rheum. 2003 Jan;48(1):35–45

Follow up

24 weeks

ACR 20

47.8% (Ada 20), 67.2% (Ada 40), and 65.8% (Ada 80), 14.5% (placebo)

ACR 50

31.9% (Ada 20), 55.2% (Ada 40), and 42.5% (Ada 80), 8.1% (placebo)

ACR 70

10.1% (Ada 20), 26.9% (Ada 40), 19.2% (Ada 80), 4.8% (placebo)

Rheumatoid Arthritis: Adalimumab

153

Note

Change of: Tender joint count -5.3 (placebo), -14.4 (20 mg Ada), -14.4 (40 mg Ada), -16.8 (80 mg Ada) Swollen joint count -2.9 (placebo), -7.7 (20 mg Ada), -10.4 (40 mg Ada), -10.8 (80 mg Ada) Patient’s assessment of pain (0–100-mm VAS) -8.6 (placebo), -24.8 (20 mg Ada), -25.1 (40 mg Ada), -27.6 (80 mg Ada) Patient’s global assessment of disease activity -8.6 (placebo), -27.1 (20 mg Ada), -29.7 (40 mg Ada), -32.0 (80 mg Ada) Physician’s global assessment of disease activity (0–100-mm VAS) -6.8 (placebo), -30.3 (20 mg Ada), -31.1 (40 mg Ada), -38.0 (80 mg Ada) HAQ -0.27 (placebo), -0.54 (20 mg Ada), -0.62 (40 mg Ada), -0.59 (80 mg Ada) CRP (mg/dL), +0.1 (placebo), -1.4 (20 mg Ada), -1.6 (40 mg Ada), -1.3 (80 mg Ada)

Adverse events

Rhinitis 23.2% (Ada 20), 25.4% (Ada 40), 23.3% (Ada 80), 19.4% (placebo) Upper respiratory infection 20.3% (Ada 20), 14.9% (Ada 40), 21.9% (Ada 80), 9.7% (placebo) Nausea 18.8% (Ada 20), 4.5% (Ada 40), 9.6% (Ada 80), 6.5% (placebo) Flu symptoms 11.6% (Ada 20), 14.9% (Ada 40), 6.8% (Ada 80), 8.1% (placebo) Headache 10.1% (Ada 20), 6.0% (Ada 40), 10.0% (Ada 80), 9.7% (placebo) Injection-site pain 8.7% (Ada 20), 10.4% (Ada 40), 11.0% (Ada 80), 3.2% (placebo) Accidental injury 5.8% (Ada 20), 14.9% (Ada 40), 8.2% (Ada 80), 11.3% (placebo) Diarrhoea 8.7% (Ada 20), 10.4% (Ada 40), 5.5% (Ada 80), 8.1% (placebo) Rash 10.1% (Ada 20), 4.5% (Ada 40), 6.8% (Ada 80), 4.8% (placebo) Injection-site reaction 4.3% (Ada 20), 1.5% (Ada 40), 11% (Ada 80), 0% (placebo) Dizziness 11.6% (Ada 20), 3% (Ada 40), 1.4% (Ada 80), 1.6% (placebo)

154

Rheumatoid Arthritis: Adalimumab

Trial

Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant Methotrexate: a pilot study

Substance

1 Single infusion of: Adalimumab 0.25 mg/kg (n = 9) Adalimumab 0.5 mg/kg (n = 9) Adalimumab 1 mg/kg (n = 9) Adalimumab 3 mg/kg (n = 9) Adalimumab 5 mg/kg (n = 9) Placebo (n = 15) Concomitant medication: Corticosteroids £ 10 mg/day NSAIDs were permitted 12.5–25 mg MTX/week was continued Previous medication: Stable doses of MTX 12.5–25 mg/week for ³ 3 months Other DMARDs discontinued ³ 3 months

Result

Addition of adalimumab to methotrexate in active RA with an in adequate response to methotrexate achieved significant, long-term improvement compared with methotrexate monotherapy. Adalimumab’s long half-life of 15 to 19 days supported every-other-week dosing. Serum levels of methotrexate did not alter after co-administration of adalimumab

Patients

RA ³ 6 swollen joints ³ 6 tender joints ESR > 28 mm/h Morning stiffness > 45 min.

Authors

Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, Teoh LS, Velagapudi RB, Noertersheuser PA, Granneman GR, Fischkoff SA, Chartash EK

Publication

Clin Ther. 2003 Jun;25(6):1700–1721

Follow up

4-week + 26-month open-label continuation

Rheumatoid Arthritis: Adalimumab

155

ACR 20/4 weeks 55.6% (Ada 0.25 mg/kg), 88.9% (Ada 0.5 mg/kg), 44.4% (Ada 1 mg/kg), 77.8% (Ada 3 mg/kg), 55.6% (Ada 5 mg/kg), 26.7% (placebo) ACR 50/4 weeks 33.3% (Ada 0.25 mg/kg), 44.4% (Ada 0.5 mg/kg), 11.1% (Ada 1 mg/kg), 22.2% (Ada 3 mg/kg), 11.1% (Ada 5 mg/kg), 0% (placebo) Note

Changes at week 4: Tender joint count -5.3 (Ada 0.25 mg/kg), -12.2 (Ada 0.5 mg/kg), -4.0 (Ada 1 mg/kg), -2.7 (Ada 3 mg/kg), -1.03 (Ada 5 mg/kg), -4.6 (placebo) Swollen joint count -6.9 (Ada 0.25 mg/kg), -7.0 (Ada 0.5 mg/kg), -4.0 (Ada 1 mg/kg), -1.7 (Ada 3 mg/kg), -4.2 (Ada 5 mg/kg), -3.1 (placebo) Patient’s assessment of pain -5.7 (Ada 0.25 mg/kg), -26.2 (Ada 0.5 mg/kg), -14.0 (Ada 1 mg/kg), -12.1 (Ada 3 mg/kg), -19.7 (Ada 5 mg/kg), +1.2 (placebo) Patient’s global assessment -10.7 (Ada 0.25 mg/kg), -25.1 (Ada 0.5 mg/kg), -17.4 (Ada 1 mg/kg), -16.6 (Ada 3 mg/kg), -22.3 (Ada 5 mg/kg), -1.3 (placebo) Physician’s global assessment -15.8 (Ada 0.25 mg/kg), -14.7 (Ada 0.5 mg/kg), -11.9 (Ada 1 mg/kg), -11.6 (Ada 3 mg/kg), -23.2 (Ada 5 mg/kg), –4.3 (placebo) HAQ Score –0.3 (Ada 0.25 mg/kg), –0.3 (Ada 0.5 mg/kg), –0.1 (Ada 1 mg/kg), –0.2 (Ada 3 mg/kg), –0.3 (Ada 5 mg/kg), –0.2 (placebo) ESR, mm/h -5.1 (Ada 0.25 mg/kg), -16.0 (Ada 0.5 mg/kg), –10.9 (Ada 1 mg/kg), -40.3 (Ada 3 mg/kg), –11.0 (Ada 5 mg/kg), -0.4 (placebo)

Adverse events

Headache 20% (Ada), 13.3% (placebo) Nausea 13.3% (Ada), 13.3% (placebo) Rhinitis 13.3% (Ada), 13.3% (placebo) Increased cough 11.1% (Ada), 0% (placebo) Dizziness 6.7% (Ada), 13.3% (placebo)

156

Rheumatoid Arthritis: Adalimumab

Trial

Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study

Substance

Adalimumab 20 mg (n = 72) Adalimumab 40 mg (n = 70) Adalimumab 80 mg (n = 72) Placebo (n = 70) Concomitant medication: No DMARDs £ 4 weeks Prednisolone £ 10 mg/day NSAIDs were permitted After week 8: Prednisolone dose could be increased NSAIDs dose could be increased DMARDs could be invented Previous medication: Failed ³ 1 traditional DMARD

Result

Adalimumab mono-therapy of patients with longstanding, severe RA refractory to traditional DMARDs led to a rapid, sustained response. Adalimumab treatment was safe and well tolerated

Patients

284 RA patients Tender joints ³ 12 Swollen joint ³ 10 ESR ³ 28 mm/h CRP ³ 20 mg/l

Authors

van de Putte LB, Rau R, Breedveld FC, Kalden JR, Malaise MG, van Riel PL, Schattenkirchner M, Emery P, Burmester GR, Zeidler H, Moutsopoulos HM, Beck K, Kupper H

Publication

Ann Rheum Dis. 2003 Dec;62(12):1168–1177

Follow up

12 weeks

Rheumatoid Arthritis: Adalimumab

ACR 20

10% (placebo) 51% (Ada 20 mg) 57% (Ada 40 mg) 54% (Ada 20 mg)

ACR 50

1% (placebo) 24% (Ada 20 mg) 27% (Ada 40 mg) 19% (Ada 20 mg)

ACR 70

0% (placebo) 11% (Ada 20 mg) 10% (Ada 40 mg) 8% (Ada 20 mg)

Note

Mean time (weeks) achieving ACR responses: ACR 20: 6.6 week (placebo), 4.0 week (Ada 20 mg), 4.1 week (Ada 40 mg), 3.7 week (Ada 20 mg) ACR 50: 10 weeks (placebo), 7.4 weeks (Ada 20 mg), 5.9 weeks (Ada 40 mg), 5.3 weeks (Ada 20 mg) ACR 70: not applicable (placebo), 7.8 weeks (Ada 20 mg), 7.0 weeks (Ada 40 mg), 6.9 weeks (Ada 20 mg) Change of: Tender joint count –5.1 (placebo), –14.0 (Ada 20 mg), –15.3 (Ada 40 mg), –15.2 (Ada 20 mg) Swollen joint count (0–66) –2.8 (placebo), –8.1 (Ada 20 mg), –9.6 (Ada 40 mg), –10.7(Ada 20 mg) Patient assessment of pain (VAS 0–100 mm) –7.8 (placebo), –31.8 (Ada 20 mg), –35.3 (Ada 40 mg), –30.1 (Ada 20 mg) Patient global assessment of disease activity (VAS 0–100 mm) –6.9 (placebo), –31.7 (Ada 20 mg), –37.6 (Ada 40 mg), –31.0 (Ada 20 mg) Doctor global assessment of disease activity (VAS 0–100 mm) –5.0 (placebo), –28.8 (Ada 20 mg), –35.7 (Ada 40 mg), –33.4 (Ada 20 mg) Disability Index of the HAQ (0–3) –0.04 (placebo), –0.45 (Ada 20 mg), –0.47 (Ada 40 mg), –0.48 (Ada 20 mg) CRP (mg/l) –1 (placebo), –24 (Ada 20 mg), –32 (Ada 40 mg), –34 (Ada 20 mg) ESR (mm/h) –2.0 (placebo), –14.2 (Ada 20 mg), –17.9 (Ada 40 mg), –17.3 (Ada 20 mg) DAS28 –0.5 (placebo), –1.8 (Ada 20 mg), –2.1 (Ada 40 mg), –2.0 (Ada 20 mg)

157

158

Adverse events

Rheumatoid Arthritis: Adalimumab

Cholesterol ³ 6.21 mmol/l 34% (placebo), 44% (Ada 20 mg), 41% (Ada 40 mg), 43% (Ada 80 mg) Haemoglobin ↓ 44% (placebo), 32% (Ada 20 mg), 39% (Ada 40 mg), 35% (Ada 80 mg) Haemorrhage 33% (placebo), 22% (Ada 20 mg), 27% (Ada 40 mg), 21% (Ada 80 mg) Triglycerides > 2.26 mmol/l 19% (placebo), 25% (Ada 20 mg), 31% (Ada 40 mg), 31% (Ada 80 mg) Injection-site reaction 6% (placebo), 29% (Ada 20 mg), 23% (Ada 40 mg), 29% (Ada 80 mg) Uric acid 0.42 µmol/l (men), 5.7 µmol/l (women) 21% (placebo), 18% (Ada 20 mg), 23% (Ada 40 mg), 26% (Ada 80 mg) Blood urea >500 mg/l 26% (placebo), 22% (Ada 20 mg), 24% (Ada 40 mg), 13% (Ada 80 mg) Blood urea nitrogen increased 9% (placebo), 15% (Ada 20 mg), 17% (Ada 40 mg), 17% (Ada 80 mg) Clinical flare 16% (placebo), 7% (Ada 20 mg), 9% (Ada 40 mg), 8% (Ada 80 mg) Rhinitis 10% (placebo), 15% (Ada 20 mg), 16% (Ada 40 mg), 10% (Ada 80 mg) Alkaline phosphatase increased 14% (placebo), 14% (Ada 20 mg), 9% (Ada 40 mg), 14% (Ada 80 mg) Alanine transaminase ↑ 9% (placebo), 8% (Ada 20 mg), 1% (Ada 40 mg), 14% (Ada 80 mg) Phosphate < 0.8 mmol/l 6% (placebo), 0% (Ada 20 mg), 13% (Ada 40 mg), 6% (Ada 80 mg) Rash 9% (placebo), 10% (Ada 20 mg), 13% (Ada 40 mg), 11% (Ada 80 mg) Cough increased 3% (placebo), 13% (Ada 20 mg), 7% (Ada 40 mg), 4% (Ada 80 mg) Pruritus 6% (placebo), 13% (Ada 20 mg), 11% (Ada 20 mg), 13% (Ada 80 mg) Headache 4% (placebo), 13% (Ada 20 mg), 11% (Ada 40 mg), 4% (Ada 80 mg) Potassium >5 mmol/l 7% (placebo), 11% (Ada 20 mg), 6% (Ada 40 mg), 10% (Ada 80 mg) Urine protein > 0.15 g/24 h 0% (placebo), 7% (Ada 20 mg), 10% (Ada 40 mg), 6% (Ada 80 mg) Sodium < 135 mmol/l 10% (placebo), 10% (Ada 20 mg), 10% (Ada 40 mg), 7% (Ada 80 mg)

Rheumatoid Arthritis: Adalimumab

159

STAR-Trial

Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of adalimumab in Rheumatoid Arthritis) STAR: Safety Trial of adalimumab in Rheumatoid Arthritis

Substance

Adalimumab 40 mg s.c. every other week (n = 318) Placebo (n = 318) Concomitant medication: Continuing standard antirheumatic therapy DMARDs ((hydroxy)chloroquine, Lef, MTX, Gold, SSZ) Prednisone £ 10 mg/day NSAIDs were permitted After week 12 (if no ACR 20 response): Increase/change DMARDs dose Increase Prednisone dose £ 10 mg/day 3 intraarticular corticosteroid injections Previous medication: No biological therapy DMARDs

Result

40 mg adalimumab every other week in addition to concomitant standard antirheumatic therapy was well tolerated and provided significant improvements in signs and symptoms of RA

Patients

636 patients with active RA Inadequate response to standard antirheumatic therapy ³ 6 swollen joints ³ 9 tender joints

Authors

Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, Fischkoff SA, Chartash EK

Publication

J Rheumatol. 2003 Dec;30(12):2563–2571

Follow up

24 weeks

ACR 20

52.8% (Ada), 34.9 (placebo)

ACR 50

28.9% (Ada), 11.3% (placebo)

ACR 70

14.8% (Ada), 3.5% (placebo)

Adverse events

Infection 52.2% (Ada), 49.4% (placebo) Serious infection 1.3% (Ada), 1.9% (placebo) Injection-site reaction 19.5% (Ada), 11.6% (placebo) Rash 10.7% (Ada), 6.0% (placebo) Nausea 9.1% (Ada), 5.3% (placebo) Headache 8.2% (Ada), 7.2% (placebo) Accidental injury 6.9% (Ada), 7.9% (placebo) Abdominal pain 6.9% (Ada), 3.8% (placebo) Diarrhoea 6.0% (Ada), 6.9% (placebo) Clinical flair reaction 5.7% (Ada), 5.7% (placebo) Back pain 5.3% (Ada), 1.6% (placebo) Surgery 5.0% (Ada), 2.5% (placebo) Upper respiratory infection 19.8% (Ada), 15.1% (placebo) Urinary tract infection 9.1% (Ada), 5.7% (placebo) Sinusitis 7.5% (Ada), 8.8% (placebo) Flu symptoms 7.2% (Ada), 5.0% (placebo) Rhinitis 6.9% (Ada), 10.4% (placebo)

160

Rheumatoid Arthritis: Adalimumab

Trial

Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with Methotrexate

Substance

Adalimumab 2 injections s.c. (1 mg/kg, n = 18) Adalimumab 2 injections i.v. (1 mg/kg, n = 18) Placebo (n = 18) Concomitant medication: Continuing 7.5–25 mg MTX/week (mean dose, 15.7 mg/week) Prednisolone £ 10 mg/day NSAIDs were permitted Reliable anticonception Previous medication: MTX

Result

Adalimumab added to methotrexate significantly improved the signs and symptoms of RA as compared with methotrexate alone. Subcutaneously administered adalimumab appeared to provide an equally great, rapid, and enduring response as that with i.v. adalimumab

Patients

54 RA patients DAS ³ 3.2

Authors

Rau R, Simianer S, van Riel PL, van de Putte LB, Krüger K, Schattenkirchner M, Allaart CF, Breedveld FC, Kempeni J, Beck K, Kupper H

Publication

Scand J Rheumatol. 2004;33(3):145–153

Follow up

34 days

ACR 20

72% (i.v. Ada), 67% (s.c. Ada), 28% (placebo)

ACR 50

11% (i.v. Ada), 17% (s.c. Ada), 0% (placebo)

Note

Moderate EULAR response 83% (i.v. ADA), 61% (s.c. Ada), 44% (placebo) Good EULAR response 11% (i.v. ADA), 17% (s.c. Ada), 0% (placebo) Change of: CRP –2.44 (i.v. Ada), –2.06 (s.c. Ada), +0.31 (placebo) ESR –13.9 (i.v. Ada), –12.2 (s.c. Ada), +0.4 (placebo) HAQ –0.33 (i.v. Ada), –0.13 (s.c. Ada), +0.08 (placebo) Physician’s global assessment –18.9 (i.v. Ada), –19.3 (s.c. Ada), –1.8 (placebo) Patient’s global assessment –25.1 (i.v. Ada), –9.5 (s.c. Ada), –1.9 (placebo) Pain (VAS 0–100) –19.9 (i.v. Ada), –12.1 (s.c. Ada), –6.7 (placebo) Swollen joint count –10.0 (i.v. Ada), –8.3 (s.c. Ada), –1.0 (placebo) Tender joint count –7.4 (i.v. Ada), –5.1 (s.c. Ada), –1.1 (placebo)

Adverse events

Fever 17% (i.v. Ada), 17% (s.c. Ada), 44% (placebo) Rhinitis 22% (i.v. Ada), 11% (s.c. Ada), 17% (placebo) Hypertension 22% (i.v. Ada), 17% (s.c. Ada), 6% (placebo) Nausea 22% (i.v. Ada), 0% (s.c. Ada), 11% (placebo) Flu syndrome 6% (i.v. Ada), 17% (s.c. Ada), 6% (placebo) Headache 6% (i.v. Ada), 17% (s.c. Ada), 0% (placebo) Dizziness 11% (i.v. Ada), 11% (s.c. Ada), 11% (placebo) Bronchitis 0% (i.v. Ada), 11% (s.c. Ada), 11% (placebo) Increased urinary frequency 11% (i.v. ADA), 0% (s.c. Ada), 0% (placebo) Asthenia 6% (i.v. Ada), 0% (s.c. Ada), 11% (placebo) Mouth ulcerations 0% (i.v. Ada), 0% (s.c. Ada), 11% (placebo)

Rheumatoid Arthritis: Adalimumab

161

Trial

Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody), in patients with active rheumatoid arthritis receiving concomitant Methotrexate therapy: a randomized, placebo-controlled, 52-week trial

Substance

Adalimumab 40 mg subcutaneously every other week (n = 207) Adalimumab 20 mg subcutaneously every week (n = 212) Placebo (n = 200) Concomitant medication: Continuing 7.5–25 mg MTX/week (mean dose, 15.7 mg/week) No other DMARDs £ 28 days Prednisone £ 10 mg/day or equivalent NSAIDs were permitted 1 intraarticular corticosteroid injection was permitted until week 16 2 intraarticular corticosteroid injections were permitted was between week 24–44 After week 16, if no ACR 20 response was achieved: Rescue DMARD medication Previous medication: MTX ³ 3 months No prior biologic therapy

Result

Adalimumab was more effective than placebo in patients with active RA who had demonstrated an incomplete response to MTX at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function

Patients

619 patients with active RA Inadequate response to MTX ³ 9 tender joints ³ 6 swollen joints CRP > 10 mg/l Rheumatoid factor pos. or 1 erosive joint

Authors

Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK

Publication

Arthritis Rheum. 2004 May;50(5):1400–1411

Follow up

52 weeks

ACR 20

Week 24: 63% (40 mg Ada/2 weeks), 61% (20 mg Ada/weekly), 30% (placebo) Week 52: 59% (40 mg Ada/2 weeks), 55% (20 mg Ada/weekly), 24% (placebo)

ACR 50

Week 24: 39% (40 mg Ada/2 weeks), 41% (20 mg Ada/weekly), 10% (placebo) Week 52: 42% (40 mg Ada/2 weeks), 38% (20 mg Ada/weekly), 10% (placebo)

ACR 70

Week 24: 21% (40 mg Ada/2 weeks), 18% (20 mg Ada/weekly), 3% (placebo) Week 52: 23% (40 mg Ada/2 weeks), 21% (20 mg Ada/weekly), 5% (placebo)

162

Note

Rheumatoid Arthritis: Adalimumab

Total sharp score/52 week 0.1 (40 mg Ada/2 weeks), 0.8 (20 mg Ada/weekly), 2.7 (placebo) Change of: Tender joint count (0–68 scale) –16.6 (Ada 40 mg/2 weeks), –16.8 (20 mg Ada/week), –9.6 (MTX) Swollen joint count (0–66 scale) –11.9 (Ada 40 mg/2 week), –11.7 (20 mg Ada/week), –5.6 (MTX) Patient’s assessment of pain (mm, 0–100–mm VAS) –29.4 (Ada 40 mg/2 weeks), –27.4 (20 mg Ada/week), –11.2 (MTX) Patient’s global assessment of disease activity (mm, 0–100–mm VAS) –27.5 (Ada 40 mg/2 weeks), –24.1 (20 mg Ada/week), –10.9 (MTX) Physician’s global assessment of disease activity (mm, 0–100–mm VAS) –39.4 (Ada 40 mg/2 weeks), –36.2 (20 mg Ada/weeks), –19.5 (MTX) HAQ score (0–3 scale) –0.59 (Ada 40 mg/2 weeks), –0.61 (20 mg Ada/week), –0.25 (MTX) CRP (mg/dL) –0.7 (Ada 40 mg/2 week), –0.7 (20 mg Ada/week), –0.1 (MTX)

Adverse events

Injection-site reactions 26% (40 mg Ada/2 weeks), 22% (20 mg Ada/weekly), 24% (placebo) Upper respiratory tract infections 20% (40 mg Ada/2 weeks), 19% (20 mg Ada /weekly), 14% (placebo) Rhinitis 16% (40 mg Ada/2 weeks), 18% (20 mg Ada/weekly), 17% (placebo) Sinusitis 16% (40 mg Ada/2 weeks), 15% (20 mg Ada/weekly), 13% (placebo) Accidental injury 14% (40 mg Ada/2 weeks), 13% (20 mg Ada/weekly), 12% (placebo) Headache 13% (40 mg Ada/2 weeks), 14% (20 mg Ada/weekly), 6% (placebo) Infection 7% (40 mg Ada/2 weeks), 16% (20 mg Ada/weekly), 5% (placebo) Nausea 9% (40 mg Ada/2 weeks), 12% (20 mg Ada/weekly), 13% (placebo) Diarrhoea 9% (40 mg Ada/2 weeks), 11% (20 mg Ada/weekly), 15% (placebo) Arthralgia 7% (40 mg Ada/2 weeks), 14% (20 mg Ada/weekly), 12% (placebo) Rash 11% (40 mg Ada/2 weeks), 9% (20 mg Ada/weekly), 8% (placebo) Joint disorder 6% (40 mg Ada/2 weeks), 7% (20 mg Ada/weekly), 12% (placebo) Clinical flair 6% (40 mg Ada/2 weeks), 4% (20 mg Ada/weekly), 15% (placebo)

Rheumatoid Arthritis: Adalimumab

Trial

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

Substance

Adalimumab 20 mg every other week (n = 106) Adalimumab 20 mg weekly (n = 102) Adalimumab 40 mg every other week (n = 113) Adalimumab 40 mg weekly (n =103) Placebo (n =110)

163

Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Reliable contraceptive method No DMARDs £ 28 days Previous medication: ³ 1 DMARD Result

Adalimumab treatment of RA patients for whom previous DMARD treatment had failed led to a significant, rapid, and sustained improvement in disease activity. Physical function improved in parallel

Patients

544 patients with RA Failed ³ 1 DMARD >12 tender joints >10 swollen joints (66 joint evaluation) ESR >28 mm/h or CRP >20 mg/l

Authors

van de Putte LB, Atkins C, Malaise M, Sany J, Russell AS, van Riel PL, Settas L, Bijlsma JW, Todesco S, Dougados M, Nash P, Emery P, Walter N, Kaul M, Fischkoff S, Kupper H

Publication

Ann Rheum Dis. 2004 May;63(5):508–516

Follow up

26 weeks

ACR 20

35.8% (Ada 20/2 weeks), 39.3% (Ada 20/week), 46.0% (Ada 40/2 weeks), 53.4% (Ada 40/week), 19.1% (placebo)

ACR 50

18.9% (Ada 20/2 weeks), 20.5% (Ada 20/week), 22.1% (Ada 40/2 weeks), 35.0% (Ada 40/week), 8.2% (placebo)

ACR 70

8.5% (Ada 20/2 weeks), 9.8% (Ada 20/week), 12.4% (Ada 40/2 weeks), 18.4% (Ada 40/week), 1.8% (placebo)

164

Note

Rheumatoid Arthritis: Adalimumab

EULAR-Response 41.5% (Ada 20/2 weeks), 48.2% (Ada 20/week), 55.8% (Ada 40/2 weeks), 63.1% (Ada 40/weeks), 26.4% (placebo) Change of: Tender joint count (range 0–68) –11.2 (Ada 20/2 weeks), –14.9 (Ada 20/week), –13.6 (Ada 40/2 weeks), –17.1 (Ada 40/week), –6.6 (placebo) Swollen joint count (range 0–66) –5.7 (Ada 20/2 weeks), –7.2 (Ada 20/week), –8.5 (Ada 40/2 weeks), –8.3 (Ada 40/week), –2.4 (placebo) Patient assessment of pain (scale 0–100) –20.1 (Ada 20/2 weeks), –25.2 (Ada 20/week), –27.6 (Ada 40/2 weeks), –32.0 (Ada 40/week), –11.0 (placebo) Patient global assessment of disease activity (scale 0–100) –19.5 (Ada 20/2 week), –26.5 (Ada 20/week), –27.9 (Ada 40/2 weeks), –35.0 (Ada 40/week), –10.6 (placebo) Physician global assessment of disease activity (scale 0–100) –20.5 (Ada 20/2 weeks), –26.4 (Ada 20/week), –27.3 (Ada 40/2 weeeks), –32.5 (Ada 40/week), –10.9 (placebo) HAQ change –0.29 (Ada 20/2 weeks), –0.39 (Ada 20/week), –0.38 (Ada 40/2 weeks), –0.49 (Ada 40/week), –0.07 (placebo) CRP (mg/l) –4.3 (Ada 20/2 weeks), –10.7 (Ada 20/week), –19.5 (Ada 40/2 weeks), –16.7 (Ada 40/week), +3.0 (placebo) ESR (mm/h) –2.5 (Ada 20/2 weeks), –5.5 (Ada 20/week), –12.0 (Ada 40/2 weeks), –12.0 (Ada 40/weeks), –2.0 (placebo) DAS28 –1.3 (Ada 20/2 weeks), –1.6 (Ada 20/week), –1.7 (Ada 40/2 weeks), –2.0 (Ada 40/week), –0.7 (placebo)

Adverse events

Clinical flair 23.6% (Ada 20/2 weeks), 19.6% (Ada 20/week), 15.9% (Ada 40/2 weeks), 15.5% (Ada 40/week), 21.8% (placebo) Rhinitis 10.4% (Ada 20/2 weeks), 18.8% (Ada 20/week), 18.6% (Ada 40/2 weeks), 21.4% (Ada 40/week), 10.9% (placebo) Headache 20.8% (Ada 20/2 weeks), 17.9% (Ada 20/week), 21.2% (Ada 40/2 weeks), 20.4% (Ada 40/week), 10.0% (placebo) Rash 14.2% (Ada 20/2 weeks), 16.1% (Ada 20/week), 20.4% (Ada 40/2 weeks), 11.7% (Ada 40/week), 5.5% (placebo) Injection-site reactions 4.7% (Ada 20/2 weeks), 11.6% (Ada 20/week), 9.7% (Ada 40/2 weeks), 16.5% (Ada 40/week), 0.9% (placebo) Sore throat 13.2% (Ada 20/2 weeks), 3.6% (Ada 20/week), 9.7% (Ada 40/2 weeks), 4.9% (Ada 40/week), 6.4% (placebo) Back pain 8.5% (Ada 20/2 weeks), 3.6% (Ada 20/week), 6.2% (Ada 40/2 weeks), 12.6% (Ada 40/week), 3.6% (placebo) Gastrointestinal pain 12.3% (Ada 20/2 weeks), 4.5% (Ada 20/week), 4.4% (Ada 40/2 weeks), 2.9% (Ada 40/week), 4.5% (placebo) Pruritus 10.4% (Ada 20/2 weeks), 7.1% (Ada 20/week), 11.5% (Ada 40/2 weeks), 8.7% (Ada 40/week), 0.9% (placebo) Nausea 7.5% (Ada 20/2 weeks), 7.1% (Ada 20/week), 8.0% (Ada 40/2 weeks), 10.7% (Ada 40/week), 7.3% (placebo) Diarrhoea 5.7% (Ada 20/2 weeks), 6.3% (Ada 20/week), 7.1% (Ada 40/2 weeks), 2.9% (Ada 40/week), 10.0% (placebo)

Rheumatoid Arthritis: Adalimumab

PremierTrial

A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment PREMIER: Patients Receiving Methotrexate and Infliximab for the Treatment of Early Rheumatoid Arthritis

Substance

7.5 mg MTX/week + Placebo (increased to 20 mg/week until week 9, n = 268) MTX + 40 mg adalimumab (n = 274) Adalimumab monotherapy (n = 257) Concomitant medication: Folic acid 5–10 mg/week Corticosteroids were permitted, mean dose (mg/d) 6.7 (MTX + Ada), 6.7 (Ada), 6.4 (MTX) Previous medication: No prior MTX, Cyc, CsA, Aza or ³ 2 other DMARDs

Result

Clinical and radiological disease progression in recent onset RA patients was significantly reduced on combination treatment adalimumab and methotrexate vs. methotrexate monotherapy

Patients

799 early aggressive MTX naïve Disease duration of < 3a ³ 8 swollen joints ³ 10 tender joints ESR ³ 28 mm/h or CRP ³ 1.5 mg/dL Rheumatoid factor positive or have ³ 1 joint erosion

Authors

Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT

Publication

Arthritis Rheum. 2006 Jan;54(1):26–37

Follow up

2 years

ACR 20

Year 1: 63% (MTX), 73% (MTX + Ada), 54% (Ada) Year 2: 56% (MTX), 69% (MTX + Ada), 49% (Ada)

ACR 50

Year 1: 46% (MTX), 62% (MTX + Ada), 41% (Ada) Year 2: 43% (MTX), 59% (MTX + Ada), 37% (Ada)

ACR 70

Year 1: 28% (MTX), 46% (MTX + Ada), 26% (Ada) Year 2: 28% (MTX), 47% (MTX + Ada), 28% (Ada)

ACR 90

Year 1: 8% (MTX), 24% (MTX + Ada), 13% (Ada) Year 2: 13% (MTX), 27% (MTX + Ada), 9% (Ada)

165

166

Note

Rheumatoid Arthritis: Adalimumab

DAS < 2.6 Year 1: 21% (MTX), 43% (MTX + Ada), 23% (Ada) Year 2: 25% (MTX), 49% (MTX + Ada), 25% (Ada) Change of: Total Sharp score +10.4 (MTX), +1.9 (MTX + Ada), +5.5 (Ada) HAQ DI -0.9 (MTX), +1.0 (MTX + Ada), -0.9 (Ada)

Adverse events

Infectious adverse events 0.25/patientyear (MTX + Ada), 0.25/patientyear (Ada), 0.27/patientyear (MTX) Serious infections 0.006/patientyear (MTX + Ada), 0.0017/patientyear (Ada), 0.0037/patientyear (MTX) Tuberculosis 0.0042/patientyear (MTX + Ada), 0/patientyear (Ada), 0/patientyear (MTX) Malignancies 0.00083/patientyear (MTX + Ada), 0.0021/patientyear (Ada), 0.0021/patientyear (MTX) Lymphoma 0/patientyear (MTX + Ada), 0/patientyear (Ada), 0.00047/patientyear (MTX)

Rheumatoid Arthritis: Adalimumab

167

ARMADA-Trial Long term efficacy and safety of adalimumab plus Methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study, ARMADA. Anti–Tumor Necrosis Factor Research Study Program of the Monoclonal Antibody adalimumab (D2E7), in Rheumatoid Arthritis ARMADA: Anti–Tumor Necrosis Factor Research Study Program of the Monoclonal Antibody adalimumab in Rheumatoid Arthritis Substance

40 mg adalimumab dose in combination with MTX (n = 221 at 6 months, n = 147 at 48 months) After 6 months of: Adalimumab 20 mg/2 weeks (n = 69) Adalimumab 40 mg/2 weeks (n = 67) Adalimumab 80 mg/2 weeks (n = 73) Placebo (n = 62) Concomitant medication: 12.5–25 mg MTX/week was continued All other DMARDs were discontinued Prednisone £ 10 mg/day Folic acid or leucovorin was permitted No high potency opioid analgesics (e.g., methadone, hydromorphone, or morphine) NSAIDs were permitted Previous medication: 12.5–25 mg MTX/week £ 6 months ³ 1 DMARD besides MTX £ 4 DMARDs

Result

Combination therapy employing adalimumab and methotrexate sustained clinical response and remission in patients with RA during 4 years. Reduction of corticosteroid and/or MTX dosages did not adversely affect long term efficacy

Patients

271 RA patients Inadequate response to MTX (12.5–25 mg for 6 months) ³ 9 tender joints ³ 6 swollen joints (of 66 joints)

Authors

Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG

Publication

Ann Rheum Dis. 2006 Jun;65(6):753–759. Epub 2005 Nov 24

Follow up

4 years

ACR 20

78%

ACR 50

57%

ACR 70

31%

168

Note

Rheumatoid Arthritis: Adalimumab

Change of: Tender joint count (0–68 joints) -19.7 (-70.8%) Swollen joint count (0–66 joints) -12.3 (-60.7%) HAQ (0–3 scale) -0.7 (-52.1%) CRP (mg/l) -18 DAS28 -2.7 (-46.5%) No. of patients with (year 4): Tender joint count = 0: n = 42 (28%) Swollen joint count = 0: n = 33 (22%) CRP < 8 mg/l: n = 110 (74%) ACR 70: n = 46 (31%) DAS <2.6: n = 63 (43%) HAQ reduction ³ 0.22: n = 118 (81%) HAQ = 0: n = 31 (22%)

Adverse events

Serious infections 2.03 events/100 patient years Pneumonia 0.56 events/100 patient years Urinary tract infections 0.23 events/100 patient years Septic arthritis 0.11 events/100 patient years Tuberculosis 0.00 events/100 patient years Histoplasmosis 0.00 events/100 patient years Demyelinating diseases 0.11 events/100 patient years Lymphoma 0.00 events/100 patient years SLE/lupus-like syndrome 0.00 events/100 patient years Congestive heart failure 0.11 events/100 patient years Pancytopenia 0.00 events/100 patient years

Rheumatoid Arthritis: Adalimumab

ReAct-Trial

Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct), trial REACT: Research in Active Rheumatoid Arthritis

Substance

Adalimumab 40 mg every other week for 12 weeks Optional extension phase (Open label study)

169

Concomitant medication: DMARDs were continued Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Result

Adalimumab monotherapy or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult-to-treat patients with active RA

Authors

Burmester GR, Mariette X, Montecucco C, Monteagudo-Sáez I, Malaise M, Tzioufas AG, Bijlsma JW, Unnebrink K, Kary S, Kupper H

Publication

Ann Rheum Dis. 2007 Jun;66(6):732–739. Epub 2007 Feb 28

Follow up

12 weeks + 5 years open label extension

Patients

6610 patients with active RA Despite treatment with DMARDs or Prior treatment with a tumour necrosis factor antagonist DAS28 ³ 3.2

ACR 20

69% (all patients), 60% (no DMARDs), 72% (1 DMARD), 73% (2DMARDs), 73% (³ 3 DMARDs)

ACR 50

40% (all patients), 32% (no DMARDs), 43% (1 DMARD), 41% (2DMARDs), 42% (³ 3 DMARDs)

ACR 70

18% (all patients), 15% (no DMARDs), 19% (1 DMARD), 18% (2 DMARDs), 21% (³ 3 DMARDs)

Note

Moderate EULAR response 83% (all patients), 74% (no DMARDs), 85% (1 DMARD), 88% (2 DMARDs), 92% (³ 3 DMARDs) Good EULAR response 33% (all patients), 23% (no DMARDs), 37% (1 DMARD), 36% (2 DMARDs), 42% (³ 3 DMARDs) Change of: DAS -1.9 (no DMARDs), -2.2 (>1 DMARD), -2.2 (1 DMARD), -2.3 (2 DMARDs), -2.3 (>3 DMARDs) HAQ -0.47 (no DMARDs), -0.56 (>1 DMARD), -0.56 (1 DMARD), -0.56 (2 DMARDs), -0.56 (>3 DMARDs) Tender joint count -7.0 (no DMARDs), -8.0 (>1 DMARD), -8.0 (1 DMARD), -8.0 (2 DMARDs), -9.0 (>3 DMARDs) Swollen joint count -6.0 (no DMARDs), -6.0 (>1 DMARD), -6.0 (1 DMARD), -6.0 (2 DMARDs), -7.0 (>3 DMARDs) CRP (mg/l) -4.5 (no DMARDs), -5.7 (>1 DMARD), -5.5 (1 DMARD), -7.0 (2 DMARDs), -5.7 (>3 DMARDs)

170

Adverse events/100 patient years

Rheumatoid Arthritis: Adalimumab

All serious adverse events 40.0 (no DMARDs), 24.6 (Concomitant DMARDs) Blood and lymphatic system disorders 1.2 (no DMARDs), 0.3 (Concomitant DMARDs) Anaemia’s 0.9 (no DMARDs), 0.3 (Concomitant DMARDs) Cardiac disorders 1.9 (no DMARDs), 1.3 (Concomitant DMARDs) Heart failures 0.8 (no DMARDs), 0.3 (Concomitant DMARDs) Gastrointestinal disorders 1.8 (no DMARDs), 1.2 (Concomitant DMARDs), General disorders 1.9 (no DMARDs), 1.4 (Concomitant DMARDs) Hepatobiliary disorders 0.8 (no DMARDs), 0.3 (Concomitant DMARDs), Immune system disorders 0.4 (no DMARDs), 0.2 (Concomitant DMARDs), Allergic conditions 0.4 (no DMARDs), 0.2 (Concomitant DMARDs), Infections and infestations 6.6 (no DMARDs), 5.1 (Concomitant DMARDs), Lower respiratory tract and lung infections 1.2 (no DMARDs), 1.0 (Concomitant DMARDs) Abdominal and gastrointestinal infections 1.0 (no DMARDs 0.2 (Concomitant DMARDs) Sepsis, bacteraemia and viraemia 0.5 (no DMARDs), 0.4 (Concomitant DMARDs) Bone and joint 0.2 (no DMARDs), 0.1 (Concomitant DMARDs) Injury, poisoning and procedural complications 3.3 (no DMARDs), 1.7 (Concomitant DMARDs) Musculoskeletal and connective tissue disorders 11.0 (no DMARDs), 5.5 (Concomitant DMARDs) Joint disorders 8.5 (no DMARDs), 4.3 (Concomitant DMARDs) Neoplasm 1.3 (no DMARDs), 1.0 (Concomitant DMARDs) Malignancy 1.2 (no DMARD), 1.0 (Concomitant DMARDs) Nervous system disorders 1.7 (no DMARDs), 1.2 (Concomitant DMARDs) Renal and urinary disorders 0.6 (no DMARDs), 0.5 (Concomitant DMARDs) Reproductive system and breast disorders 0.8 (no DMARDs), 0.3 (Concomitant DMARDs) Respiratory, thoracic, and mediastinal disorders 1.3 (no DMARDs), 1.3 (Concomitant DMARDs) Parenchymal lung disorders (not elsewhere classified), 0.3 (no DMARDs), 0.2 (Concomitant DMARDs) Skin and subcutaneous tissue disorders 0.8 (no DMARDs), 0.4 (Concomitant DMARDs) Surgical and medical procedures 0.9 (no DMARDs), 1.1 (Concomitant DMARDs) Vascular disorders 1.0 (no DMARDs), 0.8 (Concomitant DMARDs)

Rheumatoid Arthritis: Adalimumab

171

CHANGE-Trial

Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study CHANGE: Clinical investigation in Highly disease Affected rheumatoid arthritis patients in Japan with Adalimumab applying staNdard and General Evaluation

Substance

Placebo (n = 87) Adalimumab 20 mg (n = 87) Adalimumab 40 mg (n = 91) Adalimumab 80 mg (n = 87) Concomitant medication: DMARDs were continued ³ 28 days Reliable contraceptive method After 8 weeks less than 10% reduction of tender joint count: Higher doses of steroids NSAIDs Conventional DMARDs Previous medication: DMARDs 91.5% Prednisolone 29.3% Diclophenac 10.8% Triamcinolone 8.5%

Result

adalimumab 40 mg monotherapy every other week was the appropriate dosage to treat RA in Japanese patients

Patients

342 active RA patients Failed treatment with at least one prior DMARD ³ 10 swollen joints ³ 12 tender joints CRP ³ 2 mg/dL

Authors

Miyasaka N; Taneichi K, Atsumi T, Takahashi H, Mukai M, Onishi K, Sasaki T, Izumiyama T, Hatakeyama A, Ota S, Sumida T, Nojima Y, Minoda S, Iwamoto I, Nakagawa N, Matsumura R, Mimura T, Takeuchi T, Kuroda T, Murasawa A, Hanyu T, Yamamoto K, Nanki T, Hirakata M, Hashimoto H, Yamaji K, Kamatani N, Ide H, Kasamatsu T, Sawada S, Yamada T, Inokuma S, Kuga Y, Yamagata H, Osone Y, Ozaki S, Hirose I, Nagaoka S, Nishikawa T, Toma S, Kondo H, Suzuki Y, Karahashi T, Tsuboi S, Wakitani S, Kanamono T, Sugiyama E, Nakazaki S, Sugimoto K, Tsuji T, Ishiguro N, Tsukamoto M, Yoshida S, Oguchi T, Fujii T, Kawahito Y, Tanaka T, Saeki Y, Kumagai S, Sano H, Matsubara T, Yamamura M, Yoshinaga Y, Okamoto A, Tani K, Nakata S, Takasugi K, Otsuka T, Nakajima H, Suematsu E, Fukuda T, Eguchi K, Saito K, Matsuda T, Kaul M, Nakabayashi K, Yoshizawa Y, Harada T, Yoshizawa Y, Miyake S, Inase N, Usui Y, Umino T, Sumi Y, Isogai S, Koyama N

Publication

Mod Rheumatol. 2008;18(3):252–262. Epub 2008 Mar 12

Follow up

24 weeks

ACR 20

13.8% (placebo), 28.7% (Ada 20), 44.0% (Ada 40), 50.6% (Ada 80)

ACR 50

5.7% (placebo), 16.1% (Ada 20), 24.2% (Ada 40), 32.2% (Ada 80)

ACR 70

1.1% (placebo), 10.3% (Ada 20), 12.1% (Ada 40), 14.9% (Ada 80)

172

Rheumatoid Arthritis: Adalimumab

Note

Change of: Tender joint count –0.5 (placebo), –6.6 (Ada 20), –10.7 (Ada 40), –10.0 (Ada 80) Swollen joint count –1.8 (placebo), –5.9 (Ada 20), –8.2 (Ada 40), –8.7 (Ada 80) Physician’s global assessment –8.0 (placebo), –20.1 (Ada 20), –30.3 (Ada 40), –31.0 (Ada 80) Patient’s global assessment +2.6 (placebo), –16.6 (Ada 20), –19.9 (Ada 40), –25.8 (Ada 80) Patient’s assessment of pain +3.5 (placebo), –12.8 (Ada 20), –17.4 (Ada 40), –20.3 (Ada 80) HAQ +0.1 (placebo), –0.2 (Ada 20), –0.2 (Ada 40), –0.4 (Ada 80) CRP (mg/dL) +0.1 (placebo), –0.5 (Ada 20), –1.6 (Ada 40), –2.3 (Ada 80)

Adverse events

Infectious AE 36.8% (placebo), 34.5% (Ada 20), 45.1% (Ada 40), 42.5% (Ada 80) Serious infectious AE 1.1% (placebo), 4.6% (Ada 20), 6.6% (Ada 40), 3.4% (Ada 80) Injection-site reaction 2.3% (placebo), 31.0% (Ada 20), 30.8% (Ada 40), 33.3% (Ada 80) Immunologic reaction 0.0% (placebo), 4.6% (Ada 20), 2.2% (Ada 40), 0.0% (Ada 80) Malignancies 2.3% (placebo), 0.0% (Ada 20), 0.0% (Ada 40), 0.0% (Ada 80) Opportunistic infection including TB 0.0% (placebo), 0.0% (Ada 20), 0.0% (Ada 40), 0.0% (Ada 80) AE leading to death 0.0% (placebo), 0.0% (Ada 20), 1.1% (Ada 40), 1.1% (Ada 80) AE leading to early withdrawal 4.6% (placebo), 5.7% (Ada 20), 13.2% (Ada 40 g), 3.4% (Ada 80) Probable or possibly related AEs 36.8% (placebo), 73.6% (Ada 20), 73.6% (Ada 40), 70.1% (Ada 80)

Rheumatoid Arthritis: Adalimumab

173

PREMIER-Trial

Less radiographic progression with adalimumab plus Methotrexate versus Methotrexate monotherapy across the spectrum of clinical response in early rheumatoid arthritis PREMIER: Patients Receiving Methotrexate and Infliximab for the Treatment of Early Rheumatoid Arthritis

Substance

Adalimumab 40 mg s.c. every other week MTX dosages were rapidly increased to £ 20 mg/week Stable dosages of NSAIDs Prednisone £ 10 mg of per day (n = 799) After 2 years of: 7.5 mg MTX/week + placebo (increased to 20 mg/week until week 9, n = 216) MTX + 40 mg adalimumab (n = 240) Adalimumab monotherapy (n = 222) Concomitant medication: Folic acid 5–10 mg/week Corticosteroids were permitted, mean dose (mg/d): 6.7 (MTX + Ada), 6.7 (Ada), 6.4 (MTX) Previous medication: No prior MTX, Cyc, CsA, Aza or ³ 2 other DMARDs

Result

In patients with early RA, adalimumab plus methotrexate resulted in less radiographic and clinical progression than methotrexate monotherapy

Patients

799 early aggressive MTX naive, disease duration of < 3a ³ 8 swollen joints ³ 10 tender joints ESR ³ 28 mm/h or CRP ³ 1.5 mg/dL Rheumatoid factor positive or have ³ 1 joint erosion

Authors

Emery P, Genovese MC, van Vollenhoven R, Sharp JT, Patra K, Sasso EH

Publication

J Rheumatol. 2009 Jul;36(7):1429–1441. Epub 2009 Apr 15

Follow up

104 weeks

Note

Patients with radiological progression (Change in TSS > 0.5) Patients with < ACR20 38% (Ada + MTX), 53% (Ada), 75% (MTX) Patients with ACR20 33% (Ada + MTX), 53% (Ada), 62% (MTX) Patients with ACR50 31% (Ada + MTX), 53% (Ada), 60% (MTX) Patients with ACR70 28% (Ada + MTX), 53% (Ada), 57% (MTX) Patients with tender joint count = 0 32% (Ada + MTX), 47% (Ada), 59% (MTX) Patients with DAS28 > 2.6 33% (Ada + MTX), 39% (Ada), 53% (MTX) Patients with swollen joint count = 0 34% (Ada + MTX), 37% (Ada), 44% (MTX) Patients with ACR100 32% (Ada + MTX), 0% (Ada), 46% (MTX)

174

Rheumatoid Arthritis: Adalimumab

GUEPARD -Trial Evaluation of two strategies (initial Methotrexate monotherapy vs. its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. GUEPARD: GUérir la PolyArthrite Rhumatoide De’butante (cure early RA) Substance

Group 1: 0.3 mg/kg MTX monotherapy/week (maximum of 20 mg/week) DAS 28 > 3.2 after 12 weeks MTX + 40 mg adalimumab/2 weeks DAS 28 > 3.2 after 24 weeks MTX + 2 × 25 mg Etanercept/week DAS 28 > 3.2 after 36 weeks MTX + Leflunomide DAS 28 < 2.6 ³ 6 months MTX was tapered (2.5 mg/month) to 7.5 mg/week Flair: Reintroduction of initial MTX dose Group 2: 0.3 mg/kg MTX/week (maximum of 20 mg/week) + 40 mg adalimumab/2 weeks DAS 28 > 3.2 after 12 weeks MTX + 40 mg adalimumab/1 week DAS 28 > 3.2 after 24 weeks MTX + 2 × 25 mg Etanercept/week DAS 28 > 3.2 after 36 weeks MTX + Leflunomide DAS 28 < 3.2 (week 12) adalimumab was stopped DAS 28 < 2.6 ³ 6 months MTX was tapered (2.5 mg/month) to 7.5 mg/week Flair: Reintroduction of initial MTX dose Concomitant medication: NSAIDs were permitted Single i.a. steroid injection was allowed Folic acid (20 mg 72 h after MTX therapy) Prednisone £ 10 mg/day Previous medication: No prior MTX No prior biologic therapy

Result

Initial combination of methotrexate and adalimumab, followed by a continuous disease activity status-triggered therapeutic adjustment, achieved a faster control of disease activity. It did not increase the number of patients for whom anti-TNF-alpha treatment was not needed after 12 weeks. No improved clinical or radiological outcome was found in patients with a 3-month delayed initiation of anti-TNF

Patients

65 early and active RA Not prior treated with MTX or biologics Disease duration < 6 months DAS28 > 5.1

Authors

Soubrier M, Puéchal X, Sibilia J, Mariette X, Meyer O, Combe B, Flipo RM, Mulleman D, Berenbaum F, Zarnitsky C, Schaeverbeke T, Fardellone P, Dougados M

Publication

Rheumatology (Oxford). 2009 Nov;48(11):1429–1434. Epub 2009 Sep 9

Follow up

52 weeks

Rheumatoid Arthritis: Adalimumab

175

ACR 20

Week 12: 50% (MTX) 84% (Ada + MTX) Week 52: 81% (MTX) 85% (Ada + MTX)

ACR 50

Week 12: 27% (MTX) 66% (Ada + MTX) Week 52: 68% (MTX) 67% (Ada + MTX)

ACR 70

Week 12: 19% (MTX) 44% (Ada + MTX) Week 52: 58% (MTX) 42% (Ada + MTX)

Note

Week 12 Good EULAR response 25% (MTX) 63.6% (Ada + MTX) EULAR response (low diseases activity) 25% (MTX) 63.6% (Ada + MTX) EULAR response (Remission) 12.5% (MTX) 36.4% (Ada + MTX) HAQ -0.51 (MTX) -0.30 (Ada + MTX) Week 52 Good EULAR response 65.6% (MTX) 63.6% (Ada + MTX) EULAR response (low diseases activity) 65.6% (MTX) 63.6% (Ada + MTX) EULAR response (Remission) 59.4% (MTX) 39.4% (Ada + MTX) Modified Sharp score from baseline was 1.8 (MTX) 1.9 (Ada + MTX) HAQ -0.93 (MTX) -1.02 (Ada + MTX)

Adverse events

Ovarian carcinoma n = 0 (MTX) n = 1 (Ada + MTX) Pancreatic cancer n = 0 (MTX) n = 1 (Ada + MTX) Hepatitis n = 1 (MTX) n = 1 (Ada + MTX) MTX pneumonia n = 0 (MTX) n = 1 (Ada + MTX) Acoustic neuroma n = 0 (MTX) n = 1 (Ada + MTX) Vasculitis, revision of diagnosis to Sharp syndrome (Week 6) Hip prosthesis operation n = 1 (MTX) n = 0 (Ada + MTX) Weight loss n = 1 (MTX) n = 0 (Ada + MTX) Haemoptysis n = 1 (MTX) n = 0 (Ada + MTX)

176

Rheumatoid Arthritis: Anakinra

Trial

Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist

Substance

Placebo (n = 121) Anakinra 30 mg/day (n = 119) Anakinra 75 mg/day (n = 116) Anakinra 150 mg/day (n = 116) Concomitant medication: Prednisolone £ 10 mg/day NSAIDs were permitted No DMARDs £ 6 weeks Previous medication: DMARDs were discontinued at least 6 weeks No prior treatment chlorambucil + CYC, chlorambucil, or any monoclonal antibodies

Result

IL-1R antagonist treatment of active and severe RA patients was effective and safe. It had a beneficial effect on the rate of joint erosion

Patients

472 RA patients with active disease Symptoms of RA for > 6 months and < 8 years Swollen joint count ³ 10 Or ³ 3 of the following 4 criteria: Tender or painful joints ³ 10 Disease activity graded as severe by the patient Disease activity graded as severe by the physician CRP > 1.5 mg/dL

Authors

Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, Nuki G, Pavelka K, Rau R, Rozman B, Watt I, Williams B, Aitchison R, McCabe D, Musikic P

Publication

Arthritis Rheum. 1998 Dec;41(12):2196–2204

Follow up

24 weeks

Rheumatoid Arthritis: Anakinra

Note

ACR Response 27% (placebo), 39% (30 mg anakinra), 34% (75 mg anakinra), 43% (150 mg anakinra) Paulus 21% (placebo), 39% (30 mg anakinra), 37% (75 mg anakinra), 44% (150 mg anakinra) Withdrawal because of efficacy n = 24 (placebo), n = 16 (30 mg anakinra), n = 14 (75 mg anakinra), n = 11 (150 mg anakinra) Change of: No. of painful joints –5.7 (placebo), –7.9 (30 mg anakinra), –6.7 (75 mg anakinra), –9.5 (150 mg anakinra) No. of tender joints –5.2 (placebo), –8.6 (30 mg anakinra), –9.3 (75 mg anakinra), –11.9 (150 mg anakinra) Investigator’s assessment of disease activity –0.6 (placebo), –0.9 (30 mg anakinra), –0.9 (75 mg anakinra), –1.0 (150 mg anakinra) Patient’s assessment of disease activity –0.5 (placebo), –0.7 (30 mg anakinra), –0.8 (75 mg anakinra), +0.9 (150 mg anakinra) Pain (VAS 0–1 cm) –0.05 (placebo), –0.13 (30 mg anakinra), –0.12 (75 mg anakinra), –0.17 (150 mg anakinra) HAQ score 0 (placebo), –0.2 (30 mg anakinra), –0.2 (75 mg anakinra), –0.3 (150 mg anakinra) Duration of morning stiffness (min) -14.1 (placebo), –36.1 (30 mg anakinra), –54.8 (75 mg anakinra), –48.0 (150 mg anakinra) ESR (mm/h) +0.9 (placebo), –9.1 (30 mg anakinra), –7.9 (75 mg anakinra), –10.3 (150 mg anakinra) CRP (mg/dL) –0.4 (placebo), –1.3 (30 mg anakinra), –1.0 (75 mg anakinra), –1.0 (150 mg anakinra) Larsen score +6.4 (placebo), +3.6 (30 mg anakinra), +3.9 (75 mg anakinra), +4.0 (150 mg anakinra) Erosive joint count +2.6 (placebo), +1.5 (30 mg anakinra), 1.0 (75 mg anakinra), +1.7 (150 mg anakinra)

Adverse events

177

Injection-site reactions 2% (placebo), <1% (30 mg anakinra), 3% (75 mg anakinra), 5% (150 mg anakinra) Neutropenia 0% (placebo), <1% (30 mg anakinra), 0% (75 mg anakinra), 2% (150 mg anakinra) Neoplasm 0% (placebo), <1% (30 mg anakinra), 0% (75 mg anakinra), <1% (150 mg anakinra) Infections <1% (placebo), <1% (30 mg anakinra), 0% (75 mg anakinra), 2% (150 mg anakinra) Isolated events 3% (placebo), 2% (30 mg anakinra), 4% (75 mg anakinra), 2% (150 mg anakinra)

178

Rheumatoid Arthritis: Anakinra

Trial

A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores

Substance

Placebo (n = 121) Anakinra 30 mg/day (n = 119) Anakinra 75 mg/day (n = 116) Anakinra 150 mg/day (n = 116) Concomitant medication: Prednisolone £ 10 mg/day NSAIDs were permitted Previous medication: DMARDs were discontinued at least 6 weeks No patients who failed to ³ 3 DMARDs

Result

IL-1Ra reduced radiologic progression of RA

Patients

472 RA patients Symptoms of RA for 0.5–8.0 years ³ 10 or more swollen joints 2 of the following 3 criteria: ³ 10 or more tender or painful joints Disease activity graded by the physician as severe or very severe CRP > 1.5 mg/dL

Authors

Jiang Y, Genant HK, Watt I, Cobby M, Bresnihan B, Aitchison R, McCabe D

Publication

Arthritis Rheum. 2000 May;43(5):1001–1009

Follow up

24 weeks

Note

Change of Genant score: Erosions +1.86 (placebo), +1.03 (anakinra 30 mg), +1.26 (anakinra 75 mg), +1.16 (anakinra 150 mg) Joint space narrowing +1.65 (placebo), +0.79 (anakinra 30 mg), +0.57 (anakinra 75 mg), +0.67 (anakinra 150 mg) Change of Larsen score: Total score +6.32 (placebo), +3.61 (anakinra 30 mg), +3.83 (anakinra 75 mg), +3.94 (anakinra 150 mg) Larsen erosive joint count +2.60 (placebo), +1.46 (anakinra 30 mg), +1.03 (anakinra 75 mg), +1.70 (anakinra 150 mg)

Rheumatoid Arthritis: Anakinra

Trial

Treatment of rheumatoid arthritis with Anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with Methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial

Substance

Anakinra 2.0 mg/kg/day (n = 72) Anakinra 1.0 mg/kg/day (n = 59) Anakinra 0.4 mg/kg/day (n = 77) Anakinra 0.1 mg/kg/day (n = 74) Anakinra 0.04 mg/kg/day (n = 63) Placebo (n = 74)

179

Concomitant medication: 15–25 MTX mg/week Prednisone £ 10 mg/day NSAIDs were permitted Previous medication: Despite MTX therapy (15–25 mg/week) ³ 6 weeks No penicillamine, gold, Aza, or CsA £12 weeks No HCQ, SSZ £ 8 weeks Result

Treatment of patients with persistently active RA with the combination of anakinra and methotrexate was safe, well tolerated and provided significantly greater clinical benefit than methotrexate monotherapy

Patients

419 RA patients with active disease Despite MTX therapy (15–25 mg/week) ³ 6 weeks ³ 6 swollen joints At least 2 of the following: ³ 9 tender or painful joints Morning stiffness ³ 45 min CRP ³ 1.5 mg/dL

Authors

Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, Kremer J, Bear MB, Rich WJ, McCabe D

Publication

Arthritis Rheum. 2002 Mar;46(3):614–624

Follow up

24 weeks

ACR 20

Week 12: 46% (Anakinra 1 mg/kg), 38% (Anakinra 2 mg/kg), 19% (placebo) Week 24: 42% (Anakinra 1 mg/kg), 35% (Anakinra 2 mg/kg), 23% (placebo)

ACR 50

Week 12: 19% (Anakinra 1 mg/kg), 24% (Anakinra 2 mg/kg), 4% (placebo) Week 24: 24% (Anakinra 1 mg/kg), 17% (Anakinra 2 mg/kg), 4% (placebo)

ACR 70

Week 12: 5% (Anakinra 1 mg/kg), 11% (Anakinra 2 mg/kg), 0% (placebo) Week 24: 10% (Anakinra 1 mg/kg), 7% (Anakinra 2 mg/kg), 0% (placebo)

180

Rheumatoid Arthritis: Anakinra

Note

Change of: Swollen joint count -4.17 (placebo), -6.30 (anakinra 1 mg/kg), -7.61 (anakinra 2 mg/kg) Tender or painful joint count -8.28 (placebo), -8.83 (anakinra 1 mg/kg), -11.18 (anakinra 2 mg/kg) Physician’s global assessment -14.08 (placebo), -22.34 (anakinra 1 mg/kg), -24.46 (anakinra 2 mg/kg) Patient’s assessment of pain -2.58 (placebo), -12.90 (anakinra 1 mg/kg), -22.78 (anakinra 2 mg/kg) HAQ -0.15 (placebo), -0.37 (anakinra 1 mg/kg), -0.51 (anakinra 2 mg/kg) CRP (mg/l) -0.19 (placebo), -0.77 (anakinra 1 mg/kg), -0.77 (anakinra 2 mg/kg) ESR (mm/h) -4.15 (placebo), -12.36 (anakinra 1 mg/kg), -14.45 (anakinra 2 mg/kg) Duration of morning stiffness (min) -49.56 (placebo), -74.24 (anakinra 1 mg/kg), -81.48 (anakinra 2 mg/kg)

Adverse events

Injection-site reactions 2.7% (placebo), 6.8% (anakinra 1 mg/kg), 9.7% (anakinra 2 mg/kg) Hematologic 0% (placebo), 1.7% (anakinra 1 mg/kg), 1.4% (anakinra 2 mg/kg) Respiratory 1.4% (placebo), 1.7% (anakinra 1 mg/kg), 0% (anakinra 2 mg/kg) Chest pain 0% (placebo), 1.7% (anakinra 1 mg/kg), 1.4% (anakinra 2 mg/kg)

Rheumatoid Arthritis: Anakinra

Trial

Long-term safety and maintenance of clinical improvement following treatment with Anakinra (recombinant human interleukin-1 receptor antagonist), in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial

Substance

24 weeks of: Placebo (n = 121) Anakinra 30 mg/day (n = 119) Anakinra 75 mg/day (n = 116) Anakinra 150 mg/day (n = 116) Extension phase: Placebo => anakinra 30 mg/day (n = 30, n = 21 completed) Placebo => anakinra 75 mg/day (n = 24, n = 17 completed) Placebo => anakinra 150 mg/day (n = 22, n = 17 completed) Anakinra 30 mg/day => anakinra 30 mg/day (n = 81, n = 61 completed) Anakinra 75 mg/day => anakinra 75 mg/day (n = 79, n = 53 completed) Anakinra 150 mg/day => anakinra 150 mg/day (n = 73, n = 49 completed) Concomitant medication: Prednisolone £ 10 mg/day NSAIDs were permitted No DMARDs £ 6 weeks Previous medication: DMARDs were discontinued at least 6 weeks No prior treatment with CYC, chlorambucil, or monoclonal antibodies

Result

The clinical benefits of anakinra in active RA patients were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks

Patients

472 patients with active RA 345 patients who completed the placebo-controlled phase of the study 309 continued in a 52-week follow up

Authors

Nuki G, Bresnihan B, Bear MB, McCabe D; European Group Of Clinical Investigators

Publication

Arthritis Rheum. 2002 Nov;46(11):2838–2846

Follow up

24 weeks + 52 weeks extension phase

ACR 20

Placebo => anakinra 51% (all doses), 47% (anakinra 30 mg), 46% (anakinra 75 mg), 64% (anakinra 150 mg) anakinra => anakinra 46% (all doses), 41% (anakinra 30 mg), 51% (anakinra 75 mg), 47% (anakinra 150 mg)

ACR 50

18% (Placebo => anakinra), 20% (anakinra => anakinra)

ACR 70

3% (Placebo => anakinra), 1% (anakinra => anakinra)

181

182

Rheumatoid Arthritis: Anakinra

Note

Change of: No. of swollen joints Placebo => anakinra –4.1 (all doses), –3.2 (anakinra 30 mg), –5.0 (anakinra 75 mg), –4.4 (anakinra 150 mg), anakinra => anakinra –0.9 (all doses), –0.3 (anakinra 30 mg), –1.3 (anakinra 75 mg), –0.9 (anakinra 150 mg) No. of tender joints Placebo => anakinra –5.6 (all doses), –5.2 (anakinra 30 mg), –6.1 (anakinra 75 mg), –5.5 (anakinra 150 mg), anakinra => anakinra –0.2 (all doses), –0.3 (anakinra 30 mg), –1.2 (anakinra 75 mg), +1.0 (anakinra 150 mg) Patient global assessment Placebo => anakinra –0.3 (all doses), –0.2 (anakinra 30 mg), –0.3 (anakinra 75 mg), –0.3 (anakinra 150 mg), anakinra => anakinra +0.1 (all doses), +0.1 (anakinra 30 mg), 0.0 (anakinra 75 mg), +0.2 (anakinra 150 mg) Investigator assessment Placebo => anakinra –0.3 (all doses), –0.4 (anakinra 30 mg), –0.3 (anakinra 75 mg), –0.2 (anakinra 150 mg), anakinra => anakinra 0.0 (all doses), 0.0 (anakinra 30 mg), 0.0 (anakinra 75 mg), +0.1 (anakinra 150 mg) Pain assessment Placebo => anakinra –0.09 (all doses), –0.08 (anakinra 30 mg), –0.07 (anakinra 75 mg), –0.12 (anakinra 150 mg), anakinra => anakinra +0.03 (all doses), +0.04 (anakinra 30 mg), –0.01 (anakinra 75 mg), –0.07 (anakinra 150 mg) HAQ Placebo => anakinra –0.26 (all doses), –0.33 (anakinra 30 mg), –0.11 (anakinra 75 mg), –0.35 (anakinra 150 mg), anakinra => anakinra +0.06 (all doses), +0.08 (anakinra 30 mg), –0.01 (anakinra 75 mg), +0.1 (anakinra 150 mg) CRP (mg/dL) Placebo => anakinra –1.0 (all doses), –1.2 (anakinra 30 mg), –0.8 (anakinra 75 mg), –1.1 (anakinra 150 mg), anakinra => anakinra –0.02 (all doses), –0.02 (anakinra 30 mg), –0.07 (anakinra 75 mg), –0.01 (anakinra 150 mg) ESR (mm/h) Placebo => anakinra –11.9 (all doses), –11.9 (anakinra 30 mg), –15.0 (anakinra 75 mg), –8.2 (anakinra 150 mg), anakinra => anakinra –1.7 (all doses), –1.3 (anakinra 30 mg), –3.2 (anakinra 75 mg), –0.5 (anakinra 150 mg)

Adverse events

Injection-site reaction 0.82/year (placebo), 1.01/year (anakinra 30 mg), 2.43/year (anakinra 75 mg), 3.73/year (anakinra 150 mg) Rheumatoid arthritis flare 1.05/year (placebo), 0.49/year (anakinra 30 mg), 0.43/year (anakinra 75 mg), 0.38/year (anakinra 150 mg) arthralgia 0.37/year (placebo), 0.21/year (anakinra 30 mg), 0.15/year (anakinra 75 mg), 0.15/year (anakinra 150 mg) Abdominal pain 0.14/year (placebo), 0.19/year (anakinra 30 mg), 0.12/year (anakinra 75 mg), 0.19/year (anakinra 150 mg) arthritis 0.05/year (placebo), 0.10/year (anakinra 30 mg), 0.13/year (anakinra 75 mg), 0.16/year (anakinra 150 mg) Influenza-like symptoms 0.19/year (placebo), 0.09/year (anakinra 30 mg), 0.19/year (anakinra 75 mg), 0.11/year (anakinra 150 mg) Upper respiratory 0.19/year (placebo), 0.10/year (anakinra 30 mg), 0.13/year (anakinra 75 mg), 0.15/year (anakinra 150 mg) Pruritus 0.14/year (placebo), 0.09/year (anakinra 30 mg), 0.10/year (anakinra 75 mg), 0.07/year (anakinra 150 mg) Diarrhoea 0.14/year (placebo), 0.09/year (anakinra 30 mg), 0.10/year (anakinra 75 mg), 0.05/year (anakinra 150 mg) Rhinitis 0.07/year (placebo), 0.08/year (anakinra 30 mg), 0.10/year (anakinra 75 mg), 0.07/year (anakinra 150 mg)

Rheumatoid Arthritis: Anakinra

183

Trial

Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial

Substance

100 mg Anakinra/day (n = 1116) Placebo (n = 283) Concomitant medication: DMARDs were permitted, stable dose ³ 2 months Combination therapy of DMARDs was permitted Corticosteroids were permitted, stable dose ³ 1 month NSAIDs were permitted, stable dose ³ 1 month No TNF antagonists

Result

Anakinra was safe and well tolerated in a diverse population of patients with RA with single and multiple comorbid conditions or concomitant therapies. The frequency of serious infection was slightly higher in the anakinra group. no infection was attributed to opportunistic microorganisms or resulted in death

Patients

RA patients with active disease Disease duration ³ 3 months ³ 3 swollen joints ³ 3 tender or painful joints ³ 45 min of morning stiffness

Authors

Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, Modafferi D, Poulakos J, Sun G

Publication

Arthritis Rheum. 2003 Apr;48(4):927–934

Follow up

6 months + 30 months open label phase

Adverse events

Overall adverse events 92.2% (placebo), 92.0% (anakinra) Death 0.4% (placebo), 0.4% (anakinra) Serious adverse events 7.8% (placebo), 7.7% (anakinra) Severe adverse events 13.1% (placebo), 15.5% (anakinra) Withdrawal due to adverse event 9.2% (placebo) 13.4% (anakinra) Infectious episode 43.5% (placebo), 41.2% (anakinra) Serious infection 0.4% (placebo), 2.1% (anakinra) Malignancies n = 5 (placebo), n = 4 (anakinra)

184

Rheumatoid Arthritis: Anakinra

Trial

The safety of Anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions

Substance

Anakinra (100 mg, n = 1116) Placebo (n = 283) Concomitant medication: DMARDs were permitted, stable dose ³ 2 months Combination therapy of DMARDs was permitted Corticosteroids were permitted, stable dose ³ 1 month NSAIDs were permitted, stable dose ³ 1 month No TNF antagonists

Result

Treatment with anakinra of patients with active RA and coexisting comorbidities demonstrated a favourable safety profile

Patients

1,414 patients with active RA with active disease Disease duration ³ 3 months ³ 3 swollen joints ³ 3 tender or painful joints Morning stiffness lasting ³ 45 min

Authors

Schiff MH, DiVittorio G, Tesser J, Fleischmann R, Schechtman J, Hartman S, Liu T, Solinger AM

Publication

Arthritis Rheum. 2004 Jun;50(6):1752–1760

Follow up

6 months

Adverse events

At least 1 adverse event 93.4% (placebo, comorbidity), 93.4% (anakinra, comorbidity), 89.7% (placebo, no comorbidity), 89.2% (anakinra, no comorbidity) Injection-site reaction 29.6% (placebo, comorbidity), 72.5% (anakinra, comorbidity), 40.2% (placebo, no comorbidity), 72.9% (anakinra, no comorbidity) Rheumatoid arthritis symptoms 29.6% (placebo, comorbidity), 20.3% (anakinra, comorbidity), 23.0% (placebo, no comorbidity), 19.4% (anakinra, no comorbidity) Upper respiratory tract infection 19.9% (placebo, comorbidity), 14.6% (anakinra, comorbidity), 17.2% (placebo, no comorbidity), 13.9% (anakinra, no comorbidity) Headache 9.7% (placebo, comorbidity), 14.4% (anakinra, comorbidity), 16.1% (placebo, no comorbidity), 14.4% (anakinra, no comorbidity) Nausea 8.2% (placebo, comorbidity), 10.5% (anakinra, comorbidity), 8.0% (placebo, no comorbidity), 6.9% (anakinra, no comorbidity) Sinusitis 8.7% (placebo, comorbidity), 7.9% (anakinra, comorbidity), 4.6% (placebo, no comorbidity), 6.6% (anakinra, no comorbidity) Diarrhoea 6.6% (placebo, comorbidity), 7.7% (anakinra, comorbidity), 4.6% (placebo, no comorbidity), 7.2% (anakinra, no comorbidity) Influenza-like symptoms 5.6% (placebo, comorbidity), 5.6% (anakinra, comorbidity), 8.0% (placebo, no comorbidity), 8.3% (anakinra, no comorbidity) Arthralgia 5.6% (placebo, comorbidity), 4.6% (anakinra, comorbidity), 6.9% (placebo, no comorbidity), 5.8% (anakinra, no comorbidity) Abdominal pain 6.1% (placebo, comorbidity), 5.4% (anakinra, comorbidity), 4.6% (placebo, no comorbidity), 6.1% (anakinra, no comorbidity) Dizziness 6.1% (placebo, comorbidity), 5.6% (anakinra, comorbidity), 5.7% (placebo, no comorbidity), 4.2% (anakinra, no comorbidity)

Rheumatoid Arthritis: Anakinra

185

Urinary tract infection 4.6% (placebo, comorbidity), 4 9% (anakinra, comorbidity), 6.9% (placebo, no comorbidity), 4.2% (anakinra, no comorbidity) Indigestion 5.1% (placebo, comorbidity), 5.0% (anakinra, comorbidity), 2.3% (placebo, no comorbidity), 3.9% (anakinra, no comorbidity) Rash, not isolated to Injection-site 6.1% (placebo, comorbidity), 4.2% (anakinra, comorbidity), 4.6% (placebo, no comorbidity), 3.0% (anakinra, no comorbidity) At least 1 serious adverse event 8.7% (placebo, comorbidity), 8.6% (anakinra, comorbidity), 5.7% (placebo, no comorbidity), 5.8% (anakinra, no comorbidity) Rheumatoid arthritis symptoms 2.6% (placebo, comorbidity), 0.9% (anakinra, comorbidity), 0.0% (placebo, no comorbidity), 0.8% (anakinra, no comorbidity) Chest pain 1.0% (placebo, comorbidity), 0.1% (anakinra, comorbidity), 0% (placebo, no comorbidity), 0.3% (anakinra, no comorbidity) Pneumonia 0% (placebo, comorbidity), 0.9% (anakinra, comorbidity), 0% (placebo, no comorbidity), 0% (anakinra, no comorbidity) Abdominal pain 0% (placebo, comorbidity), 0.3% (anakinra, comorbidity), 0% (placebo, no comorbidity), 0.6% (anakinra, no comorbidity) Fracture 0.5% (placebo, comorbidity), 0.3% (anakinra, comorbidity), 0% (placebo, no comorbidity), 0.6% (anakinra, no comorbidity) Hypertension 0.5% (placebo, comorbidity), 0.4% (anakinra, comorbidity), 0.0% (placebo, no comorbidity), 0.0% (anakinra, no comorbidity) At least 1 infectious event 45.4% (placebo, comorbidity), 42.4% (anakinra, comorbidity), 39.1% (placebo, no comorbidity), 38.8% (anakinra, no comorbidity) Upper respiratory tract infection 19.4% (placebo, comorbidity), 13.6% (anakinra, comorbidity), 16.1% (placebo, no comorbidity), 12.5% (anakinra, no comorbidity) Sinusitis 6.6% (placebo, comorbidity), 7.2% (anakinra, comorbidity), 4.6% (placebo, no comorbidity), 5.8% (anakinra, no comorbidity) Influenza-like symptoms 5.6% (placebo, comorbidity), 5.2% (anakinra, comorbidity), 8.0% (placebo, no comorbidity), 7.2% (anakinra, no comorbidity) Urinary tract infection 4.6% (placebo, comorbidity), 4.8% (anakinra, comorbidity), 6.9% (placebo, no comorbidity), 4.2% (anakinra, no comorbidity) Bronchitis 4.6% (placebo, comorbidity), 4.1% (anakinra, comorbidity), 4.6% (placebo, no comorbidity), 1.9% (anakinra, no comorbidity) Infection, anatomic location unspecified 4.1% (placebo, comorbidity), 2.9% (anakinra, comorbidity), 1.1% (placebo, no comorbidity), 2.8% (anakinra, no comorbidity) At least 1 serious infectious event 0.0% (placebo, comorbidity), 2.5% (anakinra, comorbidity), 1.1% (placebo, no comorbidity), 1.1% (anakinra, no comorbidity) Pneumonia 0.0% (placebo, comorbidity), 1.1% (anakinra, comorbidity), 0.0% (placebo, no comorbidity), 0.3% (anakinra, no comorbidity) Unspecified infection, resistance mechanism 0.0% (placebo, comorbidity), 0.4% (anakinra, comorbidity), 0.0% (placebo, no comorbidity), 0.0% (anakinra, no comorbidity) Cellulitis 0.0% (placebo, comorbidity), 0.4% (anakinra, comorbidity), 0.0% (placebo, no comorbidity), 0.0% (anakinra, no comorbidity) Osteomyelitis 0.0% (placebo, comorbidity), 0.1% (anakinra, comorbidity), 0.0% (placebo, no comorbidity), 0.3% (anakinra, no comorbidity)

186

Rheumatoid Arthritis: Anakinra

Trial

Effects of Anakinra monotherapy on joint damage in patients with rheumatoid arthritis. Extension of a 24-week randomized, placebo-controlled trial

Substance

24 weeks of: Placebo (n = 121) Anakinra 30 mg/day (n = 119) Anakinra 75 mg/day (n = 116) Anakinra 150 mg/day (n = 116) Extension phase: Placebo => anakinra 30 mg/day (n = 30, n = 21 completed) Placebo => anakinra 75 mg/day (n = 24, n = 17 completed) Placebo => anakinra 150 mg/day (n = 22, n = 17 completed) Anakinra 30 mg/day => anakinra 30 mg/day (n = 81, n = 61 completed) Anakinra 75 mg/day => anakinra 75 mg/day (n = 79, n = 53 completed) Anakinra 150 mg/day => anakinra 150 mg/day (n = 73, n = 49 completed) Concomitant medication: Prednisolone £ 10 mg/day NSAIDs were permitted No DMARDs £ 6 weeks Previous medication: DMARDs were discontinued at least 6 weeks No prior treatment with CYC, chlorambucil, or monoclonal antibodies

Result

Anakinra treatment of RA patients for 48 weeks demonstrated significant slowing of radiographic joint damage. The treatment effect observed after a 24-week period increased when anakinra was continued for 48 weeks

Patients

473 RA patients Symptoms of RA for 0.5–8.0 years and active disease ³ 10 or more swollen joints 2 of the following 3 criteria: ³ 10 or more tender or painful joints Disease activity graded by the physician as severe or very severe CRP > 1.5 mg/dL

Authors

Bresnihan B, Newmark R, Robbins S, Genant HK

Publication

J Rheumatol. 2004 Jun;31(6):1103–1111

Follow up

48 weeks

Note

Change of (second 24 weeks): Modified Sharp Score placebo => anakinra -1.46 (30 mg anakinra), -1.13 (75 mg anakinra), -3.81 (150 mg anakinra), anakinra => anakinra -0.13 (30 mg anakinra), -1.00 (75 mg anakinra), -0.93 (150 mg anakinra) Modified Sharp Erosion Score placebo => anakinra –0.67 (30 mg anakinra), -0.82 (75 mg anakinra), -1.93 (150 mg anakinra), anakinra => anakinra -0.29 (30 mg anakinra), -0.96 (75 mg anakinra), -0.78 (150 mg anakinra) Modified Sharp Joint Narrowing Score placebo => anakinra –0.78 (30 mg anakinra), -0.31 (75 mg anakinra), -1.87 (150 mg anakinra), anakinra => anakinra +0.16 (30 mg anakinra), -0.04 (75 mg anakinra), -0.15 (150 mg anakinra)

Rheumatoid Arthritis: Anakinra

Trial

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

Substance

100 mg Anakinra/day s.c. (n = 250) Placebo (n = 251)

187

Concomitant medication: With background MTX Prednisone £ 10 mg/day NSAIDs were permitted Previous medication: Stable dose of MTX (10–25 mg/week or 25–50 mg/2 weeks) stable ³ 24 consecutive weeks Result

Anakinra in combination with methotrexate was an effective and safe treatment for RA patients who have inadequate responses to methotrexate monotherapy

Patients

506 Patients with active RA Disease duration ³ 24 weeks Radiographic evidence of bone ³ 6 swollen joints ³ 9 tender or painful joints CRP ³ 15 mg/l ESR ³ 28 mm/h

Authors

Cohen SB, Moreland LW, Cush JJ, Greenwald MW, Block S, Shergy WJ, Hanrahan PS, Kraishi MM, Patel A, Sun G, Bear MB; 990145 Study Group

Publication

Ann Rheum Dis. 2004 Sep;63(9):1062–1068. Epub 2004 Apr 13

Follow up

24 weeks

ACR 20

38% (anakinra), 22% (placebo)

ACR 50

17% (anakinra), 8% (placebo)

ACR 70

6% (anakinra), 2% (placebo)

Note

Change of: Swollen joint count (0–66) -6.8 (anakinra), -6.5 (placebo) Tender or painful joint count (0–68) -12.0 (anakinra), -8.7 (placebo) Physician’s assessment of disease activity (0–100) -25.2 (anakinra), -20.1 (placebo) Patient’s assessment of disease activity (0–100) -17.7 (anakinra), -8.9 (placebo) Patient’s assessment of pain (0–100) –19.0 (anakinra), -11.7 (placebo) HAQ (0–3) -0.29 (anakinra), -0.18 (placebo) CRP (mg/l) -5 (anakinra), -1 (placebo) ESR (mm/h) -16.2 (anakinra), -6.0 (placebo)

Adverse events

Total 90% (anakinra), 81% (placebo) AE leading to withdrawal 14% (anakinra), 13% (placebo) SAE 4% (anakinra), 3% (placebo) Injection-site reactions 65% (anakinra), 24% (placebo)

188

Rheumatoid Arthritis: Certolizumab pegol

Trial

Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870), in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial

Substance

Placebo (n = 12) 1 mg/kg certolizumab pegol (n = 8) 5 mg/kg certolizumab pegol (n = 8) 20 mg/kg certolizumab pegol (n = 8) After 8 weeks: Open-label infusion of 1, 5 or 20 mg/kg of certolizumab pegol within 2 weeks Concomitant medication: Prednisone £ 7.5 mg/d NSAIDs were permitted Previous medication: No previous failure to anti -TNF therapy

Result

Certolizumab pegol treatment of RA patients suffering from active disease was effective, well tolerated, and had an extended duration of action following one or more intravenous doses

Authors

Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA

Publication

Rheumatology (Oxford). 2002 Oct;41(10):1133–1137

Follow up

8 weeks

Patients

66 RA patients and active disease ³ 3 swollen joints ³ 6 painful or tender joints ³ 045 min. of early morning stiffness ESR ³ 028 mm/h Failed ³ 1 DMARD

ACR 20

Week 4: 16.7% (placebo), 50% (1 mg CZP), 87.5% (5 mg CZP), 62.5% (20 mg CZP) Week 8: 16.7% (placebo), 25% (1 mg CZP), 75% (5 mg CZP), 75% (20 mg CZP)

ACR 50

Week 4: 0% (placebo), 12.5% (1 mg CZP), 12.5% (5 mg CZP), 50% (20 mg CZP) Week 8: 0% (placebo), 12.5% (1 mg CZP), 12.5% (5 mg CZP), 50% (20 mg CZP)

Note

Change of: DAS -0.15 (placebo), -1.14 (1 mg CZP), -1.91 (5 mg CZP), -1.95 (20 mg CZP)

Adverse events

Headache n = 8 (CZP), n = 1 (placebo) Respiratory tract infections n = 3 (CZP), n = 1 (placebo) 1 episode of neck pain Urinary tract infections n = 3 (CZP), n = 1 (placebo) Increased ANA titer n = 3 (CZP), n = 1 (placebo)

Rheumatoid Arthritis: Certolizumab pegol

RAPID-1-Trial

Certolizumab pegol plus Methotrexate is significantly more effective than placebo plus Methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study RAPID: Rheumatoid Arthritis Prevention of structural Damage

Substance

Subcutaneous certolizumab pegol 200 mg + MTX (n =392) Certolizumab pegol 400 mg + MTX given every 2 weeks (n =389) Placebo + MTX (n = 199) Certolizumab pegol was applied with 400 mg at weeks 0 – 2 – 4 Followed by 200/400 mg every 2 weeks

189

Concomitant medication: Prednisone £ 10 mg/day or equivalent No parenteral corticosteroids NSAIDs were permitted MTX was continued No DMARDs £ 28 days No leflunomide £ 6 or cholestyramine washout Previous medication: No previous certolizumab pegol treatment MTX ³ 6 months, stable dosage of ³10 mg/week ³ 2 months Result

Combination therapy of RA patients with certolizumab pegol and methotrexate led to a rapid and sustained reduction in signs and symptoms of the disease, it inhibited the progression of structural joint damage, and improved physical function

Patients

982 patients with active rheumatoid arthritis Inadequate response to MTX (for ³ 6 months, with a stable dosage of ³ 10 mg/week for ³ 2 months prior to baseline) Disease duration > 6 months < 15a ³ 9 tender joints ³ 9 swollen joints ESR ³ 30 mm/h CRP >15 mg/l

Authors

Keystone E, Heijde D, Mason D Jr, Landewé R, Vollenhoven RV, Combe B, Emery P, Strand V, Mease P, Desai C, Pavelka K

Publication

Arthritis Rheum. 2008 Nov;58(11):3319–3329

Follow up

52 weeks

ACR 20

58.8% (CZP 200 mg), 60.8% (CZP 400 mg), 13.6 (placebo)

ACR 50

37.1% (CZP 200 mg), 39.9% (CZP 400 mg), 7.6 (placebo)

ACR 70

20.6% (CZP 200 mg), 21.4% (CZP 400 mg), 3.0% (placebo)

190

Note

Rheumatoid Arthritis: Certolizumab pegol

Change at Week 12: Swollen joint count –10.7% (placebo), –56.7% (CZP 200 mg), –61.5% (CZP 400 mg) Tender joint count –10.8% (placebo), –52.6% (CZP 200 mg), –56.8% (CZP 400 mg) Physician’s global assessment –11.8% (placebo), –49.7% (CZP 200 mg), –47.9% (CZP 400 mg) Patient’s global assessment –4.9% (placebo), –38.3% (CZP 200 mg), –39.2% (CZP 400 mg) Patient’s assessment of arthritis pain change –4.8% (placebo), –38.2% (CZP 200 mg), –39.6% (CZP 400 mg) HAQ –8.2% (placebo), –30.4% (CZP 200 mg), –27.6% (CZP 400 mg) ESR 0.84% (placebo), 0.53% (CZP 200 mg), 0.52% (CZP 400 mg) CRP 0.87% (placebo), 0.45% (CZP 200 mg), 0.43% (CZP 400 mg) At week 52: Total Sharp Score 0.4 (CZP 200 mg), 0.2% (CZP 400 mg), –2.8 (placebo)

Adverse events

Incidence rate/100 patient years: Headache 12.0 (placebo), 7.3 (200 mg CZP), 5.7 (400 mg CZP) Hypertension 2.2 (placebo), 8.2 (200 mg CZP), 10.2 (400 mg CZP) Back pain 2.2 (placebo), 5.6 (200 mg CZP), 6.4 (400 mg CZP) Malignancy 1.1 (placebo), 2.3 (200 mg CZP), 1.3 (400 mg CZP) Infections and infestations 56.9 (placebo), 56.4 (200 mg CZP), 58.4 (400 mg CZP) Urinary tract infection 14.2 (placebo), 7.6 (200 mg CZP), 10.5 (400 mg CZP) Nasopharyngitis 3.3 (placebo), 6.9 (200 mg CZP), 9.5 (400 mg CZP) Upper respiratory tract infection 5.5 (placebo), 7.9 (200 mg CZP), 6.7 (400 mg CZP) Serious infections and infestations 2.2 (placebo), 5.3 (200 mg CZP), 7.3 (400 mg CZP) Lower respiratory tract/lung infection 0.0 (placebo), 1.0 (200 mg CZP), 1.3 (400 mg CZP) Gastroenteritis 1.1 (placebo), 0 (200 mg CZP), 0 (400 mg CZP) Urinary tract infection 0 (placebo), 0.7 (200 mg CZP), 1.0 (400 mg CZP) Tuberculosis infection 0 (placebo), 0.7 (200 mg CZP), 1.0 (400 mg CZP) Upper respiratory tract infection 0 (placebo), 0.3 (200 mg CZP), 0.6 (400 mg CZP) Herpes viral infection 0 (placebo), 0.3 (200 mg CZP), 0.3 (400 mg CZP) Bacterial peritonitis 0 (placebo), 0.3 (200 mg CZP), 0 (400 mg CZP) Opportunistic infection 0 (placebo), 0 (200 mg CZP), 0 (400 mg CZP)

Rheumatoid Arthritis: Certolizumab pegol

RAPID-2-Trial

Efficacy and safety of Certolizumab pegol plus Methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. RAPID: Rheumatoid Arthritis Prevention of structural Damage 2

Substance

Certolizumab pegol 200 mg (n = 246) Certolizumab pegol 400 mg (n = 246) Placebo (n = 127) Certolizumab pegol was applied with 400 mg at weeks 0 – 2 – 4 Followed by 200/400 mg every 2 weeks

191

Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted MTX was continued Previous medication: MTX ³ 6 months, stable dosage of ³10 mg/week ³ 2 months Previous anti-TNF use was permitted DMARDs were permitted Result

Combination therapy of certolizumab pegol and methotrexate was superior to methotrexate monotherapy

Patients

619 RA patients Disease duration 6 months – 15 years Prior MTX for > 6 months (stable dose >10 mg/week for >2 months) No prior biological agent within 6 months Oral corticosteroids (10 mg/day prednisone) NSAIDs were permitted

Authors

Smolen J, Landewé RB, Mease P, Brzezicki J, Mason D, Luijtens K, van Vollenhoven RF, Kavanaugh A, Schiff M, Burmester GR, Strand V, Vencovsky J, van der Heijde D

Publication

Ann Rheum Dis. 2009 Jun;68(6):797–804. Epub 2008 Nov 17

Follow up

24 weeks

ACR 20

57.3% (CZP 200 mg), 57.6% (CZP 400 mg), 8.7% (placebo)

ACR 50

32.5% (CZP 200 mg), 33.1% (CZP 400 mg), 3.1% (placebo)

ACR 70

15.9% (CZP 200 mg), 10.6% (CZP 400 mg), 0.8% (placebo)

192

Rheumatoid Arthritis: Certolizumab pegol

Note

Change of: Swollen joint count -2.7 (MTX), -13.8 (CZP 200), -14.2 (CZP 400) Tender joint count -3.8 (MTX), -17.3 (CZP 200), -19.5 (CZP 400) Physician’s global assessment of arthritis -9.2 (MTX), -34.8 (CZP 200), -35.6 (CZP 400) Patient’s global assessment of arthritis -4.2 (MTX), -24.5 (CZP 200), -26.6 (CZP 400) Patient’s assessment of arthritic pain -4.7 (MTX), -23.7 (CZP 200), -26.1 (CZP 400) HAQ change -0.14 (MTX), -0.5 (CZP 200), -0.5 (CZP 400) CRP change (Ratio to Baseline) 0.92 (MTX), 0.42 (CZP 200), 0.34 (CZP 400) Total Sharp score change +1.2 (MTX), +0.2 (CZP 200), -0.4 (CZP 400) Erosion score change +0.7 (MTX), +0.1 (CZP 200), -0.3 (CZP 400) Joint space narrowing +0.5 (MTX), +0.1 (CZP 200), -0.1 (CZP 400)

Adverse events

Urinary tract infect. 7.2% (placebo), 4.4% (CZP 200), 2.0% (CZP 400) Upper respiratory tract infection 1.6% (placebo), 4.4% (CZP 200), 1.6% (CZP 400) Headache 0.8% (placebo), 3.6% (CZP 200), 3.3% (CZP 400) Bacteriuria 3.2% (placebo), 3.2% (CZP 200), 2.4% (CZP 400) Nasopharyngitis 0.8% (placebo), 3.2% (CZP 200), 1.6% (CZP 400) Rheumatoid arthritis 3.2% (placebo), 2.8% (CZP 200), 0.8% (CZP 400), Hypertension 1.6% (placebo), 2.4% (CZP 200), 3.7% (400 CZP 400) Hematuria 4.0% (placebo), 1.6% (CZP 200), 1.6% (CZP 400) Hepatic enzyme increased 3.2% (placebo), 1.2% (CZP 200), 1.2% (CZP 400) AST increased 4.0% (placebo), 0.8% (CZP 200), 2.4% (CZP 400) ALT increased 4.08% (placebo), 0.4% (CZP 200), 3.3% (CZP 400) Development of tuberculosis n = 0 (placebo), n = 5 (CZP)

Rheumatoid Arthritis: Certolizumab pegol

Fast4WardTrial

Efficacy and safety of Certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study FAST4WARD: ‘eFficAcy and Safety of cerTolizumab pegol – 4 Weekly dosAge in RheumatoiD arthritis’

Substance

400 mg Certolizumab pegol every 4 weeks (n = 111) Placebo (n = 109) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted No intraarticular, periarticular, intramuscular or i.v. corticosteroids Previous medication: Min. 1 DMARD No prior biological therapy

Result

The disease activity of RA in patients who previously failed min. one DMARD was effectively reduced after certolizumab pegol monotherapy

Patients

220 RA patients Previously failing min 1 DMARD Disease duration > 6 months Tender joint count > 9 (out of 68) Swollen joint count > 9 (out of 66) + >1 of the following: > 45 min of morning stiffness ESR > 28 mm/h CRP ³ 10 mg/l DMARDs were discontinued for >28 days or five half lives

Authors

Fleischmann R, Vencovsky J, van Vollenhoven RF, Borenstein D, Box J, Coteur G, Goel N, Brezinschek HP, Innes A, Strand V

Publication

Ann Rheum Dis. 2009 Jun;68(6):805–811. Epub 2008 Nov 17

Follow up

24 weeks

ACR 20

45.5% (CZP), 9.3% (placebo)

ACR 50

22.7% (CZP), 3.7% (placebo)

ACR 70

5.5% (CZP), 0% (placebo)

193

194

Rheumatoid Arthritis: Certolizumab pegol

Note

Change of: No. of swollen joints –6.3 (placebo), –11.6 (CZP) Tender joint count –7.3 (placebo), –16.0 (CZP) Patients global assessment 0.0 (placebo), –0.7 (CZP) Physician’s global assessment –0.2 (placebo), –1.1 (CZP) Patient’s pain Assessment +1.7 (placebo), –20.6 (CZP) HAQ-DI +0.13 (placebo), –0.36 (CZP) CRP +1.2 mg/L (placebo), +0.5 mg/L (CZP) ESR +1 mm (placebo), +0.8 mm (CZP)

Adverse events

Injection-site pain 1.8% (CZP), 0% (placebo) Injection-site reactions 13.8% (CZP), 4.5% (placebo) Serious infections 0% (placebo), 1.8% (CZP) Certolizumab pegol treated patients (5%): Headache, nasopharyngitis, upper respiratory tract infections, diarrhoea and sinusitis Placebo treated patients (n = 3): Vomiting, chronic renal failure and pneumonitis Certolizumab pegol treated patients n = 8: Bacterial arthritis, mastitis, benign parathyroid tumour, postural dizziness, ischemic stroke and menometrorrhagia

Rheumatoid Arthritis: Etanercept

Trial

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial

Substance

Etanercept 2 × 10 mg/week (n = 76) Etanercept 2 × 25 mg/week (n = 78) Placebo (n = 80)

195

Concomitant medication: Prednisone £ 10 mg/dayor equivalent NSAIDs were permitted DMARDs were washed out No intraarticular corticosteroids Previous medication: DMARD therapy Result

Etanercept in patients with active rheumatoid arthritis provided rapid, significant, and sustained benefit. Treatment was safe

Patients

234 patients with active RA Inadequate response to DMARDs ESR ³ 28 mm/h CRP > 20 mg/L Morning stiffness ³ 45 min

Authors

Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ, Ruderman EM, Horwitz DA, Arkfeld DG, Garrison L, Burge DJ, Blosch CM, Lange ML, McDonnell ND, Weinblatt ME

Publication

Ann Intern Med. 1999 Mar 16;130(6):478–486

Follow up

6 months

ACR 20

11% (placebo), 51% (10 mg ETN), 59% (25 mg/ETN)

ACR 50

5% (placebo), 24% (10 mg ETN), 40% (25 mg/ETN)

ACR 70

1% (placebo), 9% (10 mg ETN), 15% (25 mg/ETN)

196

Note

Rheumatoid Arthritis: Etanercept

Change of: Tender joint count -6% (placebo), -44% (10 mg ETN), -56% (25 mg ETN) Swollen joint count +7% (placebo), -45% (10 mg ETN), -47% (25 mg ETN) Morning stiffness +23% (placebo), -34% (10 mg ETN), -13% (25 mg ETN) Physician’s assessment -2% (placebo), -33% (10 mg ETN), -44% (25 mg ETN) Patient’s assessment +3% (placebo), -31% (10 mg ETN), -46% (25 mg ETN) Pain (VAS) +22% (placebo), -39% (10 mg ETN), -53% (25 mg ETN) ESR +18% (placebo), -10% (10 mg ETN), -18% (25 mg ETN) CRP +207% (placebo), +18% (10 mg ETN), -31% (25 mg ETN) Quality of Life: Disability index -2 (placebo), 34 (10 mg ETN), 39 (25 mg ETN) General health status +12 (placebo), 34 (10 mg ETN), 33 (25 mg ETN) Arthritis-specific health status +22 (placebo), 31 (10 mg ETN), 44 (25 mg ETN) Vitality domain -2 (placebo), 22 (10 mg ETN), 25 (25 mg ETN) Mental health domain -3 (placebo), 17 (10 mg ETN), 35 (25 mg ETN)

Adverse events

Injection-site reaction 13 (placebo), 43 (10 mg ETN), 49 (25 mg/ETN) Upper respiratory tract infection 16 (placebo), 29 (10 mg ETN), 33% (25 mg ETN) Headache 10% (placebo), 20% (10 mg ETN), 14% (25 mg ETN) Sinusitis 11% (placebo), 11% (10 mg ETN), 12% (25 mg ETN) Rhinitis 11% (placebo), 12% (10 mg ETN), 10% (25 mg ETN) Diarrhoea 6% (placebo), 11% (10 mg ETN), 5% (25 mg ETN)

Rheumatoid Arthritis: Etanercept

ERA-Trial

A comparison of Etanercept and Methotrexate in patients with early rheumatoid arthritis ERA Early rheumatoid arthritis

Substance

2 × 10 mg etanercept/week (n = 217) 2 × 25 mg etanercept/week (n = 208) 7.5 mg MTX/week (increased to 20 mg/week over 8 weeks, mean 19 mg/w, n = 207)

197

Concomitant medication: DMARDs were discontinued ³ 4 weeks Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: No MTX Result

Etanercept was more rapid to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis as compared with oral methotrexate

Patients

632 patients with early RA Positive rheumatoid factor ³ 3 bone erosions ³ 10 swollen joints ³ 12 tender or painful joints; and ESR ³ 28 mm/h CRP ³ 2.0 mg/dL Morning stiffness ³ 45 min

Authors

Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK

Publication

N Engl J Med. 2000 Nov 30;343(22):1586–1593

Follow up

12 months

ACR 20

72% (ETN 25 mg), 65% (MTX)

Note

No increase of Erosion score 72% (10 mg ETN), 60% (MTX) Change of: Erosion score 6 months 0.30 (25 mg ETN), 0.68 (MTX) 12 months 0.57 (25 mg ETN), 1.06 (MTX)

198

Adverse events

Rheumatoid Arthritis: Etanercept

Injection-site reaction 7% (MTX), 30% (10 mg ETN), 37% (25 mg ETN) Upper respiratory tract infection 39% (MTX), 27% (10 mg ETN), 35% (25 mg ETN) Headache 27% (MTX), 25% (10 mg ETN), 22% (25 mg ETN) Nausea 29% (MTX), 14% (10 mg ETN), 17% (25 mg ETN) Rhinitis 14% (MTX), 17% (10 mg ETN), 15% (25 mg ETN) Diarrhoea 12% (MTX), 12% (10 mg ETN), 14% (25 mg ETN) Bleeding at Injection-site 10% (MTX), 14% (10 mg ETN), 14% (25 mg ETN) Skin infections 10% (MTX), 11% (10 mg ETN), 14% (25 mg ETN) Asthenia 12% (MTX), 9% (10 mg ETN), 13% (25 mg ETN) Influenza like symptoms 12% (MTX), 10% (10 mg ETN), 13% (25 mg ETN) Rash 23% (MTX), 16% (10 mg ETN), 12% (25 mg ETN) Dyspepsia 10% (MTX), 10% (10 mg ETN), 12% (25 mg ETN) Dizziness 11% (MTX), 5% (10 mg ETN), 12% (25 mg ETN) Back pain 6% (MTX), 6% (10 mg ETN), 11% (25 mg ETN) Abdominal pain 10% (MTX), 11% (10 mg ETN), 10% (25 mg ETN) Sinusitis 17% (MTX), 13% (10 mg ETN), 10% (25 mg ETN) Ecchymosis 10% (MTX), 8% (10 mg ETN), 9% (25 mg ETN) Alopecia 12% (MTX), 7% (10 mg ETN), 6% (25 mg ETN) Mouth ulcer 14% (MTX), 6% (10 mg ETN), 5% (25 mg ETN)

Rheumatoid Arthritis: Etanercept

ERA-Trial

Etanercept versus Methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes ERA Early rheumatoid arthritis

Substance

2 × 10 mg etanercept/week (n = 166) 2 × 25 mg etanercept/week (n = 177) 7.5 mg MTX/week (increased to 20 mg/week over 8 weeks, mean 19 mg/w, n = 169) Concomitant medication: DMARDs were discontinued ³ 4 weeks Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: No MTX

Result

Etanercept monotherapy was safe and superior to methotrexate in early, destructive RA

Patients

632 patients with early RA Disease duration < 3 years Positive rheumatoid factor ³ 3 bone erosions ³ 10 swollen joints ³ 12 tender or painful joints; and ESR ³ 28 mm/h CRP ³ 2.0 mg/dL Morning stiffness ³ 45 min

Authors

Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Cannon GW, Spencer-Green G, Finck BK

Publication

Arthritis Rheum. 2002 Jun;46(6):1443–1450

Follow up

24 months

ACR 20

72% (ETN 2 × 25), 59% (MTX)

ACR 50

49% (ETN 2 × 25), 42% (MTX)

ACR 70

29% (ETN 2 × 25), 24% (MTX)

199

200

Note

Rheumatoid Arthritis: Etanercept

Sharp score decrease 1.3 (2 × 25 mg ETN), 3.2 (MTX) Erosion score 0.66 (2 × 25 mg ETN), 1.86 (MTX) HAQ improvement 55% (ETN 2 × 25 mg), 37% (MTX) No radiological progression: Total Sharp score 51% (MTX), 53% (ETN 2 × 10 mg), 63% (ETN 2 × 25 mg) Erosions 58% (MTX), 60% (ETN 2 × 10 mg), 70% (ETN 2 × 25 mg) Joint space narrowing 69% (MTX), 73% (ETN 2 × 10 mg), 78% (ETN 2 × 25 mg)

Adverse events

Injection-site reaction 9% (MTX), 32% (ETN 2 × 10 mg), 39% (ETN 2 × 25 mg) Headache 28% (MTX), 27% (ETN 2 × 10 mg), 25% (ETN 2 × 25 mg) Nausea 31% (MTX), 14% (ETN 2 × 10 mg), 20% (ETN 2 × 25 mg) Rash 25% (MTX), 19% (ETN 2 × 10 mg), 18% (ETN 2 × 25 mg) Rhinitis 15% (MTX), 20% (ETN 2 × 10 mg), 18% (ETN 2 × 25 mg) Diarrhoea 15% (MTX), 14% (ETN 2 × 10 mg), 17% (ETN 2 × 25 mg) Asthenia 17% (MTX), 12% (ETN 2 × 10 mg), 16% (ETN 2 × 25 mg) Bleeding at Injection-site 10% (MTX), 15% (ETN 2 × 10 mg), 16% (ETN 2 × 25 mg) Dyspepsia 12% (MTX), 16% (ETN 2 × 10 mg), 15% (ETN 2 × 25 mg) Dizziness 12% (MTX), 7% (ETN 2 × 10 mg), 15% (ETN 2 × 25 mg) Abdominal pain 15% (MTX), 13% (ETN 2 × 10 mg), 13% (ETN 2 × 25 mg) Back pain 7% (MTX), 8% (ETN 2 × 10 mg), 12% (ETN 2 × 25 mg) Accidental injury 9% (MTX), 12% (ETN 2 × 10 mg), 11% (ETN 2 × 25 mg) Pain 11% (MTX), 8% (ETN 2 × 10 mg), 11% (ETN 2 × 25 mg) Ecchymosis 11% (MTX), 9% (ETN 2 × 10 mg), 11% (ETN 2 × 25 mg) Vomiting 9% (MTX), 3% (ETN 2 × 10 mg), 10% (ETN 2 × 25 mg) Hypertension 6% (MTX), 11% (ETN 2 × 10 mg), 9% (ETN 2 × 25 mg) Peripheral edema 4% (MTX), 11% (ETN 2 × 10 mg), 7% (ETN 2 × 25 mg) Myalgia 10% (MTX), 9% (ETN 2 × 10 mg), 6% (ETN 2 × 25 mg) Alopecia 12% (MTX), 7% (ETN 2 × 10 mg), 6% (ETN 2 × 25 mg) Mouth ulcer 17% (MTX), 7% (ETN 2 × 10 mg), 5% (ETN 2 × 25 mg)

Rheumatoid Arthritis: Etanercept

Trial

Once-weekly administration of 50 mg Etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial

Substance

50 mg Etanercept/week (n = 214) 2 × 25 mg Etanercept/week (n = 153) Placebo for 8 weeks followed by 2 × 25 mg Etanercept/week Concomitant medication: No DMARDs £ 28 days Prednisone £ 10 mg/day or equivalent MTX £ 25 mg/week NSAIDs were permitted Previous medication: No prior anti-TNF therapy No prior Etanercept treatment No Cyc £ 6 months

Result

Etanercept 2 × 25 mg and 1 × 50 mg/week was equally safe and effective

Patients

476 RA patients ³ 6 tender joints ³ 6 swollen joints

Authors

Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, Burge DJ

Publication

Arthritis Rheum. 2004 Feb;50(2):353–363

Follow up

16 weeks

ACR 20

Week 8: 50% (ETN 50), 49% (ETN 25), 19% (placebo) Week 16: 55% (ETN 50), 63% (ETN 25)

ACR 50

Week 8: 18% (ETN 50), 18% (ETN 25), 6% (placebo) Week 16: 29% (ETN 50), 33% (ETN 25)

ACR 70

Week 8: 2% (ETN 50), 5% (ETN 25), 2% (placebo) Week 16: 8% (ETN 50), 8% (ETN 25)

201

202

Note

Rheumatoid Arthritis: Etanercept

No. of tender joints: Week 8: -26.3% (placebo), -53.3% (ETN 50), -47.2% (ETN 25) Week 16 -68.1% (ETN 50), -70.7% (ETN 25) No. of swollen joints Week 8: -17.4% (placebo), -42.3% (ETN 50), -47.4% (ETN 25) Week 16: 52.2% (ETN 50), 58.8% (ETN 25) Pain assessment: Week 8: +3.9% (placebo), -44.6% (ETN 50), -41.9% (ETN 25) Week 16: -54.5% (ETN 50), -55.2% (ETN 25) Physician global assessment: Week 8: -33.3% (placebo), -50.0% (ETN 50), -50.0% (ETN 25) Week 16: -60.0% (ETN 50), -57.1% (ETN 25) Patient global assessment: Week: 0.0% (placebo), -33.3% (ETN 50), -33.3% (ETN 25) Week 16: -50.0% (ETN 50), -42.9% (ETN 25) HAQ Disability Index: Week 8: +5.9% (placebo), –26.7% (ETN 50), –25.0% (ETN 25) Week 16: –42.9% (ETN 50), –33.3% (ETN 25) CRP: Week 8: 0.0% (placebo), -5.6% (ETN 50), 0.0% (ETN 25) Week 16: -9.3% (ETN 50), -13.6% (ETN 25) Duration of morning stiffness: Week 8: 0.0% (placebo), -66.7% (ETN 50), -77.8% (ETN 25) Week 16: -81.7% (ETN 50), -87.5% (ETN 25)

Adverse events

Week 16: Accidental injury 0% (Placebo, week 8), 1% (ETN 50), 7% (ETN 25) Asthenia 6% (Placebo, week 8), 3% (ETN 50), 9% (ETN 25) Cough increased 0% (Placebo, week 8), 4% (ETN 50), 5% (ETN 25) Diarrhoea 4% (Placebo, week 8), 8% (ETN 50), 7% (ETN 25) Headache 9% (Placebo, week 8), 15% (ETN 50), 14% (ETN 25) Injection/site reaction 6% (Placebo, week 8), 19% (ETN 50), 19% (ETN 25) Nausea 15% (Placebo, week 8), 8% (ETN 50), 16% (ETN 25) Pain (not otherwise specified) 0% (Placebo, week 8), 7% (ETN 50), 3% (ETN 25) Rash 9% (Placebo, week 8), 9% (ETN 50), 5% (ETN 25) Sinusitis 0% (Placebo, week 8), 6% (ETN 50), 6% (ETN 25) Upper respiratory infection 13% (Placebo, week 8), 8% (ETN 50), 12% (ETN 25) Vomiting 0% (Placebo, week 8), 2% (ETN 50), 5% (ETN 25)

Rheumatoid Arthritis: Etanercept

TEMPO-Trial

Therapeutic effect of the combination of Etanercept and Methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial TEMPO: Trial of Etanercept and Methotrexate with radiographic patient outcomes

Substance

7.5 mg MTX/week (increased to 20 mg/week over 8 weeks) + 2 × 25 Etanercept/week (n = 231) 7.5 mg MTX/week (increased to 20 mg/week over 8 weeks, n = 228) 2 × 25 Etanercept/week monotherapy (n = 223)

203

Concomitant medication: No DMARDs £ 28 days Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: Min. 1 DMARD other than MTX No prior anti-TNF therapy No Corticosteroid injection within 4 weeks Result

Etanercept and methotrexate combination therapy reduced disease activity, radiographic progression more than monotherapy of etanercept or methotrexate

Patients

686 patients with active RA Despite DMARD treatment other than MTX ³ 10 swollen joints ³ 12 painful joints ESR ³ 28 mm CRP ³ 20 mg/L Morning stiffness ³ 45 min Disease duration 6 months - 20 years

Authors

Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martín Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M; TEMPO study investigators

Publication

Lancet. 2004 Feb 28;363(9410):675–681

Follow up

52 weeks

ACR 20

85% (ETN + MTX), 75% (MTX), 76% (ETN)

ACR 50

69% (ETN + MTX), 43% (MTX), 48% (ETN)

ACR 70

43% (ETN + MTX), 19% (MTX), 24% (ETN)

204

Rheumatoid Arthritis: Etanercept

Note

Total Sharp score 2.80 (MTX), 0.52 (ETN), -0.54 (ETN + MTX) Erosion score change 1.68 (MTX), 0.21 (ETN), -0.3 (ETN + MTX) Joint-space narrowing 1.12 (MTX), 0.32 (ETN), -0.23 (ETN + MTX)

Adverse events

Abdominal pain 18% (MTX), 12% (ETN), 18% (ETN + MTX) Accidental injury 11% (MTX), 9% (ETN), 9% (ETN + MTX) Asthenia 9% (MTX), 10% (ETN), 10% (ETN + MTX) Back pain 9% (MTX), 13% (ETN), 10% (ETN + MTX) Cough increased 7% (MTX), 6% (ETN), 11% (ETN + MTX) Diarrhoea 9% (MTX), 10% (ETN), 8% (ETN + MTX) Headache 14% (MTX), 15% (ETN), 15% (ETN + MTX) Injection-site reaction 2% (MTX), 21% (ETN), 10% (ETN + MTX) Nausea 32% (MTX), 10% (ETN), 24% (ETN + MTX) Rash 9% (MTX), 7% (ETN), 10% (ETN + MTX) Vomiting 11% (MTX), 3% (ETN), 5% (ETN + MTX) Infections: all 64% (MTX), 59% (ETN), 67% (ETN + MTX) Serious 4% (MTX), 4% (ETN), 4% (ETN + MTX)

Rheumatoid Arthritis: Etanercept

Trial

A comparative study of Etanercept plus Methotrexate and Methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study

Substance

Etanercept 2 × 25 mg/week (n = 29) Placebo (n = 29) Concomitant medication: 12.5–20 mg MTX/week was continued No DMARDs £ 4 weeks NSAIDs were permitted Corticosteroids were permitted Previous medication: No prior anti-TNF therapy No prior anti CD 4 treatment

Result

Combination therapy with etanercept and methotrexate was well tolerated and provided significantly more clinical benefit than methotrexate monotherapy in Taiwanese patients with active RA

Patients

58 patients with active RA Stable MTX therapy (12.5 to 20 mg per week for 4 weeks) ³ 6 tender joints ³ 6 swollen joints

Authors

Lan JL, Chou SJ, Chen DY, Chen YH, Hsieh TY, Young M Jr

Publication

J Formos Med Assoc. 2004 Aug;103(8):618–623

Follow up

12 weeks

ACR 20

90% (ETN), 34% (placebo)

ACR 50

66% (ETN), 10% (placebo)

ACR 70

24% (ETN), 0% (placebo)

205

206

Rheumatoid Arthritis: Etanercept

Note

Change of: Tender joint count -7.00 (ETN), -2.45 (placebo) Swollen joints count -8.55 (ETN), -3.86 (placebo) C-reactive protein -1.26 mg/dL (ETN), -0.45 mg/dL (placebo) Patient’s global assessment -2.83 mg/dL (ETN), -0.83 mg/dL (placebo) Physician’s global assessment -5.24 mg/dL (ETN), -2.55 mg/dL (placebo) Pain (VAS) -23.57 mg/dL (ETN), -0.03 mg/dL (placebo) Disability index –0.65 mg/dL (ETN), –0.24 mg/dL (placebo)

Adverse events

Abdominal pain 10% (ETN), 3% (placebo) Arthralgia 7% (ETN), 21% (placebo) Cough 17% (ETN), 21% (placebo) Diarrhoea 7% (ETN), 0% (placebo) Dizziness 0% (ETN), 14% (placebo) Dry eyes 7% (ETN), 17% (placebo) Dry mouth 17% (ETN), 7% (placebo) Dyspepsia 3% (ETN), 10% (placebo) Dysuria 0% (ETN), 7% (placebo) Fever 0% (ETN), 7% (placebo) Hypertension 7% (ETN), 7% (placebo) Accidental injury 17% (ETN), 3% (placebo) Insomnia 3% (ETN), 10% (placebo) Pain 14% (ETN), 17% (placebo) Pharyngitis 31% (ETN), 38% (placebo) Pruritus 3% (ETN), 10% (placebo) Rash 10% (ETN), 0% (placebo) Rhinitis 17% (ETN), 17% (placebo) SGOT Increase 7% (ETN), 7% (placebo) SGPT Increase 14% (ETN), 7% (placebo) Stomatitis ulcers 7% (ETN), 7% (placebo)

Rheumatoid Arthritis: Etanercept

207

TEMPO-Trial

Comparison of Etanercept and Methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial TEMPO: Trial of Etanercept and Methotrexate with radiographic patient outcomes

Substance

7.5 mg MTX/week (increased to 20 mg/week over 8 weeks) + 2 × 25 Etanercept/week (n = 188) 7.5 mg MTX/week (increased to 20 mg/week over 8 weeks, n = 152) 2 × 25 mg etanercept/week monotherapy (n = 188) Concomitant medication: No DMARDs £ 28 days Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: Min. 1 DMARD other than MTX No prior anti-TNF therapy No corticosteroid injection within 4 weeks

Result

Etanercept in combination with methotrexate reduced disease activity and slowed radiographic progression more than monotherapy of either substance

Patients

503 of 686 patients with active rheumatoid arthritis ³ 10 swollen joints ³ 12 painful joints ESR ³ 28 mm CRP ³ 20 mg/L Morning stiffness ³ 45 min Disease duration 6 months – 20 years

Authors

van der Heijde D, Klareskog L, Rodriguez-Valverde V, Codreanu C, Bolosiu H, Melo-Gomes J, Tornero-Molina J, Wajdula J, Pedersen R, Fatenejad S; TEMPO Study Investigators

Publication

Arthritis Rheum. 2006 Apr;54(4):1063–1074

Follow up

2 years

ACR 20

86% (combination), 71% (MTX), 75% (ETN)

ACR 50

71% (combination), 42% (MTX), 54% (ETN)

ACR 70

49% (combination), 21% (MTX), 27% (ETN)

DAS < 2,4

65,4% (combination), 38,6% (MTX), 44,4% (ETN)

208

Joint Erosions

Rheumatoid Arthritis: Etanercept

Total Sharp Score -0,56 (combination), 3,34 (MTX), 1,1 (ETN) Erosion score -0,76 (combination), 2,12 (MTX), 0,36 (ETN) Joint space narrowing 0,2 (combination), 1,23 (MTX), 0,74 (ETN) Change of: No. of swollen joints -82.1% (MTX), -87.2% (ETN), -91.3 (combination) No. of painful joints -74.8% (MTX), -84.5% (ETN), -84.0% (combination) Pain (0–100 VAS) -54.5% (MTX), -60.6% (ETN), -67.5% (combination) Physician’s global assessment (0–10 scale) -63.4% (MTX), -68.4% (ETN), –74.4% (combination) Patient’s global assessment (0–10 scale) -51.8% (MTX), -58.2% (ETN), -66.4% (combination) HAQ -45.2% (MTX), -52.6% (ETN), -60.3% (combination) CRP (mg/liter) -60.6% (MTX), -59.8% (ETN), -74.6% (combination)

Adverse events

Nausea 29% (combination), 39% (MTX), 13% (ETN) Abdominal pain 22% (combination), 22% (MTX), 17% (ETN) Injection-site reaction 11% (combination), 2% (MTX), 21% (ETN) Accidental injury 16% (combination), 18% (MTX), 14% (ETN) Headache 17% (combination), 16% (MTX), 17% (ETN) Back pain 16% (combination), 12% (MTX), 17% (ETN) Cough increased 14% (combination), 11% (MTX), 9% (ETN) Vomiting 9% (combination), 14% (MTX), 4% (ETN) Asthenia 13% (combination), 11% (MTX), 11% (ETN) Hypertension 9% (combination), 5% (MTX), 13% (ETN) Rash 12% (combination), 12% (MTX), 8% (ETN) Diarrhoea 11% (combination), 11% (MTX), 11% (ETN) Pain 8% (combination), 9% (MTX), 10% (ETN) Infections 76% (combination), 75% (MTX), 71% (ETN) Serious infections 6% (combination), 7% (MTX), 6% (ETN)

Rheumatoid Arthritis: Etanercept

209

Trial

Comparison of 2 doses of Etanercept (50 vs. 100 mg), in active rheumatoid arthritis: a randomized double-blind study

Substance

50 mg etanercept 2x/weekly (n = 51) 25 mg etanercept 2x/weekly (n =26) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: No prior anti-TNF therapy No prior anti CD4 treatment No intraarticular corticosteroids £ 2 weeks No DMARDs £ 2 weeks

Result

50 mg Etanercept monotherapy twice weekly did not improve the efficacy when compared to the standard dose of 25 mg twice weekly in TNF-alpha blocker-naive patients

Patients

77 RA patients TNF-naive active rheumatoid arthritis Failed at least one DMARD ³ 10 swollen joints and > 12 tender/painful joints CRP ³ 2.0 mg/dL Morning stiffness lasting ³ 45 min

Authors

Johnsen AK, Schiff MH, Mease PJ, Moreland LW, Maier AL, Coblyn JS, Helfgott SM, Leff JA, Weinblatt ME

Publication

J Rheumatol. 2006 Apr;33(4):659–664. Epub 2006 Feb 15

Follow up

24 weeks

ACR 20

65% (25 mg ETN), 59% (50 mg ETN)

ACR 50

38% (25 mg ETN), 37% (50 mg ETN)

ACR 70

15% (25 mg ETN), 16% (50 mg ETN)

Note

ACR-N AUC 1.7% (25 mg ETN), 1.4% (50 mg ETN) Good EULAR response 88% (25 mg ETN), 84% (50 mg ETN) Change of: Tender joint count (median) -22.9 (25 mg ETN), -21.8 (50 mg ETN) Swollen joint count (median) -16.5 (25 mg ETN), -12.0 (50 mg ETN) Patient pain assessment (VAS, median) -3.7 (25 mg ETN), -4.6 (50 mg ETN) Physical global assessment (median) -3.5 (25 mg ETN), -4.0 (50 mg ETN) Patient global assessment (median) -3.0 (25 mg ETN), -3.0 (50 mg ETN) HAQ (median) -0.3 (25 mg ETN), -0.4 (50 mg ETN) CRP (mg/dL, median) -0.5 (25 mg ETN), -0.6 (50 mg ETN)

Adverse events

Any infection 50% (25 mg ETN), 53% (50 mg ETN) Sinusitis 15% (25 mg ETN), 16% (50 mg ETN) Cystitis 12% (25 mg ETN), 4% (50 mg ETN) Bronchitis 8% (25 mg ETN), 6% (50 mg ETN) Urinary tract infection 8% (25 mg ETN), 2% (50 mg ETN) Flu syndrome 4% (25 mg ETN), 26% (50 mg ETN) Fungal infection 0% (25 mg ETN), 6% (50 mg ETN) Gastroenteritis 0% (25 mg ETN), 6% (50 mg ETN)

210

Rheumatoid Arthritis: Etanercept

Trial

Etanercept and Sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving Sulfasalazine: a double-blind comparison

Substance

2–3 g sulfasalazine/day (n = 50) 2 × 25 mg etanercept/week (n = 103) 2 × 25 mg etanercept/week + 2–3 g sulfasalazine/day (n = 101) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: No other DMARDs than SSZ £ 3 months

Result

Patients with active rheumatoid arthritis improved upon combination therapy of etanercept and sulfasalazine. All three treatment arms were generally well tolerated

Patients

254 active RA patients Despite stable sulfasalazine (2–3 g/day) treatment Disease duration < 20 years > 6 swollen joints >10 painful joints + at least one of the following: ESR > 28 mm/h CRP > 20 mg/l Morning stiffness > 45 min

Authors

Combe B, Codreanu C, Fiocco U, Gaubitz M, Geusens PP, Kvien TK, Pavelka K, Sambrook PN, Smolen JS, Wajdula J, Fatenejad S; Etanercept European Investigators Network (Etanercept Study 309 Investigators)

Publication

Ann Rheum Dis. 2006 Oct;65(10):1357–1362. Epub 2006 Apr 10

Follow up

24 weeks

ACR 20

73.8% (ETN), 74.0% (ETN + SSZ), 28.0% (SSZ)

ACR 50

46.6% (ETN), 52.0% (ETN + SSZ), 14.0% (SSZ)

ACR 50

21.4% (ETN), 25.0% (ETN + SSZ), 2.0% (SSZ)

Note

Change of: Painful joints -22.7% (SSZ), -65.4% (ETN), -62.0% (ETN + SSZ) Swollen joints -38.5% (SSZ), -68.7% (ETN), -70.1% (ETN + SSZ) Pain VAS -13.3% (SSZ), 55.6% (ETN), -53.9% (ETN + SSZ) HAQ -9.2% (SSZ), -35.3% (ETN), -40.2% (ETN + SSZ) DAS -19.6% (SSZ), -48.2% (ETN), -49.7% (ETN + SSZ) EuroQOL VAS -20.1% (SSZ), -64.6% (ETN), -67.6% (ETN + SSZ) Morning stiffness +21.1% (SSZ), -62.8% (ETN), -68.5% (ETN + SSZ) Physician global assessment -16.0% (SSZ), -59.9% (ETN), -62.0% (ETN + SSZ) Patient global assessment -13.6% (SSZ), -50.5% (ETN), -53.5% (ETN + SSZ) ESR -0.2% (SSZ), -37.6% (ETN), -3% (ETN + SSZ) CRP-change -32.9% (SSZ), -69.9% (ETN), -66.7% (ETN + SSZ)

Rheumatoid Arthritis: Etanercept

Adverse events

211

Injection-site reaction 1% (SSZ), 33% (ETN), 16% (ETN + SSZ) Headache 4% (SSZ), 5% (ETN), 15% (ETN + SSZ) Nausea 3% (SSZ), 3% (ETN), 12% (ETN + SSZ) Asthenia 1% (SSZ), 3% (ETN), 10% (ETN + SSZ) Rash 2% (SSZ), 10% (ETN), 8% (ETN + SSZ) Cough increased 4% (SSZ), 3% (ETN), 6% (ETN + SSZ) Arthralgia 4% (SSZ), 3% (ETN), 5% (ETN + SSZ) Rhinitis 4% (SSZ), 1% (ETN), 2% (ETN + SSZ) Abdominal pain 0% (SSZ), 7% (ETN), 8% (ETN + SSZ) Bronchitis 1% (SSZ), 8% (ETN), 4% (ETN + SSZ) Pruritus 2% (SSZ), 1% (ETN), 7% (ETN + SSZ) Injection-site haemorrhage 3% (SSZ), 5% (ETN), 5% (ETN + SSZ) Pharyngitis 3% (SSZ), 5% (ETN), 4% (ETN + SSZ) Pain 3% (SSZ), 4% (ETN), 2% (ETN + SSZ) Fever 3% (SSZ), 0% (ETN), 2% (ETN + SSZ) Dyspepsia 1% (SSZ), 5% (ETN), 6% (ETN + SSZ) Dizziness 1% (SSZ), 4% (ETN), 6% (ETN + SSZ) Accidental injury 0% (SSZ), 6% (ETN), 3% (ETN + SSZ) Hypertension 0% (SSZ), 3% (ETN), 6% (ETN + SSZ) Leucopoenia 0% (SSZ), 1% (ETN), 5% (ETN + SSZ) Paresthesia 1% (SSZ), 2% (ETN), 6% (ETN + SSZ) Infectious adverse events total 13% (SSZ), 47% (ETN), 31% (ETN + SSZ) Pharyngitis or laryngitis 3% (SSZ), 12% (ETN), 5% (ETN + SSZ) Upper respiratory infection 5% (SSZ), 10% (ETN), 11% (ETN + SSZ) Flu syndrome 1% (SSZ), 8% (ETN), 5% (ETN + SSZ) Miscellaneous skin infections 1% (SSZ), 9% (ETN), 5% (ETN + SSZ)

212

Rheumatoid Arthritis: Etanercept

ADORE-Trial

Efficacy and safety of combination Etanercept and Methotrexate versus Etanercept alone in patients with rheumatoid arthritis with an inadequate response to Methotrexate: the ADORE study ADORE: Add Enbrel or Replace Methotrexate

Substance

2 × 25 mg etanercept/week (n = 160) Substitution of MTX (³ 12.5 mg/week) 2 × 25 mg Etanercept/week + ³ 12.5 mg MTX/week (n = 155) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: Any DMARDs other than MTX within 12 weeks of screening No bolus corticosteroids £ 6 weeks No intraarticular corticosteroids £ 6 weeks No biological treatment

Result

Addition to and substitution of etanercept for methotrexate in RA patients resulted in substantial improvements of clinical signs and symptoms

Patients

315 active rheumatoid arthritis DAS 28 > 3.2 > 5 swollen joints > 5 painful joints ESR >10 mm/h

Authors

van Riel PL, Taggart AJ, Sany J, Gaubitz M, Nab HW, Pedersen R, Freundlich B, MacPeek D; Add Enbrel or Replace Methotrexate Study Investigators

Publication

Ann Rheum Dis. 2006 Nov;65(11):1478–1483. Epub 2006 Feb 7

Follow up

16 weeks

ACR 20

71.0% (ETN), 67.1% (ETN + MTX)

ACR 50

41.9% (ETN), 40.1% (ETN + MTX)

ACR 70

17.4% (ETN), 18.4% (ETN + MTX)

Note

DAS28 change > 1.2 72.8% (ETN + MTX), 75.2 (ETN)

Adverse events

Nasopharyngitis 8.2% (ETN), 12.9% (MTX) Headache 8.8% (ETN), 6.5% (MTX) Rheumatoid arthritis 7.5% (ETN), 7.1% (MTX) Injection-site reaction 6.3% (ETN), 6.5% (MTX) Arthralgia 6.3% (ETN), 3.2% (MTX) Injection-site erythema 5.7% (ETN), 3.2% (MTX) Cough 2.5% (ETN), 5.2% (MTX) Infections 24.5% (ETN), 32.3% (MTX) Death 0% (ETN), 1.3% (MTX)

Rheumatoid Arthritis: Etanercept

Trial

A placebo-controlled, randomized, double-blinded study evaluating the safety of Etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases

Substance

2 × 25 mg etanercept/week (n = 269) Placebo (m = 266)

213

Concomitant medication: Corticosteroids were permitted NSAIDs were permitted DMARDs (except Aza, CsA and Cyc) were permitted Previous medication: No other TNF antagonists Result

RA patients with comorbidities tolerated etanercept generally well. Serious adverse events and death occurred more frequently in the etanercept group

Patients

535 RA patients ³ 1 comorbidity

Authors

Weisman MH, Paulus HE, Burch FX, Kivitz AJ, Fierer J, Dunn M, Kerr DR, Tsuji W, Baumgartner SW

Publication

Rheumatology (Oxford). 2007 Jul;46(7):1122–1125. Epub 2007 Apr 29

Follow up

16-week

Note

Patients with diabetes: infections: n = 5 (placebo), n = 3 (ETN), SAE n = 9 (placebo), n = 12 (ETN), Patients without diabetes infections: n = 5 (placebo), n = 5 (ETN), SAE n = 7 (placebo), n = 11 (ETN) Patients with chronic pulmonary disease infections: n = 6 (placebo), n = 5 (ETN), SAE n = 7 (placebo), n = 12 (ETN) Patients without chronic pulmonary disease infections: n = 4 (placebo), n = 3 (ETN), SAE n = 9 (placebo), n = 11 (ETN)

214

Rheumatoid Arthritis: Etanercept

TEMPO-Trial

The safety and efficacy of adding Etanercept to Methotrexate or Methotrexate to Etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy TEMPO: Trial of Etanercept and Methotrexate with radiographic patient outcomes

Substance

Combination of methotrexate + etanercept (n =96) Methotrexate added (n = 76) Etanercept monotherapy added (n = 55) Concomitant medication: Corticosteroids were permitted NSAIDs were permitted DMARDs (except Aza, CsA and Cyc) were permitted Previous medication: No other TNF antagonists

Result

Etanercept and methotrexate combination treatment had better therapeutic effects in RA patients with moderate disease activity despite monotherapy with either agent. Responses achieved by patients with combination therapy after 3 years were sustained or improved during the fourth year of treatment

Patients

After finishing 3 years ot the TEMPO Trial and with active disease

Authors

van der Heijde D, Burmester G, Melo-Gomes J, Codreanu C, Mola EM, Pedersen R, Freundlich B, Chang DJ; Etanercept Study 400 Investigators

Publication

Ann Rheum Dis. 2008 Feb;67(2):182–188. Epub 2007 Aug 29

Follow up

52 weeks

Rheumatoid Arthritis: Etanercept

Note

215

Good EULAR response 7.3% (combination), 30.9% (ETN added), 17.1% (MTX added) Moderate or good EULAR response 33.3% (combination), 63.3% (ETN added), 40.8% (MTX added) DAS28 low disease activity 74.0% (combination), 72.7% (ETN added), 57.9% (MTX added) DAS28 Remission 50.0% (combination), 41.8% (ETN added), 36.8% (MTX added) Change of: DAS28 remission +12.4% (combination), +18.2% (ETN added), +10.1% (MTX added) DAS –0.2 (combination), –0.6 (ETN added), –0.4 (MTX added) DAS28 –0.2 (combination), –0.9 (ETN added), –0.4 (MTX added) Tender joint count (0–71) –0.6 (combination), –3.4 (ETN added), –0.7 (MTX added) Swollen joint count (0–68) –1.0 (combination), –2.4 (ETN added), –0.4 (MTX added) Tender joint count (0–28) –0.3 (combination), –2.4 (ETN added), –0.6 (MTX added) Swollen joint count (0–28) –0.8 (combination), –1.8 (ETN added), –0.2 (MTX added) Physician global assessment (0–10) –0.5 (combination), –0.7 (ETN added), –0.3 (MTX added) Patient global assessment (0–10) –0.3 (combination), –0.1 (ETN added), –0.2 (MTX added) Patient general health VAS (0–100) –1.6 (combination), –2.3 (ETN added), –1.9 (MTX added) Patient pain VAS (0–100) –3.1 (combination), –2.8 (ETN added), –2.9 (MTX added) HAQ (0–3) 0 (combination), –0 (ETN added), –0.1 (MTX added) ESR (mm/h) +0.6 (combination), –7.2 (ETN added), –3.5 (MTX added) CRP (mg/l) –0.2 (combination), –2.4 (ETN added), –2.5 (MTX added)

Adverse events

Accidental injury 8.3% (combination), 3.6% (ETN added), 6.6% (MTX added) Back pain 2.1% (combination), 5.5% (ETN added), 6.6% (MTX added) Fever 1.0% (combination), 5.5% (ETN added), 0% (MTX added) Headache 2.1% (combination), 1.8% (ETN added), 5.3% (MTX added) Nausea 5.2% (combination), 3.6% (ETN added), 7.9% (MTX added) Anaemia 2.1% (combination), 3.6% (ETN added), 7.9% (MTX added) SGOT increased 3.1% (combination), 0% (ETN added), 6.6% (MTX added) SGPT increased 4.2% (combination), 0% (ETN added), 7.9% (MTX added) Arthralgia 4.2% (combination), 1.8% (ETN added), 6.6% (MTX added) Alopecia 0% (combination), 0% (ETN added), 5.3% (MTX added) Hematuria 1.0% (combination), 0% (ETN added), 5.3% (MTX added) Serious adverse events 5.2% (combination), 5.5% (ETN added), 10.5% (MTX added) Death 1.0% (combination), 0% (ETN added), 1.3% (MTX added) Infection 37.5% (combination), 29.1% (ETN added), 38.2% (MTX added) Serious infection 1.0% (combination), 1.8% (ETN added), 3.9% (MTX added)

216

Rheumatoid Arthritis: Etanercept

Trial

Efficacy and safety of Etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to Etanercept 50 mg once a week: results of a multicenter, randomized, double-blind, active drug-controlled study

Substance

Etanercept 50 mg twice weekly (n = 160) + MTX Etanercept 50 mg once weekly plus a placebo (n = 40) Followed by open lable therapy: Responders: Contintinue treatment Non responders: 50 mg/week => 2 × 50 mg/week Concomitant medication: Stable MTX ³ 15 mg/week Previous medication: No other TNF antagonists

Result

Etanercept 50 mg once weekly was an optimal dosage in most patients with RA. Increasing the dosage in suboptimal responders from 50 mg once weekly to 50 mg twice weekly did not significantly improve their DAS28 responses

Patients

RA patients Suboptimal response to 50 mg of etanercept (³ 6 month) ³ 5 swollen joints ³ 5 tender joints

Authors

Weinblatt ME, Schiff MH, Ruderman EM, Bingham CO 3rd, Li J, Louie J, Furst DE

Publication

Arthritis Rheum. 2008 Jul;58(7):1921–1930

Follow up

12 weeks + 12 week open label extension

ACR 20

31.9% (2x/week), 22.5% (1x/week)

ACR 50

13.1% (2x/week), 7.5% (1x/week)

ACR 70

1.3% (2x/week), 2.5% (1x/week)

Note

DAS28 Remission 6.3% (2x/week), 7.5% (1x/week) Change of: Tender joint count –35.2% (2x/week) –17.2% (1x/week) Swollen joint count –38.7% (2x/week) –35.6% (1x/week) Patient’s global assessment of joint pain –5.0% (2x/week) –5.3% (1x/week) Patient’s global assessment of disease activity –2.7% (2x/week) –1.4% (1x/week) Physician’s global assess. of disease activity –24.7% (2x/week) –17.6% (1x/week) HAQ DI Score –10.1% (2x/week) +13.3% (1x/week) Erythrocyte sedimentation rate +11.6% (2x/week) +16.6% (1x/week) CRP +52.4% (2x/week) +25.2% (1x/week) DAS28 improvement 15.4% (2x/week), 10.7% (1x/week) SF36 improvement (physical component) 13.9% (2x/week), 4.7% (1x/week) SF36 improvement (mental component) 2.6% (2x/week), 6.6% (1x/week) EuroQol Index-5D improvement 27.3% (2x/week), 46.4% (1x/week)

Adverse events

Increase of RA activity 5.0% (2x/week), 5.0% (1x/week) Sinusitis 2.5% (2x/week), 7.5% (1x/week) Upper respiratory tract infection 3.8% (2x/week), 0% (1x/week)

Rheumatoid Arthritis: Etanercept

217

COMET-Trial

Comparison of Methotrexate monotherapy with a combination of Methotrexate and Etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. COMET: Combination of Methotrexate and Etanercept in early rheumatoid arthritis

Substance

7.5 mg MTX/week (increased to max. 20 mg/week by week 8, n = 268, 221 completed) MTX (same titration) + etanercept 2 ´ 25 mg/week (n = 274, 189 completed) Concomitant medication: Prednisone £ 10 mg/day Folic acid 5 mg/week NSAIDs were permitted Previous medication: No DMARDs £ 4 weeks No biologic therapy £ 4 weeks No corticosteroid injections £ 4 weeks No MTX

Result

Treating early RA patients with etanercept plus methotrexate achieved clinical remission and radiographic non-progression in a significant percentage of patients

Patients

542 RA patients MTX naïve Early moderate to severe rheumatoid arthritis for 3–24 months DAS28 > 3.2 ESR > 28 mm/h CRP ³ 20 mg/L

Authors

Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, Singh A, Pedersen RD, Koenig AS, Freundlich B

Publication

Lancet. 2008 Aug 2;372(9636):375–382. Epub 2008 Jul 16

Follow up

52 weeks

ACR 20

67% (MTX), 73% (ETN + MTX)

ACR 50

49% (MTX), 55% (ETN + MTX)

ACR 70

28% (MTX), 34% (ETN + MTX)

218

Rheumatoid Arthritis: Etanercept

Note

Remission (DAS28 < 2.6) and radiological non progression 50% (ETN + MTX), 28% (MTX) Radiographic non-progression (mTSS £ 0.5) 80% (ETN + MTX), 59% (MTX)

Adverse events

Cardiac n = 2 (MTX), n = 2 (ETN + MTX) Ear and labyrinth n = 0 (MTX), n = 1 (ETN + MTX) Eye n = 1 (MTX), n = 0 (ETN + MTX) Gastrointestinal n = 4 (MTX), n = 1 (ETN + MTX) General administration site n = 1 (MTX), n = 2 (ETN + MTX) Hepatobiliary n = 0 (MTX), n = 3 (ETN + MTX) Infections n = 8 (MTX), n = 5 (ETN + MTX) Injury n = 4 (MTX), n = 3 (ETN + MTX) Laboratory values n = 1 (MTX), n = 1 (ETN + MTX) Metabolic n = 0 (MTX), n = 2 (ETN + MTX) Mucosceletal n = 9 (MTX), n = 4 (ETN + MTX) Nervous system n = 1 (MTX), n = 4 (ETN + MTX) Psychiatric n = 1 (MTX), n = 1 (ETN + MTX) Renal and urinary n = 1 (MTX), n = 1 (ETN + MTX) Respiratory n = 1 (MTX), n = 3 (ETN + MTX) Skin n = 0 (MTX), n = 1 (ETN + MTX) Surgical procedures n = 2 (MTX), n = 1 (ETN + MTX) Vascular n = 2 (MTX), n = 1 (ETN + MTX) Malignant disease n = 4 (MTX), n = 4 (ETN + MTX)

Rheumatoid Arthritis: Etanercept

TEMPO-Trial

Inhibition of radiographic progression with combination Etanercept and Methotrexate in patients with moderately active rheumatoid arthritis previously treated with monotherapy TEMPO: Trial of Etanercept and Methotrexate with radiographic patient outcomes

Substance

7.5 mg MTX/week (increased to 20 mg/week over 8 weeks) + 2 × 25 Etanercept/week (n = 231) 7.5 mg MTX/week (increased to 20 mg/week over 8 weeks, n = 228) 2 × 25 mg etanercept/week monotherapy (n = 223)

219

After 1 year: Combination of methotrexate + etanercept (n = 96) Methotrexate added to etanercept (n = 76) Etanercept added to MTX (n = 55) Concomitant medication: No DMARDs £ 28 days Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: Min. 1 DMARD other than MTX No prior anti-TNF therapy No corticosteroid injection within 4 weeks Result

Combination treatment with etanercept and methotrexate inhibited radiographic progression and improved radiographic outcomes in RA patients with moderate disease activity despite previous methotrexate monotherapy

Patients

After finishing 3 years ot the TEMPO Trial and with active disease

Authors

van der Heijde D, Burmester G, Melo-Gomes J, Codreanu C, Martin Mola E, Pedersen R, Robertson D, Chang D, Koenig A, Freundlich B; Etanercept Study Investigators

Publication

Ann Rheum Dis. 2009 Jul;68(7):1113–1118. Epub 2008 Aug 21

Follow up

1 year

Note

Progression of Sharp van der Heijde Score 0.24 (combination), 0.25 (ETN added), –0.18 (MTX added) Patients with no radiological progression 81.1% (combination), 69.2% (ETN added), 79.4% (MTX added)

220

Rheumatoid Arthritis: Etanercept

Trial

Efficacy, safety and patient-reported outcomes of combination Etanercept and Sulfasalazine versus Etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study

Substance

2–3 g sulfasalazine/day (n = 34) 2 × 25 mg etanercept/week, SSZ discontinued at baseline (n = 38) 2 × 25 mg etanercept/week + 2–3 g sulfasalazine/day (n = 24) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: Stable doses of 2–3 g SSZ/day ³ 4 months

Result

Etanercept monotherapy and etanercept plus sulfasalazine were efficacious in the long-term management of patients with RA

Patients

RA patients with active disease ³ 6 swollen joints ³ 10 tender joints ESR > 28 mm/h CRP > 20 mg/l Morning stiffness ³ 45 min Stable doses of sulfasalazine (2–3 g daily) ³ 4 months

Authors

Combe B, Codreanu C, Fiocco U, Gaubitz M, Geusens PP, Kvien TK, Pavelka K, Sambrook PN, Smolen JS, Khandker R, Singh A, Wajdula J, Fatenejad S; Etanercept European Investigators Network

Publication

Ann Rheum Dis. 2009 Jul;68(7):1146–1152. Epub 2008 Sep 15

Follow up

2 year

ACR 20

67% (ETN), 77% (ETN + SSZ), 34% (SSZ)

Note

DAS28 2.8 (ETN), 2.5 (ETN + SSZ), 4.5 (SSZ) Improvement in HAQ 76% (ETN), 78% (ETN + SSZ), 40% (SSZ) Withdrawal from study 37% (ETN), 24% (ETN + SSZ), 68% (SSZ) DAS28 < 2.4 45.6% (ETN), 57.0% (ETN + SSZ), 4.0% (SSZ)

Rheumatoid Arthritis: Etanercept

Adverse events

Any AE (excluding infect.), 87.4% (ETN), 79.2% (ETN + SSZ), 64.0% (SSZ) Injection-site reaction 33% (ETN), 20.8% (ETN + SSZ), 4.0% (SSZ) Headache 10.7% (ETN), 24.8% (ETN + SSZ), 8.0% (SSZ) Back pain 8.7% (ETN), 19.8% (ETN + SSZ), 10.0% (SSZ) Nausea 6.8% (ETN), 18.8% (ETN + SSZ), 10.0% (SSZ) Accidental injury 15.5% (ETN), 16.8% (ETN + SSZ), 2.0% (SSZ) Asthenia 4.9% (ETN), 15.8% (ETN + SSZ), 2.0% (SSZ) Rash 14.6% (ETN), 7.9% (ETN + SSZ), 6.0% (SSZ) Dyspepsia 13.6% (ETN), 11.9% (ETN + SSZ), 4.0% (SSZ) Abdominal pain 13.6% (ETN), 11.9% (ETN + SSZ), 2.0% (SSZ) Injection-site haemorrhage 8.7% (ETN), 13.9% (13.9), 6.0% (SSZ) Arthralgia 7.8% (ETN), 13.9% (ETN + SSZ), 14.0% (SSZ) Rheumatoid arthritis 9.7% (ETN), 11.9% (ETN + SSZ), 10.0% (SSZ) Diarrhoea 10.7% (ETN), 5.9% (ETN + SSZ), 0.0% (SSZ) Cough increased 6.8% (ETN), 11.9% (ETN + SSZ), 8.0% (SSZ) Paresthesia 3.9% (ETN), 10.9% (ETN + SSZ), 2.0% (SSZ) Any TEAE infection 73.8% (ETN), 59.4% (ETN + SSZ), 42.0% (SSZ) Upper resp. tract infection 28.2% (ETN), 28.7% (ETN + SSZ), 20.0% (SSZ) Pharyngitis/laryngitis 23.3% (ETN), 9.9% (ETN + SSZ), 6.0% (SSZ) Bronchitis 20.4% (ETN), 11.9% (ETN + SSZ), 8.0% (SSZ) Flu syndrome 17.5% (ETN), 11.9% (ETN + SSZ), 4.0% (SSZ) Gingival/dental infection 6.8% (ETN), 11.9% (ETN + SSZ), 4.0% (SSZ) Sinusitis 11.7% (ETN), 3.0% (ETN + SSZ), 0.0% (SSZ) Miscellaneous skin infections 18.4% (ETN), 11.9% (ETN + SSZ), 0.0% (SSZ)

221

222

Rheumatoid Arthritis: Anakinra + Etanercept

Trial

Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate

Substance

Etanercept only (25 mg twice weekly, n = 80) Etanercept (25 mg twice weekly, n = 81) + anakinra (100 mg/day) Half-dosage Etanercept (25 mg once weekly, n = 81) + anakinra (100 mg/day) Concomitant medication: MTX was continued Corticosteroids were continued NSAIDs were permitted and were continued Previous medication: 10–25 mg MTX/week ³ 16 weeks, stable dosage ³ 8 weeks No other DMARDs £ 4 weeks No anakinra No TNF-inhibitors No intraarticular or systemic corticosteroids £ 4 weeks

Result

Combination therapy with etanercept and anakinra provided no additional benefit but an increased risk of adverse events as compared to etanercept monotherapy treatment of patients with RA

Patients

244 active RA patients Despite MTX therapy ³ 6 swollen joints ³ 9 tender/painful joints And 2/3 of Morning stiffness > 45 min CRP > 15 mg/L ESR > 28 mm

Authors

Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P; 20000223 Study Group

Publication

Arthritis Rheum. 2004 May;50(5):1412–1419

Follow up

6 months

ACR 20

68% (ETN), 51% (1 × 25 ETN + anakinra), 62% (ETN + anakinra)

ACR 50

41% (ETN), 39% (1 × 25 ETN + anakinra), 31% (ETN + anakinra)

ACR 70

21% (ETN), 24% (1 × 25 ETN + anakinra), 14% (ETN + anakinra)

Adverse events Injection-site reaction 40% (ETN), 67.9% (1 × 25 ETN + anakinra), 70.4% (ETN + anakinra) Upper respiratory infections 20% (ETN), 11.1% (1 × 25 ETN + anakinra), 13.6% (ETN + anakinra) Infection requirering antibiotic therapy 0% (ETN), 3.7% (1 × 25 ETN + anakinra), 7.4% (ETN + anakinra) Infection leading to withdrawal 0% (ETN), 2.5% (1 × 25 ETN + anakinra), 2.5% (ETN + anakinra) Serious pneumonia 0% (ETN), 1.2% (1 × 25 ETN + anakinra), 2.5% (ETN + anakinra) Serious cellulitis 0% (ETN), 1.2% (1 × 25 ETN + anakinra), 2.5% (ETN + anakinra)

Rheumatoid Arthritis: Golimumab

Trial

Golimumab in patients with active rheumatoid arthritis despite treatment with Methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study

Substance

Placebo (n =35) Golimumab 50 mg (n = 35 every 4 weeks, n = 34 every 2 weeks) Golimumab 100 mg (n = 34 every 4 weeks, n = 34 every 2 weeks)

223

At week 20: Placebo => 3 mg/kg infliximab at weeks 20, 22, and 28 followed every 8 weeks through week 44 Concomitant medication: MTX ³ 10 mg/week was continued Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Folic acid ³ 5 mg/week Previous medication: MTX treatment ³ 10 mg/week ³ 3 months Result

Golimumab plus methotrexate treatment effectively reduced signs and symptoms of RA. The combination therapy was well tolerated in patients with an inadequate response to methotrexate

Patients

172 RA patients Disease duration > 3 months Active disease despite MTX treatment ³ 6 swollen joints and ³ 6 tender joints ³ 2 of the following 3 CRP ³ 1.5 mg/dL ESR ³ 28 mm/h Morning stiffness of ³ 30 min

Authors

Kay J, Matteson EL, Dasgupta B, Nash P, Durez P, Hall S, Hsia EC, Han J, Wagner C, Xu Z, Visvanathan S, Rahman MU

Publication

Arthritis Rheum. 2008 Apr;58(4):964–975

Follow up

52 weeks

ACR 20

Week 16: 37.1% (placebo), 60.0% (50 mg/4 weeks Gol), 50.0% (50 mg/2 weeks Gol), 55.9% (100 mg/4 weeks Gol), 79.4% (100 mg/2 weels Gol)

ACR 50

Week 16: 5.7% (placebo), 37.1% (50 mg/4 weeks Gol), 23.5% (50 mg/2 weeks Gol), 29.4% (100 mg/4 weeks Gol), 32.4% (100 mg/2 weeks Gol)

ACR 70

Week 16: 0% (placebo), 8.6% (50 mg/4 weeks Gol), 14.7% (50 mg/2 weeks Gol), 17.6% (100 mg/4 weeks Gol), 8.8% (100 mg/2 weeks Gol)

224

Note

Rheumatoid Arthritis: Golimumab

EULAR good response 5.7% (placebo), 8.6% (50 mg/4 weeks Gol), 14.7% (50 mg/2 weeks Gol), 26.5% (100 mg/4 weeks Gol), 23.5% (100 mg/2 weeks Gol) EULAR moderate response 37.1% (placebo), 62.9% (50 mg/4 weeks Gol), 50.0% (50 mg/2 weeks Gol), 38.2% (100 mg/4 weeks Gol), 61.8% (100 mg/2 weeks Gol) EULAR no response 57.1% (placebo), 28.6% (50 mg/4 weeks Gol), 35.3% (50 mg/2 weeks Gol), 35.3% (100 mg/4 weeks Gol), 14.7% (100 mg/2 weeks Gol) EULAR remission 0% (placebo), 5.7% (50 mg/4 weeks Gol), 11.8% (50 mg/2 weeks Gol), 8.8% (100 mg/4 weeks Gol), 11.8% (100 mg/2 weeks Gol) Change of: ACR-N –2.4 (placebo), +22.7 (50 mg/4 weeks Gol), +16.2 (50 mg/2 weeks Gol), +24.8 (100 mg/4 weeks Gol), +30.4 (100 mg/2 weeks Gol) DAS28 (ESR) –1.0 (placebo), –2.1 (50 mg/4 weeks Gol), –1.9 (50 mg/2 weeks Gol), –2.1 (100 mg/4 weeks Gol), –2.3 (100 mg/2 weeks Gol)

Adverse events

Nausea 2,9% (placebo), 16.8% (Gol) Headache 2,9% (placebo), 15.3% (Gol) Injection-site erythema 11.8% (placebo), 14.6% (Gol) Worsening of RA 20.6% (placebo), 11.7% (Gol) Congestive cardiac failure 0% (placebo), 0.7% (Gol) Cardiac tamponade 0% (placebo), 0.7% (Gol) Exacerb. COPD 0% (placebo), 0.7% (Gol) Fractured coccyx 0% (placebo), 0.7% (Gol) Hyperglycemia 0% (placebo), 0.7% (Gol) Inguinal hernia 0% (placebo), 0.7% (Gol) Lung adenocarcinoma 0% (placebo), 0.7% (Gol) RA 0% (placebo), 0.7% (Gol) Sinusitis 0% (placebo), 0.7% (Gol) Superficial thrombophlebitis 0% (placebo), 0.7% (Gol)

Rheumatoid Arthritis: Golimumab

225

GO-Forward- Golimumab, a human antibody to TNF-alpha given by monthly Trial subcutaneous injections, in active rheumatoid arthritis despite Methotrexate: The GO-Forward Study Substance

MTX (n = 133) 100 mg Golimumab/4 weeks s.c. (n = 133) 50 mg Golimumab/4 weeks s.c. + MTX (n = 89) 100 mg Golimumab/4 weeks s.c. + MTX (n = 89) Concomitant medication: MTX 15–25 mg/week was continued in the groups indicated Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Previous medication: MTX 15–25 mg/week ³ 3 months No other DMARDs No anti-TNF agent, rituximab, natalizumab, alefacept, efalizumab or cytotoxic agents No i.v., intramuscular, or intraarticular corticosteroids £ 4 weeks

Result

Addition of golimumab to methotrexate in RA patients with active disease despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function

Patients

633 active RA patients Despite MTX therapy CRP ³ 1.5 mg/dL Erythrocyte sedimentation rate ³ 28 mm/h Morning stiffness > 30 min Bone erosion determined by X ray and/or magnetic resonance imaging CCP or rheumatoid factor positive

Authors

Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall ST, Miranda PC, Pazdur J, Bae SC, Palmer W, Zrubek J, Wiekowski M, Visvanathan S, Wu Z, Rahman MU

Publication

Ann Rheum Dis. 2008 Dec 11. [Epub ahead of print]

Follow up

14/24 weeks

ACR 20

Week 14: 33.1% (MTX), 44.4% (100 mg Golimumab), 55.1% (50 mg Golimumab + MTX), 56.2% (100 mg Golimumab + MTX) Week 24: 27.8% (MTX), 35.3% (100 mg Golimumab), 59.6% (50 mg Golimumab + MTX), 59.6% (100 mg Golimumab + MTX)

ACR 50

Week 14: 9.8% (MTX), 20.3% (100 mg Golimumab), 34.8% (50 mg Golimumab + MTX), 29.2% (100 mg Golimumab + MTX) Week 24: 13.5% (MTX), 19.5% (100 mg Golimumab), 37.1% (50 mg Golimumab + MTX), 32.6% (100 mg Golimumab + MTX)

ACR 70

Week 14: 3.8% (MTX), 7.5% (100 mg Golimumab), 13.5% (50 mg Golimumab + MTX), 9.0% (100 mg Golimumab + MTX) Week 24: 5.3% (MTX), 11.3% (100 mg Golimumab), 20.2% (50 mg Golimumab + MTX), 14.6% (100 mg Golimumab + MTX)

226

Rheumatoid Arthritis: Golimumab

ACR 90

Week 14: 0.8% (MTX), 0.8% (100 mg Golimumab), 2.2% (50 mg Golimumab + MTX), 0.0% (100 mg Golimumab + MTX) Week 24: 0.8% (MTX), 2.3% (100 mg Golimumab), 5.6% (50 mg Golimumab + MTX), 2.2% (100 mg Golimumab + MTX)

Note

Change of (week 14): HAQ-DI scores -0.13 (MTX), -0.25 (100 mg Golimumab), –0.38 (50 mg Golimumab + MTX), -0.38 (100 mg Golimumab + MTX) EULAR response (total percentage) 44.4% (MTX), 59.4% (100 mg Golimumab), 70.8% (50 mg Golimumab + MTX), 75.3% (100 mg Golimumab + MTX) DAS Remission (total percentage) 1.5% (MTX), 8.3% (100 mg Golimumab), 15.7% (50 mg Golimumab + MTX), 18.0% (100 mg Golimumab + MTX) Change of (week 24): HAQ-DI scores –0.13 (MTX), –0.38 (50 mg Golimumab), –0.50 (100 mg Golimumab) EULAR response (total percentage) 42.1% (MTX), 51.9% (100 mg Golimumab), 71.9% (50 mg Golimumab + MTX), 76.4% (100 mg Golimumab + MTX) DAS Remission (total percentage) 6.0% (MTX), 12.0% (100 mg Golimumab), 20.2% (50 mg Golimumab + MTX), 22.5% (100 mg Golimumab + MTX)

Adverse events

Any infection 27.6% (MTX), 37.1% (100 mg Golimumab + MTX) Serious infections 0.7% (MTX), 4.8% (Golimumab) Cellulitis 0% (MTX), 1.0% (100 mg Golimumab + MTX) Sepsis 0% (MTX), 1.9% (100 mg Golimumab + MTX) Urinary tract infection 0.7% (MTX), 1.9% (100 mg Golimumab + MTX) Bacterial arthritis 0% (MTX), 1.0% (100 mg Golimumab + MTX) Lower respiratory tract infection 0% (MTX), 1.0% (100 mg Golimumab + MTX) Subcutaneous abscess 0% (MTX), 0.5% (50 mg Golimumab + MTX) Colitis 0% (MTX), 0.8% (50 mg Golimumab + MTX) Diarrhoea 0% (MTX), 0.8% (100 mg Golimumab + MTX) Infective arthritis 0% (MTX), 0.8% (100 mg Golimumab + MTX) Skin laceration 0% (MTX), 0.8% (100 mg Golimumab + MTX) Injection-site reactions 3.0% (MTX), 7.5% (100 mg Golimumab + MTX) Malignancies 0.7% (MTX), 1,5% (100 mg Golimumab + MTX)

Rheumatoid Arthritis: Golimumab

GO-AfterTrial

Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial

Substance

50 mg golimumab/4 weeks (n = 153) 100 mg golimumab/4 weeks (n = 153) Placebo (n = 155) Week 16 if £ 20% improvement of tender/swollen joint count: Placebo and 50 mg golimumab => 100 mg golimumab/4 weeks Concomitant medication: DMARDs (alone or in combination) were permitted Prednisone £ 10 mg/day or equivalent NSAIDs were permitted Patients were allowed to discontinue MTX, HCQ, SSZ at baseline MTX 15–25 mg/week was continued in the groups indicated Previous medication: ³ 1 TNFa inhibitor ³ 8 weeks (Ada, ETN) ³ 12 weeks (IFX) Discontinued for any reason No patients with adverse reaction to a previous TNFa inhibitor No prior natalizumab, rituximab, alefacept, efalizumab less than 3 months No cytotoxic drugs

Result

Golimumab reduced the manifestations of rheumatoid arthritis in patients with active disease who had previously received one or more TNF alpha inhibitors

Patients

461 patients with active RA Despite anti-TNF treatment

Authors

Smolen JS, Kay J, Doyle MK, Landewé R, Matteson EL, Wollenhaupt J, Gaylis N, Murphy FT, Neal JS, Zhou Y, Visvanathan S, Hsia EC, Rahman MU; GO-AFTER study investigators

Publication

Lancet. 2009 Jul 18;374(9685):210–221. Epub 2009 Jun 26

Follow up

24 weeks

ACR 20

34% (50 mg golimumab), 44% (100 mg golimumab), 17% (placebo)

ACR 50

18% (50 mg golimumab), 20% (100 mg golimumab), 5% (placebo)

ACR 70

12% (50 mg golimumab), 10% (100 mg golimumab), 3% (placebo)

227

228

Note

Rheumatoid Arthritis: Golimumab

DAS28 remission (<2.6) 10% (50 mg golimumab), 16% (100 mg golimumab), 3% (placebo) DAS28 score ³ 5.1 30% (50 mg golimumab), 16% (100 mg golimumab), 49% (placebo) DAS28 score 3.2–5.1 39% (50 mg golimumab), 47% (100 mg golimumab), 37% (placebo) DAS28 score < 3.2 31% (50 mg golimumab), 37% (100 mg golimumab), 14% (placebo) DAS28 (EULAR) response 46% (50 mg golimumab), 61% (100 mg golimumab), 25% (placebo) Change of (median): Swollen joint count (0–66) –40% (50 mg golimumab), –60% (100 mg golimumab) –3.1% (placebo) Tender joint count (0–68) –38.5% (50 mg golimumab), –56.6% (100 mg golimumab), +4.8% (placebo) Patient assessment of pain (0–10 cm, VAS) –27.1% (50 mg golimumab), –37.2% (100 mg golimumab), –6.1% (placebo) Patient global assessment of disease activity (0–10 cm, VAS) –24.3% (50 mg golimumab), –35.6% (100 mg golimumab), –4.5% (placebo) Physician global assessment of disease activity (0–10 cm, VAS) –40.8% (50 mg golimumab), –58.4% (100 mg golimumab), –13.0% (placebo) Assessment of physical function (0–3, HAQ-DI) –13.3% (50 mg golimumab), –14.3% (100 mg golimumab), 0% (placebo) C-reactive protein (mg/L) –14.3% (50 mg golimumab), –16.7% (100 mg golimumab), 0% (placebo) DAS28 score –18.6% (50 mg golimumab), –25.8% (100 mg golimumab), –1.6% (placebo) FACIT-F score +5% (50 mg golimumab), +6% (100 mg golimumab), +3% (placebo)

Adverse events

Adverse events 61% (50 mg golimumab), 73% (100 mg golimumab), 70% (placebo) Upper respiratory tract infection 6% (50 mg golimumab), 11% (100 mg golimumab), 6% (placebo) Nasopharyngitis 5% (50 mg golimumab), 5% (100 mg golimumab), 6% (placebo) Diarrhoea 3% (50 mg golimumab), 7% (100 mg golimumab), 4% (placebo) Infections 27% (50 mg golimumab), 25% (100 mg golimumab), 28% (placebo) Serious adverse events 5% (50 mg golimumab), 3% (100 mg golimumab), 7% (placebo) Serious infections 2% (50 mg golimumab), 1% (100 mg golimumab), 2% (placebo) Injection-site reactions 4% (50 mg golimumab), 11% (100 mg golimumab), 3% (placebo) Malignancies 1% (50 mg golimumab), 1% (100 mg golimumab), 0% (placebo)

Rheumatoid Arthritis: Golimumab

229

GO-BEFORETrial

Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in naïve-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of Golimumab before Methotrexate as first-line therapy for early-onset rheumatoid arthritis

Substance

Placebo every 4 weeks plus 10 mg MTX/week (n = 160) Golimumab 100 mg placebo every 4 weeks (n = 159) Golimumab 50 mg every 4 weeks plus MTX (n = 159) Golimumab 100 mg every 4 weeks plus MTX (n = 159) Concomitant medication: 10 mg MTX/week increased to 20 mg/week after 8 weeks Prednisone £10 mg/day stable for ³ 2 weeks NSAIDs were permitted Previous medication: No MTX ³ 3 weeks No prior infliximab, etanercept, adalimumab, rituximab, natalizumab, or cytotoxic agents, including, chlorambucil, cyclophosphamide, nitrogen, and other alkylating agents

Result

Combination therapy with golimumab plus methotrexate of methotrexatenaive RA patients was more effective in reducing signs and symptoms of the disease than golimumab or methotrexate alone. No unexpected safety concerns were observed. However, the primary endpoints were not met

Patients

637 MTX-naive patients with RA ³ 4 swollen joints ³ 4 tender joints + 2 of the following: CRP ³ 1.5 mg/dL ESR ³ 28 mm/h Morning stiffness ³ 30 min Bone erosion by radiography and/or magnetic resonance imaging Anti–CCP antibody positivity or rheumatoid factor positivity

Authors

Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P, Nash P, Amante EJ, Churchill M, Park W, Pons-Estel BA, Doyle MK, Visvanathan S, Xu W, Rahman MU

Publication

Arthritis Rheum. 2009 Aug;60(8):2272–2283

Follow up

24 weeks

ACR 20

49.4% (MTX), 51.6% (Gol 100), 61.6% (Gol 50 + MTX), 61.6% (Gol 100 + MTX)

ACR 50

35.8% (MTX), 28.9% (Gol 100), 44.2% (Gol 50 + MTX), 44.6% (Gol 100 + MTX)

ACR 70

15.6% (MTX), 13.8% (Gol 100), 23.9% (Gol 50 + MTX), 18.2% (Gol 100 + MTX)

230

Rheumatoid Arthritis: Golimumab

ACR 90

3.1% (MTX), 3.1% (Gol 100), 9.4% (Gol 50 + MTX), 7.5% (Gol 100 + MTX)

Note

ACR-N improvement 18.2% (MTX), 21.6% (Gol 100), 33.3% (Gol 50 + MTX), 27.8% (Gol 100 + MTX) DAS28-CRP level, good or moderate response 60.6% (MTX), 66.0% (Gol 100), 75.5% (Gol 50 + MTX), 75.5% (Gol 100 + MTX) DAS28-ESR, good or moderate response 61.3% (MTX), 67.3% (Gol 100), 73.0% (Gol 50 + MTX), 76.7% (Gol 100 + MTX) DAS28-CRP remission 28.1% (MTX), 25.2% (Gol 100), 38.4% (Gol 50 + MTX), 37.7% (Gol 100 + MTX) DAS28-ESR, remission 11.3% (MTX), 15.7% (Gol 100), 25.2% (Gol 50 + MTX), 19.5% (Gol 100 + MTX) Change of (median): Swollen joint count –66.70% (MTX), –66.70% (Gol 100), –75.60% (Gol 50 + MTX), –71.40% (Gol 100 + MTX) Tender joint count –57.10% (MTX), –57.10% (Gol 100), –67.20% (Gol 50 + MTX), –66.70% (Gol 100+ MTX) Patient’s assessment of pain –44.35% (MTX), –38.30% (Gol 100), –52.15% (Gol 50 + MTX), –51.65% (Gol 100 + MTX) Patient’s assessment of disease activity –36.70% (MTX), –34.70% (Gol 100), –49.55% (Gol 50 + MTX), –51.55% (Gol 100 + MTX) Physician’s assessment of disease activity –63.00% (MTX), –57.05% (Gol 100), –66.70% (Gol 50 + MTX), –63.50% (Gol 100 + MTX) CRP level –42.90% (MTX), –25.00% (Gol 100), –57.10% (Gol 50 + MTX), –62.50% (Gol 100 + MTX) HAQ disability index –36.95% (MTX), –31.05% (Gol 100), –43.65% (Gol 50 + MTX), –48.55% (Gol 100 + MTX)

Rheumatoid Arthritis: Golimumab

Adverse events

Nausea 10.0% (MTX), 7.0% (Gol 100), 13.9 (Gol 50 + MTX), 15.1% (Gol 100 + MTX) ALT Ý 6.3% (MTX), 4.5% (Gol 100), 12.7% (Gol 50 + MTX), 7.5% (Gol 100 + MTX) AST Ý 3.8% (MTX), 3.8% (Gol 100), 8.2% (Gol 50 + MTX), 6.3% (Gol 100 + MTX) Upper respiratory tract infection 8.8% (MTX), 5.7% (Gol 100), 8.2% (Gol 50 + MTX), 11.9% (Gol 100 + MTX) Dyspepsia 4.4% (MTX), 3.2% (Gol 100), 6.3% (Gol 50 + MTX), 5.0% (Gol 100 + MTX) Headache 6.3% (MTX), 4.5% (Gol 100), 3.8% (Gol 50 + MTX), 6.9% (Gol 100 + MTX) Injection-site erythema 0% (MTX), 7.0% (Gol 100), 5.1% (Gol 50 + MTX), 5.7% (Gol 100 + MTX) Upper abdominal pain 0.6% (MTX), 3.8% (Gol 100), 5.7% (Gol 50 + MTX), 3.1% (Gol 100 + MTX) Hypertension 1.9% (MTX), 2.5% (Gol 100), 5.1% (Gol 50 + MTX), 3.8% (Gol 100 + MTX) Rash 4.4% (MTX), 3.8% (Gol 100) 5.1% (Gol 50 + MTX), 3.1% (Gol 100 + MTX) Nasopharyngitis 2.5% (MTX), 5.1% (Gol 100), 5.7% (Gol 50 + MTX), 1.9% (Gol 100 + MTX) Influenza 4.4% (MTX), 1.9% (Gol 100), 2.5% (Gol 50 + MTX), 4.4% (Gol 100 + MTX) Vomiting 1.9% (MTX), 1.3% (Gol 100), 2.5% (Gol 50 + MTX), 4.4% (Gol 100 + MTX) Dizziness 0.6% (MTX), 1.9% (Gol 100), 4.4% (Gol 50 + MTX), 1.9% (Gol 100 + MTX) Fatigue 3.8% (MTX), 6.4% (Gol 100), 1.3% (Gol 50 + MTX), 5.0% (Gol 100 + MTX) Insomnia 0.6% (MTX), 2.5% (Gol 100), 2.5% (Gol 50 + MTX), 3.8% (Gol 100 + MTX) Malignancies 1.3% (MTX), 0% (Gol 100), 0.6% (Gol 50 + MTX), 0.6% (Gol 100 + MTX) Infections 32.5% (MTX), 35.0% (Gol 100), 34.2% (Gol 50 + MTX), 31.4% (Gol 100 + MTX) Serious infections 1.9% (MTX), 1.3% (Gol 100), 1.3% (Gol 50 + MTX), 4.4% (Gol 100 + MTX) Patients receiving TB prophylaxis 0.6% (MTX), 0.0% (Gol 100), 1.3% (Gol 50 + MTX), 0.6% (Gol 100 + MTX)

231

232

Rheumatoid Arthritis: Infliximab

Trial

Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly Methotrexate in rheumatoid arthritis

Substance

cA2 (later called infliximab) 1 mg/kg (n = 29) Infliximab 3 mg/kg (n = 29) Infliximab 10 mg/kg (n = 29) Placebo + MTX 7.5 mg/week (n = 14) at weeks 0, 2, 6, 10, and 14 and were followed up through week 26 Concomitant medication: With 7.5 mg MTX/week (n = 14 per group) or without MTX (n = 15 per group) Prednisolone £ 7.5 mg/d Previous medication: 7.5–10 mg/kg MTX/week ³ 6 months Other DMARDs discontinued ³ 4 weeks

Result

Multiple infusions of 3–10 mg/kg infliximab were effective and well tolerated. A synergy of 1 mg/kg infliximab and low-dose methotrexate was observed

Authors

Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M

Publication

Arthritis Rheum. 1998 Sep;41(9):1552–1563

Follow up

26 weeks

Patients

101 RA patients on MTX >6 month Flare despite MTX therapy ³ 6 swollen joints (of 66 counted) ³ 6 tender/painful joints (of 68 counted) > 45 min of morning stiffness ESR of > 28 mm/h or CRP level of > 15 mg/dL

Note

Paulus Criteria 20% improved 60% (3 mg/kg cA2) 1 mg/kg without MTX unresponsive

Adverse events

Headache 12.6% Diarrhea 9.2% Rash 6.9% Pharyngitis 6.9% Rhinitis 6.9% Cough 5.7% Upper respiratory tract infection 4.6% Urinary tract infection 4.6%

Rheumatoid Arthritis: Infliximab

ATTRACT-Trial Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody), versus placebo in rheumatoid arthritis patients receiving concomitant Methotrexate: a randomised phase III trial. ATTRACT Study Group ATTRACT: Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy Substance

Placebo (n = 88) 3 mg/kg infliximab/4 weeks (n = 86) 3 mg/kg infliximab/8 weeks (n = 86) 10 mg/kg infliximab/8 weeks (n = 87) 10 mg/kg infliximab/4 weeks (n = 81) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted at stable doses ³ 4 weeks With 15 mg MTX/week Previous medication: ³ 12.5 mg/kg MTX/week ³ 3 months No other DMARDs £ 4 weeks No intraarticular, intramuscular, or i.v. corticosteroids £ 4 weeks No tumour necrosis factor antagonizing agents No cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents

Result

Infliximab plus methotrexate was more efficacious than methotrexate monotherapy in active RA patients not previously responding to methotrexate

Patients

428 patients who had active RA Despite MTX ³ 3 months ³ 6 swollen and tender joints Morning stiffness ³ 45 min ESR > 28 mm/h CRP > 2 mg/dL

Authors

Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P

Publication

Lancet. 1999 Dec 4;354(9194):1932–1939

Follow up

30 weeks

ACR 20

53% (3 mg/kg/8 weeks), 50% (3 mg/kg/4 weeks), 58% (10 mg/kg/8 weeks), 52% (10 mg/kg/4 weeks), 20% placebo

ACR 50

27% (IFX 3 mg/kg/8 weeks), 29% (IFX 3 mg/kg/4 weeks), 31% (IFX 10 mg/kg/8 weeks), 26% (IFX 10 mg/kg/4 weeks), 5% (placebo)

ACR 70

8% (IFX 3 mg/kg/8 weeks), 11% (IFX 3 mg/kg/4 weeks), 18% (IFX 10 mg/kg/8 weeks), 11% (IFX 10 mg/kg/4 weeks), 0% (placebo)

233

234

Rheumatoid Arthritis: Infliximab

Note

Change of: Swollen joint count –20% (placebo), –52% (3 mg/kg/8 weeks), –50% (3 mg/kg/4 weeks), –60% (10 mg/kg/8 weeks), –64% (10 mg/kg/4 weeks) Tender joint count –26% (placebo), –59% (3 mg/kg/8 weeks), –65% (3 mg/kg/4 weeks), –58% (10 mg/kg/8 weeks), –65% (10 mg/kg/4 weeks) Pain score –6% (placebo), –33% (3 mg/kg/8 weeks), –43% (3 mg/kg/4 weeks), –50% (10 mg/kg/8 weeks), –35% (10 mg/kg/4 weeks) Physician’s global assessment –13% (placebo), 53% (3 mg/kg/8 weeks), –59% (3 mg/kg/4 weeks), –58% (10 mg/kg/8 weeks), –59% (10 mg/kg/4 weeks) Patient’s global assessment –7% (placebo), –23% (3 mg/kg/8 weeks), –30% (3 mg/kg/4 weeks), –40% (10 mg/kg/8 weeks), –47% (10 mg/kg/4 weeks) HAQ –3% (placebo), –13% (3 mg/kg/8 weeks), –29% (3 mg/kg/4 weeks), –27% (10 mg/kg/8 weeks), –24% (10 mg/kg/4 weeks) CRP –9% (placebo), –60% (3 mg/kg/8 weeks), –61% (3 mg/kg/4 weeks), –68% (10 mg/kg/8 weeks), –76% (10 mg/kg/4 weeks) Rheumatoid factor 0% (placebo), –37% (3 mg/kg/8 weeks), –32% (3 mg/kg/4 weeks), –46% (10 mg/kg/8 weeks), –31% (10mg/kg/4weeks)

Adverse events

Upper respiratory infections 16% (placebo), 20–33% (IFX) Headache 10% (placebo), 20–25% (IFX) Nausea 19% (placebo), 14–18% (IFX) Sinusitis 5% (placebo), 7–15% (IFX) Rash 5% (placebo), 6–16% (IFX) Cough 3% (placebo), 7–15% (IFX) Diarrhoea 12% (placebo), 8–13% (IFX) Fatigue 7% (placebo), 3–17% (IFX) Dizziness 7% (placebo), 6–14% (IFX) Rhinitis 6% (placebo), 6–11% (IFX) Back pain 2% (placebo), 7–10% (IFX) Abdominal pain 8% (placebo), 4–8% (IFX) Pain 5% (placebo), 3–10% (IFX) Pharyngitis 5% (placebo), 5–8% (IFX) Arthralgia 2% (placebo), 2–7% (IFX) Hypertension 3% (placebo), 3–8% (IFX) Stomatitis 2% (placebo), 2–11% (IFX) Urinary tract infection 3% (placebo), 2–9% (IFX) Fever 5% (placebo), 3–8% (IFX) Dyspepsia 3% (placebo), 1–8% (IFX) Any infection 40% (placebo), 40–73% (IFX) Infection requiring antimicrobials 21% (placebo), 23–38% (IFX) Serious infections 6% (placebo), 1–6% (IFX) Serious adverse events 16% (placebo), 9–13% (IFX)

Rheumatoid Arthritis: Infliximab

235

ATTRACT-Trial Infliximab and Methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group ATTRACT: Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy Substance

Placebo (n = 88) 3 mg/kg infliximab/4 weeks (n = 86) 3 mg/kg infliximab/8 weeks (n = 86) 10 mg/kg infliximab/8 weeks (n = 87) 10 mg/kg infliximab/4 weeks (n = 81) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted at stable doses ³ 4 weeks With 15 mg MTX/week Previous medication: ³ 12.5 mg/kg MTX/week ³ 3 months No other DMARDs £ 4 weeks No intraarticular, intramuscular, or i.v. corticosteroids £ 4 weeks No tumour necrosis factor antagonizing agents No cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents

Result

Infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage in RA patients with active RA despite MTX therapy

Patients

428 active RA patients Despite MTX ³ 6 swollen joints ³ 6 tender joints Morning stiffness ³ 45 min ESR > 28mm/h C-reactive protein > 2 mg/dL

Authors

Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group

Publication

N Engl J Med. 2000 Nov 30;343(22):1594–1602

Follow up

54 weeks

ACR 20

17% (placebo), 42% (IFX 3 mg/kg/8 weeks), 48% (IFX 3 mg/kg/4 weeks), 59% (IFX 10 mg/kg/8 weeks), 59% (IFX 10 mg/kg/4 weeks)

ACR 50

8% (placebo), 21% (IFX 3 mg/kg/8 weeks), 34% (IFX 3 mg/kg/4 weeks), 39% (IFX 10 mg/kg/8 weeks), 38% (IFX 10mg/kg/4weeks)

ACR 70

2% (placebo), 10% (IFX 3 mg/kg/8 weeks), 17% (IFX 3 mg/kg/4 weeks), 25% (IFX 10 mg/kg/8 weeks), 19% (IFX 10 mg/kg/4 weeks)

236

Rheumatoid Arthritis: Infliximab

Note

Change of: Swollen joint count –23% (placebo), –37% (IFX 3 mg/kg/8 weeks), –50% (IFX 3 mg/kg/4 weeks), –60% (IFX 10 mg/kg/8 weeks), –63% (IFX 10 mg/kg/4 weeks) Tender joint count –23% (placebo), –49% (IFX 3 mg/kg/8 weeks), –55% (IFX 3 mg/kg/4 weeks), –56% (IFX 10mg/kg/8 weeks), –65% (IFX 10mg/kg/4weeks) C–reactive protein –2.8 mg/dL (placebo), –1.6 mg/dL (IFX 3mg/kg/8 weeks), –1.5 mg/dL (IFX 3 mg/kg/4 weeks), –1.2 mg/dL (IFX 10mg/kg/8 weeks), –1.1 mg/dL (IFX 10 mg/kg/4 weeks) Total radiographic score +7.0 (placebo), +1.3 (IFX 3 mg/kg/8 weeks), +1.6 (IFX 3 mg/kg/4 weeks), +0.2 (IFX 10 mg/kg/8 weeks), –0.7 (IFX 10 mg/kg/4 weeks) Erosion score +4.0 (placebo), +0.2 (IFX 3 mg/kg/8 weeks), +0.3 (IFX 3mg/kg/4 weeks), +0.2 (IFX 10mg/kg/8 weeks), –0.7 (IFX 10mg/kg/4 weeks) Joint space narrowing +2.9 (placebo), +1.1 (IFX 3mg/kg/8 weeks), +0.7 (IFX 3mg/kg/4 weeks), 0 (IFX 10mg/kg/8 weeks), 0 (IFX 10mg/kg/4 weeks)

Adverse events

Total 21% (placebo), 11% (IFX 3mg/kg/8 weeks), 16% (IFX 3mg/kg/4 weeks), 20% (IFX 10mg/kg/8 weeks), 20% (IFX 10mg/kg/4 weeks) Serious infections 8% (placebo), 2% (IFX 3mg/kg/8 weeks), 7% (IFX 3mg/kg/4 weeks), 8% (IFX 10mg/kg/8 weeks), 7% (IFX 10mg/kg/4 weeks) Antinuclear antibodies 26% (placebo), 68% (IFX 10mg/kg/8 weeks), 62% (IFX 3mg/kg/8 weeks), 62% (IFX 3mg/kg/4 weeks), 53% (IFX 10mg/kg/4 weeks) Antibodies against dsDNA 10% (placebo), 11% (IFX 3mg/kg/8 weeks), 10% (IFX 10mg/kg/8 weeks), 7% (IFX 10mg/kg/4 weeks)

Rheumatoid Arthritis: Infliximab

237

ATTRACT-Trial Infliximab in active early rheumatoid arthritis ATTRACT: Anti-TNF Therapy in RA with Concomitant Therapy Substance

Placebo (n = 88) 3mg/kg infliximab/4 weeks (n = 86) 3mg/kg infliximab/8 weeks (n = 86) 10mg/kg infliximab/8 weeks (n = 87) 10mg/kg infliximab/4 weeks (n = 81) Concomitant medication: Prednisonne £ 10 mg/day or equivalent NSAIDs were permitted at stable doses ³ 4 weeks With 15mg MTX/week Previous medication: ³ 12.5 mg/kg MTX/week ³ 3 months No other DMARDs £ 4 weeks No intraarticular, intramuscular, or i.v. corticosteroids £ 4 weeks No tumour necrosis factor antagonizing agents No cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents

Result

Combination therapy of infliximab and methotrexate inhibited the progression of structural damage in early RA patients. Early intervention with infliximab in active RA patients despite methotrexate therapy provided long term benefits by preventing radiographic progression and preserving joint integrity

Patients

428 active RA patients Despite MTX ³ 6 swollen joints ³ 6 tender joints Morning stiffness ³ 45 min ESR > 28 mm/h C-reactive protein > 2 mg/dL

Authors

Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, St Clair EW, Weisman M, Smolen J, Lipsky PE, Maini RN

Publication

Ann Rheum Dis. 2004 Feb;63(2):149–155

Follow up

102 weeks

Note

Change of Erosion Scores: Total +12.21 (MTX), –1.02 (3mg/kg IFX/8 weeks), –1.07 (3mg/kg IFX/4 weeks), +0.46 (10mg/kg IFX/8 weeks), –0.78 (10mg/kg IFX/4 weeks) Hands +5.67 (MTX), –0.67 (3mg/kg IFX/8 weeks), –0.78 (3mg/kg IFX/4 weeks), +0.22 (10mg/kg IFX/8 weeks), –1.13 (10mg/kg IFX/4 weeks) Feet +6.54 (MTX), –0.35 (3mg/kg IFX/8 weeks), –0.28 (3mg/kg IFX/4 weeks), +0.24 (10mg/kg IFX/8 weeks), –0.35 (10mg/kg IFX/4 weeks) Change of joint space narrowing: Total +12.82 (MTX), 0.39 (3mg/kg IFX/8 weeks), –1.44 (3mg/kg IFX/4 weeks), +1.21 (10mg/kg IFX/8 weeks), –0.61 (10mg/kg IFX/4 weeks) Hands +7.71 (MTX), +0.94 (3mg/kg IFX/8 weeks), –0.75 (3mg/kg IFX/4 weeks), –0.65 (10mg/kg IFX/8 weeks), –0.43 (10mg/kg IFX/4 weeks) Feet +5.11 (MTX), –0.55 (3mg/kg IFX/8 weeks), –0.69 (3mg/kg IFX/4 weeks), +0.56 (10mg/kg IFX/8 weeks), –0.19 (10mg/kg IFX/4 weeks)

238

Rheumatoid Arthritis: Infliximab

ATTRACT-Trial Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with Infliximab and Methotrexate ATTRACT: Anti-TNF Therapy in RA with Concomitant Therapy Substance

Placebo (n = 88, n = 14 completed week 102) 3mg/kg infliximab/4 weeks (n = 86, n = 47 completed week 102) 3mg/kg infliximab/8 weeks (n = 86, n = 47 completed week 102) 10mg/kg infliximab/8 weeks (n = 87, n = 59 completed week 102) 10mg/kg infliximab/4 weeks (n = 81, n = 49 completed week 102) Concomitant medication: Prednisone £ 10 mg/day or equivalent NSAIDs were permitted at stable doses ³ 4 weeks With 15 mg MTX/week Previous medication: ³ 12.5 mg/kg MTX/week ³ 3 months No other DMARDs £ 4 weeks No intraarticular, intramuscular, or i.v. corticosteroids £ 4 weeks No tumour necrosis factor antagonizing agents No cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents

Result

Combination of infliximab and methotrexate provided sustained improvement in the signs and symptoms of RA accompanied by inhibition of progressive joint damage and among patients who previously had an incomplete response to methotrexate monotherapy

Patients

428 patients with rheumatoid arthritis Previously experienced an incomplete response to MTX ³ 6 swollen joints ³ 6 tender joints + ³ 2 of the following criteria: Morning stiffness ³ 45 min. ESR ³ 28 mm/h C-reactive protein ³ 2 mg/dL

Authors

Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, St Clair EW, Keenan GF, van der Heijde D, Marsters PA, Lipsky PE; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group

Publication

Arthritis Rheum. 2004 Apr;50(4):1051–1065

Follow up

102 weeks

ACR 20

16% (MTX), 42% (3mg IFX/8 weeks), 40% (3mg IFX/4 weeks), 48% (10mg IFX/8 weeks), 40% (10mg IFX/4 weeks)

ACR 50

6% (MTX), 21% (3mg IFX/8 weeks), 30% (3mg IFX/4 weeks), 36% (10mg IFX/8 weeks), 20% (10mg IFX/4 weeks)

ACR 70

1% (MTX), 10% (3mg IFX/8 weeks), 21% (3mg IFX/4 weeks), 20% (10mg IFX/8 weeks), 10% (10mg IFX/4 weeks)

Rheumatoid Arthritis: Infliximab

239

Note

Change of: HAQ +0.4 (all IFX), +0.3 (10mg IFX/4 weeks), +0.4 (10mg IFX/8 weeks), +0.4 (3mg IFX/4 weeks), +0.4 (3mg IFX/8 weeks), +0.1 (MTX) SF36 +6.4 (all IFX), +6.7 (10mg IFX/4 weeks), +6.9 (10mg IFX/8 weeks), +6.8 (3mg IFX/4 weeks), +4.6 (3mg IFX/8 weeks), +2.8 (MTX) Physical functioning subscale -3.4 (MTX), 8.7 (3mg IFX/8 weeks), 13.1 (3mg IFX/4 weeks), 13.6 (10mg IFX/8 weeks), 10.3 (10mg IFX/4 weeks) Total radiographic score +12.59 (MTX), +1.02 (3mg IFX/8 weeks), +1.03 (3mg IFX/4 weeks), +1.14 (10mg IFX/8 weeks), -0.42 (10mg IFX/4 weeks) Erosion score +6.65 (MTX), +0.25 (3mg IFX/8 weeks), +0.50 (3mg IFX/4 weeks), +0.43 (10mg IFX/8 weeks), -0.57 (10mg IFX/4 weeks) Joint space narrowing score +5.91 (MTX), +0.77 (3mg IFX/8 weeks), +0.1 (3mg IFX/4 weeks), +0.63 (10mg IFX/8 weeks), 0.17 (10mg IFX/4 weeks)

Adverse events

Total adverse events: MTX only 33% (MTX), 23–33% (IFX + MTX) Infusion reaction 13% (MTX), 10–13% (IFX + MTX) Death 5% (MTX), 1–3% (IFX + MTX) Malignancy 1% (MTX), 0–6% (IFX + MTX)

240

Rheumatoid Arthritis: Infliximab

Trial

A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and Infliximab in patients with active rheumatoid arthritis despite Methotrexate treatment

Substance

1 single infusion of 1g methylprednisolone (n = 15) 3mg infliximab/kg (n = 12) at weeks 0, 2, and 6 Concomitant medication: MTX therapy was continued No other DMARDs were allowed No introduction of NSAIDs Prednisolone £ 10 mg/day or equivalent No intraarticular corticosteroids Previous medication: 15 mg/kg MTX/week ³ 3 months No prior TNF antagonist treatment No i.v. methylprednisolone

Result

TNF blockade was better than methylprednisolone pulse therapy in patients with severe refractory RA, with improvement in clinical parameters of disease activity and biomarkers such as CRP and MMP-3 titres

Patients

Patients with active RA Despite MTX treatment Swollen joint count ³ 6 Tender joint count ³ 6 + ³ 2 of the following disease activity criteria: Morning stiffness ³ 45 min Erythrocyte sedimentation rate ³ 28 mm/h CRP ³ 20 mg/l

Authors

Durez P, Nzeusseu Toukap A, Lauwerys BR, Manicourt DH, Verschueren P, Westhovens R, Devogelaer JP, Houssiau FA

Publication

Ann Rheum Dis. 2004 Sep;63(9):1069–1074

Follow up

14 weeks

ACR 20

8% (methylprednisolone), 67% (IFX)

ACR 50

0% (methylprednisolone), 44% (IFX)

ACR 70

0% (methylprednisolone), 0% (IFX)

Rheumatoid Arthritis: Infliximab

Note

Change of: Physical functioning -3 (methylprednisolone), +19 (IFX) Role-physical +12 (methylprednisolone), +3 (IFX) Bodily pain +6 (methylprednisolone), +17 (IFX) General health +3 (methylprednisolone), +10 (IFX) Vitality +2 (methylprednisolone), +14 (IFX) Social functioning -4 (methylprednisolone), +13 (IFX) Role-emotional +17 (methylprednisolone), +9 (IFX) Mental health 0 (methylprednisolone), +8 (IFX)

Adverse events

No serious infections or immuno-allergic reactions (both groups) Anxiety n = 1 (methylprednisolone), n = 0 (IFX) Pruritus n = 1 (methylprednisolone), n = 0 (IFX) Neck pain n = 1 (methylprednisolone), n = 0 (IFX) Herpes simplex infection n = 0 (methylprednisolone), n = 1 (IFX) Sore throat n = 0 (methylprednisolone), n = 1 (IFX) Myalgia n = 0 (methylprednisolone), n = 1 (IFX)

241

242

Rheumatoid Arthritis: Infliximab

ASPIRE-Trial

Combination of Infliximab and Methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial ASPIRE: The Actice controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset

Substance

Placebo (n = 298) 3 mg/kg infliximab (n =373) 6 mg/kg infliximab (n =378) Weeks 0–2-6, every 8 weeks thereafter Concomitant medication: 7.5 g/kg MTX/week (increased to 15mg/week by week 4) ³ 5 mg folic acid/week Prednisone £ 10 mg/day or equivalent NSAIDs were permitted at stable doses Previous medication: No MTX No TNF alpha inhibitors No DMARDs £ 4 weeks

Result

Combination therapy with methotrexate and infliximab provided greater clinical, radiographic, and functional benefits than treatment with methotrexate alone in active RA patients

Patients

1049 RA patients Not prior treated with MTX or a TNF alpha inhibitor Persistent synovitis (> 3 months, < 3 years) ³ 10 swollen joints ³ 12 tender joints ³ 1 of the following Rheumatoid factor positivity Radiographic erosions of the hands or feet Serum CRP ³ 2.0 mg/dL

Authors

St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group

Publication

Arthritis Rheum. 2004 Nov;50(11):3432–3443

Follow up

54 weeks

ACR 20

53.6% (MTX), 62.4% (3mg/kg IFX), 66.2% (6mg/kg IFX)

ACR 50

32.1% (MTX), 45.6% (3mg/kg IFX), 50.4% (6mg/kg IFX)

ACR 70

21.2% (MTX), 32.5% (3mg/kg IFX), 37.2% (6mg/kg IFX)

ACR 90

6.6% (MTX), 10% (3mg/kg IFX), 16.9% (6mg/kg IFX)

Rheumatoid Arthritis: Infliximab

Note

243

ACR-N: 38.9% (3mg/kg IFX), 46.7% (6mg/kg IFX), 26.4% (MTX) DAS remission 21.2% (3mg/kg IFX), 31.0% (6mg/kg IFX), 15.0% (MTX) Changes of: Sharp van der Heijde +0.4 (3mg/kg IFX), +0.5 (6mg/kg IFX), +3.7 (MTX) Erosion score +0.3 (3mg/kg IFX), +0.1 (6mg/kg IFX), +3.0 (MTX) Joint space narrowing +0.1 (3mg/kg IFX), +0.2 (6mg/kg IFX), +0.6 (MTX) HAQ +75.5% (3mg/kg IFX), 76.0% (6mg/kg IFX), +65.2% (MTX) SF-36 +11.7 (3mg/kg IFX), +13.2 (6mg/kg IFX), 10.1 (MTX)

Adverse events

Urinary tract infections 21% (MTX), 25% (3mg/kg IFX), 28% (6mg/kg IFX) Nausea 18% (MTX), 20% (3mg/kg IFX), 17% (6mg/kg IFX) Headache 11% (MTX), 12% (3mg/kg IFX), 11% (6mg/kg IFX) Sinusitis 8% (MTX), 12% (3mg/kg IFX), 10% (6mg/kg IFX) Pharyngitis 6% (MTX), 9% (3mg/kg IFX), 11% (6mg/kg IFX) Pneumonia 0% (MTX), 2% (3mg/kg IFX), 3% (6mg/kg IFX) Fever 0.0% (MTX), 0.0% (3mg/kg IFX), 1.3% (6mg/kg IFX) Myocardial infarction 0.7% (MTX), 0.3% (3mg/kg IFX), 1.1% (6mg/kg IFX) Asthma 0.0% (MTX), 0.5% (3mg/kg IFX), 0.5% (6mg/kg IFX) TBC 0.0% (MTX), 0.8% (3mg/kg IFX), 0.3% (6mg/kg IFX) Infusion reactions 0.0% (MTX), 0.5% (3mg/kg IFX), 0.5% (6mg/kg IFX)

244

Rheumatoid Arthritis: Infliximab

Trial

Very early treatment with Infliximab in addition to Methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after Infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial

Substance

3mg/kg IFX (Week 0, 2, 6, and then every 8-week, n = 10) Placebo (n = 10) Concomitant medication: 7,5mg MTX/week (step up to max. 25mg/week) No other DMARDs until week 54 No corticosteroids during the first 14 weeks Thereafter intraarticular or intramuscular corticosteroids were permitted as clinically required (max. 120 mg of methylprednisolone/3-month) NSAIDs were permitted at stable doses Previous medication: No corticosteroids No DMARDs No Cyc, nitrogen mustard, chlorambucil, or other alkylating agents

Result

Infliximab plus methotrexate in early arthritis patients led to persistent remissions, fewer joint erosions, and a better quality of life

Patients

RA patients < 12 months of symptoms No previous treatment with DMARDs or oral corticosteroids CRP > 20 mg/l HAQ > 4

Authors

Quinn MA, Conaghan PG, O’Connor PJ, Karim Z, Greenstein A, Brown A, Brown C, Fraser A, Jarret S, Emery P

Publication

Arthritis Rheum. 2005 Jan;52(1):27–35

Follow up

104 weeks

ACR 20

Week 14: 60% (IFX + MTX), 20% (MTX) Week 54: 80% (IFX + MTX), 60% (MTX) Week 104: 70% (IFX + MTX), 50% (MTX)

ACR 50

Week 14: 60% (IFX + MTX), 0% (MTX) Week 54: 80% (IFX + MTX), 40% (MTX) Week 104: 70% (IFX + MTX), 50% (MTX)

ACR 70

Week 14: 60% (IFX + MTX), 0% (MTX) Week 54: 70% (IFX + MTX), 30% (MTX) Week 104: 50% (IFX + MTX), 50% (MTX)

Note

Mean change in Sharp scores 12 (IFX + MTX), 10 (MTX) Remission n = 7 (IFX + MTX), n = 2 (MTX) Change of (week 14): MRI total synovitis score -2.1 (IFX + MTX), -1.2 (MTX)

Adverse events

Cutaneous vasculitis n = 1 (IFX) Abnormal liver function test n = 1 (IFX) Infusion reaction n = 1 (IFX)

Rheumatoid Arthritis: Infliximab

iRAMT-Trial

Methotrexate dosage reduction in patients with rheumatoid arthritis beginning therapy with Infliximab: the Infliximab Rheumatoid Arthritis Methotrexate Tapering (iRAMT) trial iRAMT: Infliximab Rheumatoid Arthritis Methotrexate Tapering

Substance

3 mg/kg Infliximab/8-week (loading dosages at weeks 0, 2, and 6)

245

After week 22: 40% improval in the combined tender and swollen joint score (responder): => MTX was tapered by 5mg every 8 weeks to min. 5mg/week No 40% improval in the combined tender and swollen joint score: Infliximab increased by 100mg to a max. of 10mg/kg every 4 weeks Concomitant medication: 7.5–25mg MTX/week Other DMARDs were permitted at stable dosage ³ 4 weeks Prednisone £ 10mg/d NSAIDs were permitted Folic acid/folinic acid supplementation was permitted Intraarticular corticosteroid injections were permitted Previous medication: MTX ³ 3 months No TNF antagonizing agents Result

75% of the RA patients treated with infliximab achieved at least a 40% reduction in the combined swollen and tender joint count

Patients

210 RA patients Inadequate response to MTX Oral or parenteral 7.5 to 25 mg MTX/week for min 3 months

Authors

Fleischmann RM, Cohen SB, Moreland LW, Schiff M, Mease PJ, Smith DB, Keenan G, Kremer JM; iRAMT Study Group

Publication

Curr Med Res Opin. 2005 Aug;21(8):1181–1190

Follow up

54 weeks

ACR 20

75%

Note

³ 40% improvement in the combined tender and swollen joint count and had their MTX doses tapered 76% (n = 159) Responders with no relapse n = 92 Responders with 1 relapse n =32 Responders with episodic relapses or loss of response n = 35 Change of: Tender and swollen joint count –72.5% (all patients), –82.0% (responders), –69.6% (responders with one relapse), –14.8% (responders with episodic relapse), +10.6% (none responders) HAQ; (median) –40.0% (all patients), –61.5% (responders), –31.7% (responders with one relapse), –17.6% (responders with episodic relapse) ESR –22.9% (all patients), –32.7% (responders), –20.0% (responders with one relapse), –30.8% (responders with episodic relapse) CRP –49.8% (all patients), –61.5% (responders), –58.7% (responders with one relapse), –19.6% (responders with episodic relapse)

Adverse events

Pneumonia 2.9% Chest pain 1.4% Congestive heart failure 1.4% Coronary artery disease 1.4%

246

Rheumatoid Arthritis: Infliximab

BeSt-Trial

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt-study): a randomized, controlled trial BeSt: Behandelings strategie

Substance

Group 1 (sequential monotherapy, n = 126): Sequential 15 mg/week MTX Increased MTX to 25–30mg/week Change to 2000–3000mg/day SSZ Change to 20mg/day Lef Change to MTX + IFX Change to gold + methylprednisolone Group 2 (step up, n = 121): Sequential 15mg/week MTX Increased MTX to 25–30mg/week + 2000–3000mg/day SSZ + 400mg/day HCQ + Prednisone Change to MTX + IFX Change to MTX + CSA + prednisone Change to 20mg/day Lef Group 3 (combination, n = 133): 7.5mg/week MTX + 2000mg/day SSZ + 400mg/day HCQ + 60mg/day prednisone Tapered to 7.5mg/day over 7 weeks Then increase of MTX to 25–30mg/week Change to MTX + CSA + prednisone Change to MTX + infliximab Change to leflunomide Change to gold + methylprednisolone, and Change to azathioprine + prednisone if DAS44 > 2.4 MTX with 2.5mg/kg/day ciclosporin A Group 4 (IFX, n = 128): 25–30mg/week MTX + 3mg/kg infliximab Increased to max. 10mg/kg Change to SSZ Change to leflunomide Change to MTX + CSA + prednisone Change to gold + methylprednisolone Change to AZA + prednisone Treatment was changed: DAS44 > 2.4 If DAS44 £ 2.4 for 6 months treatment was reduced

Result

Initial combination therapy with either prednisone or infliximab in early RA resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy

Rheumatoid Arthritis: Infliximab

247

Patients

508 patients with RA Disease duration £ 2years No prior DMARD therapy ³ 6 swollen joints ³ 6 tender joints ESR ³ 28 mm/h Global health score of ³ 20 mm

Authors

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA

Publication

Arthritis Rheum. 2005 Nov;52(11):3381–3390

Follow up

1 year

Note

D-HAQ scores 0.7 (group 1), 0.7 (group 3), 0.5 (group 3), 0.5 (group 4) Sharp/van der Heijde score 2.0 (group 1), 2.5 (group 2), 1.0 (group 3), 0.5 (group 4) Erosion score 1.0 (group 1), 1.0 (group 2), 0.5 (group 3), 0.0 (group 4) Joint space narrowing score 1.0 (group 1), 0.0 (group 2), 0.0 (group 3), 0.0 (group 4) DAS44 £ 2.4 53% (group 1), 64% (group 2), 71% (group 3), 74% (group 4)

Adverse events

Adverse events 43% (group 1), 47% (group 2), 37% (group 3), 39% (group 4) Gastrointestinal symptoms 16% (group 1), 15% (group 2), 8% (group 3), 11% (group 4) Skin rash or other mild dermal or mucosal events 10% (group 1), 12% (group 2), 9% (group 3), 6% (group 4) Infections, mainly upper respiratory tract infections 4% (group 1), 7% (group 2), 8% (group 3), 8% (group 4) Cardiovascular events 2% (group 1), 2% (group 2), 6% (group 3), 2% (group 4)

248

Rheumatoid Arthritis: Infliximab

Trial

A multicenter, double-blind, randomized, placebo controlled trial of Infliximab combined with low dose Methotrexate in Japanese patients with rheumatoid arthritis

Substance

Placebo (n = 47) Infliximab 3 mg/kg (n = 49) Infliximab 10 mg/kg (n = 50) at Weeks 0, 2, 6 After week 14: Open label infliximab 3 mg/kg every 8 weeks Concomitant medication: Prednisolone £ 10mg/d NSAIDs were permitted Folic acid/folinic acid supplementation was permitted 6 mg MTX/week No other DMARDs NSAIDs were permitted at stable dosage Folic acid was permitted at stable dosage No intraarticular, intramuscular, i.v., or epidural corticosteroids Previous medication: 6 mg MTX/week ³ 4 weeks No other DMARDs No arthrocentesis £ 4 weeks No plasma exchange £ 4 weeks No alkylating agents £ 5 years

Result

Infliximab combined with low dose methotrexate was effective in active RA patients

Patients

147 RA patients with active disease Despite treatment with MTX ³ 6 tender joints ³ 6 swollen joints + ³ 2 out of: Morning stiffness ³ 45 min Erythrocyte sedimentation rate ³ 28 mm/h CRP ³ 2 mg/dL

Authors

Abe T, Takeuchi T, Miyasaka N, Hashimoto H, Kondo H, Ichikawa Y, Nagaya I

Publication

J Rheumatol. 2006 Jan;33(1):37–44

Follow up

14 weeks + 36 weeks open label extension

ACR 20

Week 14: 23.4% (placebo), 61.2% (IFX 3mg/kg), 52.9% (IFX 10mg/kg)

ACR 50

Week 14: 8.5% (placebo), 30.6% (IFX 3mg/kg), 35.3% (IFX 10mg/kg)

ACR 70

Week 14: 0% (placebo), 10.2% (IFX 3mg/kg), 15.7% (IFX 10mg/kg)

Rheumatoid Arthritis: Infliximab

Adverse events

249

Double blind trial: Cold 8.5% (placebo), 18.4% (IFX 3mg/kg), 25.5% (IFX 10mg/kg) Fever 19.1% (placebo), 18.4% (IFX 3mg/kg), 15.7% (IFX 10mg/kg) Diarrhoea 4.3% (placebo), 12.2% (IFX 3mg/kg), 13.7% (IFX 10mg/kg) Cough 10.6% (placebo), 6.1% (IFX 3mg/kg), 13.7% (IFX 10mg/kg) Headache 12.8% (placebo), 14.3% (IFX 3mg/kg), 5.9% (IFX 10mg/kg) Sputum 8.5% (placebo), 6.1% (IFX 3mg/kg), 5.9% (IFX 10mg/kg) Rash 0% (placebo), 8.2% (IFX 3mg/kg), 5.9% (IFX 10mg/kg) Pneumonia 0% (placebo), 2.0% (IFX 3mg/kg), 5.9% (IFX 10mg/kg) Hot flushes, facial 2.1% (placebo), 0% (IFX 3mg/kg), 5.9% (IFX 10mg/kg) Pruritus 0% (placebo), 6.1% (IFX 3mg/kg), 3.9% (IFX 10mg/kg) Pain, pharynx 6.4% (placebo), 6.1% (IFX 3mg/kg), 2.0% (IFX 10mg/kg) Stomatitis 6.4% (placebo), 8.2% (IFX 3mg/kg), 0% (IFX 10mg/kg) Epigastralgia 0% (placebo), 6.1% (IFX 3mg/kg), 0% (IFX 10mg/kg) Any adverse event with subjective symptoms 68.1% (placebo), 73.5% (IFX 3mg/kg), 72.5% (IFX 10mg/kg) Any adverse event that resulted in discontinuation 2.1% (placebo), 2.0% (IFX 3mg/kg), 7.8% (IFX 10mg/kg) Any serious adverse event 2.1% (placebo), 0% (IFX 3mg/kg), 11.8% (IFX 10mg/kg) Any infections 36.2% (placebo), 46.9% (IFX 3mg/kg), 49.0% (IFX 10mg/kg) Any infusion reactions 36.2% (placebo), 46.9% (IFX 3mg/kg), 37.3% (IFX 10mg/kg) Open lable trial: Cold 26.8% (placebo), 28.6% (IFX 3mg/kg), 41.2% (IFX 10mg/kg) Fever 17.1% (placebo), 30.6% (IFX 3mg/kg), 29.4% (IFX 10mg/kg) Cough 12.2% (placebo), 18.4% (IFX 3mg/kg), 23.5% (IFX 10mg/kg) Diarrhoea 14.6% (placebo), 14.3% (IFX 3mg/kg), 17.6% (IFX 10mg/kg) Headache 4.9% (placebo), 14.3% (IFX 3mg/kg), 13.7% (IFX 10mg/kg) Sputum 4.9% (placebo), 16.3% (IFX 3mg/kg), 9.8% (IFX 10mg/kg) Any adverse event with subjective symptoms 78.0% (placebo), 89.8% (IFX 3mg/kg), 92.2% (IFX 10mg/kg) Any adverse event that resulted in discontinuation 22.0% (placebo), 8.2% (IFX 3mg/kg), 21.6% (IFX 10mg/kg) Any serious adverse event 14.6% (placebo), 4.1% (IFX 3mg/kg), 25.5% (IFX 10mg/kg) Any infections 53.7% (placebo), 63.3% (IFX 3mg/kg), 60.8% (IFX 10mg/kg) Any infusion reactions 41.5% (placebo), 67.3% (IFX 3mg/kg), 49.0% (IFX 10mg/kg)

250

Rheumatoid Arthritis: Infliximab

Start-Trial

The safety of Infliximab, combined with background treatments, among patients with rheumatoid arthritis and various co-morbidities: a large, randomized, placebo-controlled trial START: Safety Trial for RA with Remicade Therapy

Substance

Placebo (group 1, n = 363, start IFX 3mg/kg week 22) 3 mg/kg infliximab (group 2, n = 360) 10 mg/kg infliximab (group 3, n = 361) IFX application weeks 0, 2, 6, every 8 weeks thereafter Concomitant medication: MTX was continued at stable doses Chloroquine, Aza, D-penicillamine, gold, HCQ, SSZ, Lef, CsA were continued at stable doses Corticosteroids were continued at stable doses NSAIDs were continued at stable doses Previous medication: MTX ³ 3 months No cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents No CsA ³ 5 mg/kg No biologic agent

Result

The risk of serious infections in patients receiving 3 mg/kg infliximab and methotrexate was similar to that of patients receiving methotrexate monotherapy

Patients

1084 patients with active RA ³ 6 swollen joints ³ 6 tender joints Despite receiving methotrexate Patients in group 2 who failed to meet pre-defined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg

Authors

Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, Rahman MU; START Study Group

Publication

Arthritis Rheum. 2006 Apr;54(4):1075–1086

Rheumatoid Arthritis: Infliximab

251

Follow up

54 weeks

ACR 20

25.5% (placebo), 58.0% (3mg/kg IFX), 61.0% (10mg/kg IFX)

ACR 50

9.7% (placebo), 32.1% (3mg/kg IFX), 35.4% (10mg/kg IFX)

ACR 70

4.7% (placebo), 14.0% (3mg/kg IFX), 16.1% (10mg/kg IFX)

Note

DAS28 response 4.4 (placebo), 3.5 (3mg/kg IFX), 3.3 (10mg/kg IFX) DAS-Remission (DAS28 < 2.6) 14% (placebo), 31% (3mg/kg IFX + MTX), 32% (10mg/kg IFX) DAS28 > 5.1 33% (placebo), 12% (3mg/kg IFX), 10% (10mg/kg IFX) Good or moderate response 44% (placebo), 75% (3mg/kg IFX), 79% (10mg/kg IFX)

Adverse events

Upper respiratory tract infections 10.5% (placebo), 9.7% (3mg/kg IFX), 11.9% (10mg/kg IFX) Headache 6.1% (placebo), 9.7% (3mg/kg IFX), 10.2% (10mg/kg IFX) Nausea 8% (placebo), 6.4% (3mg/kg IFX), 6.4% (10mg/kg IFX) Pharyngitis 3.3% (placebo), 3.1% (3mg/kg IFX), 6.4% (10mg/kg IFX) Rash 1.7% (placebo), 4.7% (3mg/kg IFX), 4.4% (10mg/kg IFX) Diarrhoea 3.3% (placebo), 2.5% (3mg/kg IFX), 6.4% (10mg/kg IFX) ALT level increased 2.8% (placebo), 3.6% (3mg/kg IFX), 5.3% (10mg/kg IFX) Hypertension 3.3% (placebo), 3.6% (3mg/kg IFX), 5.0% (10mg/kg IFX) Sinusitis 3.9% (placebo), 3.6% (3mg/kg IFX), 5.0% (10mg/kg IFX) Coughing 2.8% (placebo), 3.9% (3mg/kg IFX), 4.4% (10mg/kg IFX)

252

Rheumatoid Arthritis: Infliximab

BESt-Trial

Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial BeSt: Behandelings strategie

Substance

Group 1 (sequential monotherapy, n = 126): Sequential 15 mg/week MTX Increased MTX to 25–30mg/week Change to 2000–3000mg/day SSZ Change to 20mg/day Lef Change to MTX + IFX Change to Gold + methylprednisolone Group 2 (step up, n = 121): Sequential 15mg/week MTX Increased MTX to 25–30mg/week + 2000–3000mg/day SSZ + 400mg/day HCQ + Prednisone Change to MTX + IFX Change to MTX + CSA + prednisone Change to 20mg/day Lef Group 3 (combination, n = 133): 7.5mg/week MTX + 2000mg/day SSZ + 400mg/day HCQ + 60mg/day Prednisone Tapered to 7.5mg/day over 7 weeks Then increase of MTX to 25–30mg/week Change to MTX + CSA + prednisone Change to MTX + infliximab Change to leflunomide Change to gold + methylprednisolone Change to azathioprine + prednisone if DAS44 > 2.4 MTX with 2.5mg/kg/day ciclosporin A Group 4 (IFX, n = 128): 25–30mg/week MTX + 3mg/kg infliximab Increased to max. 10mg/kg Change to SSZ Change to leflunomide Change to MTX + CSA + prednisone Change to Gold + methylprednisolone Change to AZA + prednisone Treatment was changed if: DAS44 > 2.4 If DAS44 £ 2.4 for 6 months treatment was reduced

Rheumatoid Arthritis: Infliximab

253

Result

Antirheumatic drugs in patients with early rheumatoid arthritis were highly effective in a setting of tight disease control. Initial combination therapies seemed to provide earlier clinical improvement and less progression of joint damage. All treatment strategies eventually showed similar clinical improvements. Combination therapy could be withdrawn successfully and less treatment adjustments are needed than with initial monotherapies

Patients

508 patients with RA Disease duration £ 2 years No prior DMARD therapy ³ 6 of 66, swollen joints ³ 6 of 68 tender joints ESR ³ 28 mm/h or a global health score of ³ 20 mm

Authors

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Peeters AJ, de Jonge-Bok JM, Mallée C, de Beus WM, de Sonnaville PB, Ewals JA, Breedveld FC, Dijkmans BA

Publication

Ann Intern Med. 2007 Mar 20;146(6):406–415

Follow up

2 years

Note

Change of: HAQ -0.7 (group 1), -0.8 (group 2), -0.9 (group 3), -0.9 (group 4) Total Sharp van der Heijde score +9.0 (group 1), +5.2 (group 2), +2.6 (group 3), +2.5 (group 4) Erosion score +4.7 (group 1), +3.1 (group 2), +1.1 (group 3), +1.3 (group 4) Narrowing score +4.3 (group 1), +2.1 (group 2), +1.5 (group 3), +1.2 (group 4)

Adverse events

Gastrointestinal adverse events 12% (group 1), 9% (group 2), 9% (group 3), 12% (group 4) Skin rash or other mild dermal or mucosal events 10% (group 1), 8% (group 2), 11% (group 3), 6% (group 4) Infections in 8% (group 1), 8% (group 2), 8% (group 3), 10% (group 4) Cardiovascular events 4% (group 1), 4% (group 2), 7% (group 3), 6% (group 4)

254

Rheumatoid Arthritis: Infliximab

BeSt-Trial

Infliximab and Methotrexate as induction therapy in patients with early rheumatoid arthritis BeSt: Behandelings strategie

Substance

Group 4: Initial combination therapy with MTX and IFX (n = 128): Started IFX 3mg/kg n = 120 Progressed to IFX 5mg/kg n = 65 Progressed to IFX 7.5mg/kg n = 39 Progressed to IFX 10mg/kg n = 30 At weeks 0, 2, and 6 and every 8 weeks Continued treatment with other DMARDs n = 22

Result

Initial treatment of infliximab plus methotrexate led to a discontinuation of infliximab in 56% of the patients after achieving a DAS28 of £ 2.4. Low disease activity was maintained in these patients while the methotrexate dosage was tapered to 10 mg/week

Patients

128 patients with RA Disease duration £ 2years No prior DMARD therapy ³ 6 of 66 swollen joints ³ 6 of 68 tender joints, and ESR ³ 28 mm/h Or a global health score of ³ 20 mm

Authors

van der Bijl AE, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Ten Wolde S, Han KH, van Krugten MV, Allaart CF, Breedveld FC, Dijkmans BA

Publication

Arthritis Rheum. 2007 Jul;56(7):2129–2134

Follow up

2 years

Note

Persistent low disease activity 56% Disease flare after discontinuation and resumed infliximab n = 10 Not achieve persistent low disease activity n = 13 Responders n = 67 (Responders) Patients requirering continuous IFX n = 23 (continue IFX) Patients with treatment failure n = 30 (failure) Change of: DAS -2.7 (responders), -2.1 (continue IFX), -1.9 (Failure) HAQ -1.0 (responders), -0.7 (continue IFX), -0.8 (Failure) SHS +1.4 (responders), +2.5 (continue IFX), +4.9 (Failure)

Rheumatoid Arthritis: Infliximab

255

Trial

Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of Methotrexate alone, Methotrexate in combination with Infliximab, and Methotrexate in combination with intravenous pulse methylprednisolone

Substance

MTX monotherapy (n = 14) MTX + 1 mg i.v. methylprednisolone/day (IV MP) on day 0 and weeks 2, 6, 14, 22, 30, 38, and 46 (n = 15) MTX + 3 mg/kg infliximab infused on day 0 and weeks 2, 6, 14, 22, 30, 38, and 46 (n = 15) Concomitant medication: 7.5mg MTX/week (increased to 20mg/week at week 14 NSAIDs were continued at stable doses No intraarticular corticosteroids No introduction of new DMARDs No introduction of oral corticosteroids Previous medication: No MTX No glucocorticoids for >3 months Not treated with > DMARDs No i.v. Methylprednisolone pulses

Result

Combination therapy with methotrexate and infliximab in patients with early RA was superior to methotrexate monotherapy for reducing MRI-detected signs of synovitis and bone edema. Progression of MRI-detected erosion was greater in patients treated with methotrexate plus i.v. methylprednisolone compared with that in patients who received methotrexate plus infliximab

Patients

44 patients with early RA Active disease duration < 1 year Swollen joint count ³ 6 Tender joint count ³ 8 Not previously been treated with MTX No glucocorticoids for > 3 months No DMARDs, MTX, or i.v. methylprednisolone pulses

Authors

Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, Luyten FP, Corluy L, Houssiau FA, Verschueren P

Publication

Arthritis Rheum. 2007 Dec;56(12):3919–3927

Follow up

52 weeks

Note

ACR20/50/70 were significantly better in the IVMP and IFX groups EULAR remission 40% (MTX), 70% (IV MP), 70% (IFX) Change of: Synovitis on MRI (median) –4.5 (MTX), –8 (IV MP), –10.5 (IFX) Edema on MRI (median) –2 (MTX), –2 (IV MP), –9 (IFX) Erosions on MRI (median) +1 (MTX), +6 (IV MP), +1 (IFX) CRP (mg/l) –4.5 (MTX), –24.5 (IV MP), –15.5 (IFX) DAS–CRP –1.59 (MTX), –2.62 (IV MP), –2.78 (IFX)

Adverse events

MTX-related pneumonitis n = 1

256

Rheumatoid Arthritis: Infliximab

BeSt-Trial

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial BeSt: Behandelings strategie

Substance

Group 1 (sequential monotherapy, n = 126): Sequential 15mg/week MTX Increased MTX to 25–30mg/week Change to 2000–3000mg/day SSZ Change to 20mg/day Lef Change to MTX + IFX Change to gold + methylprednisdone Group 2 (step up, n = 121): Sequential 15mg/week MTX Increased MTX to 25–30mg/week + 2000–3000mg/day SSZ + 400mg/day HCQ + Prednisone Change to MTX + IFX Change to MTX + CSA + prednisone Change to 20mg/day Lef Group 3 (combination, n = 133): 7.5mg/week MTX + 2000mg/day SSZ + 400mg/day HCQ + 60mg/dayPrednisone Tapered to 7.5mg/day over 7 weeks Then increase of MTX to 25–30mg/week Change to MTX + CSA + prednisone Change to MTX + infliximab Change to leflunomide Change to gold + methylprednisolone, and Change to azathioprine + prednisone If DAS44 > 2.4 MTX with 2.5mg/kg/day ciclosporin A Group 4 (IFX, n = 128): 25–30mg/week MTX + 3mg/kg infliximab Increased to max. 10mg/kg Change to SSZ Change to leflunomide Change to MTX + CSA + prednisone Change to Gold + methylprednisolone Change to AZA + prednisone Treatment was changed: DAS44 > 2.4 If DAS44 £ 2.4 for 6 months treatment was reduced

Rheumatoid Arthritis: Infliximab

Result

In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy

Patients

508 patients with RA Disease duration £ 2years No prior DMARD therapy ³ 6 swollen joints ³ 6 tender joints ESR ³ 28 mm/h Global health score of ³ 20 mm

Authors

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA

Publication

Arthritis Rheum. 2008 Feb;58(2 Suppl):S126–S135

Follow up

12 months

Note

Change of: D-HAQ -0.7 (Group 1), -0.7 (Group 2), -0.9 (Group 3), -0.9 (Group 4) Week 12: Total SHS +2.0 (Group 1), +2.5 (Group 2), +1.0 (Group 3), +0.5 (Group 4) Erosion score +1.0 (Group 1), +1.0 (Group 2), +0.5 (Group 3), 0.0 (Group 4) Joint space narrowing +1.0 (Group 1), 0.0 (Group 2), 0.0 (Group 3), 0.0 (Group 4) DAS44 > 2.4 53% (Group 1), 64% (Group 2), 71% (Group 3), 74% (Group 4)

Adverse events

Gastrointestinal symptoms 16% (Group 1), 15% (Group 2), 8% (Group 3), 11% (Group 4) Mild dermal/mucosal events 10% (Group 1), 12% (Group 2), 9% (Group 3), 6% (Group 4) Upper respiratory infections 4% (Group 1), 7% (Group 2), 8% (Group 3), 8% (Group 4) Cardiovascular events 2% (Group 1), 2% (Group 2), 6% (Group 3), 2% (Group 4)

257

258

Rheumatoid Arthritis: Infliximab

ASPIRE-Trial

Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with Methotrexate monotherapy and Infliximab plus Methotrexate: the impacts of remission and TNF-blockade ASPIRE: The Active controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset

Substance

Placebo (n = 298) 3 mg/kg Infliximab (n =373) 6 mg/kg Infliximab (n =378) Weeks 0–2-6, every 8 weeks thereafter Concomitant medication: 7.5 mg/kg MTX/week (increased to 15mg/week by week 4) MTX dose (week 54) 15.1mg/week (placebo), 15.5mg/week (3mg IFX), 14.9mg/week (6mg IFX) ³ 5 mg folic acid/week Prednisone £ 10 mg/day or equivalent NSAIDs were permitted at stable doses Previous medication: No MTX No TNF alpha inhibitors No DMARDs £ 4 weeks

Result

Joint damage progressed despite methotrexate therapy even at low and moderate disease activity levels. Methotrexate plus infliximab inhibited radiographic progression across all disease activity states

Patients

1049 patients with active RA persistent synovitis Diseases duration > 3 months < 3 years ³ 10 swollen joints ³ 12 tender joints ³ 1 of the following: Rheumatoid factor positivity Radiographic erosions of the hands or feet, or Serum CRP ³ 2.0 mg/dL

Authors

Smolen JS, Han C, van der Heijde DM, Emery P, Bathon JM, Keystone E, Maini RN, Kalden JR, Aletaha D, Baker D, Han J, Bala M, St Clair EW

Publication

Ann Rheum Dis. 2009 Jun;68(6):823–827. Epub 2008 Jul 1

Follow up

54 weeks

Rheumatoid Arthritis: Infliximab

Note

Patients with: Remission week 14: 10.7% (IFX), 2.8% (placebo) Remission week 54: 21.3% (IFX), 12.3% (placebo) Low disease activity week 14: 26.0% (IFX), 14.6% (placebo) Low disease activity week 54: 35.5% (IFX), 29.5% (placebo) Moderate disease activity week 14: 37.4% (IFX), 45.5% (placebo) Moderate disease activity week 54: 28.5% (IFX), 29.5% (placebo) High disease activity week 14: 25.9% (IFX), 37.2% (placebo) High disease activity week 54: 14.7% (IFX), 28.6% (placebo) Change of Total Sharp Score in these groups: Remission week 14: -0.3 (IFX), +0.1 (placebo) Remission week 54: -0.2 (IFX), +1.1 (placebo) Low disease activity week 14: 0.0 (IFX), +2.8 (placebo) Low disease activity week 54: -0.4 (IFX), +2.2 (placebo) Moderate disease activity week 14: +0.3 (IFX), +2.1 (placebo) Moderate disease activity week 54: +0.6 (IFX), +3.9 (placebo) High disease activity week 14: +1.3 (IFX), +6.5 (placebo) High disease activity week 54: +2.1 (IFX), +5.8 (placebo)

259

260

Rheumatoid Arthritis: Infliximab

Trial

Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?

Substance

Infliximab 3mg/kg at weeks 0, 2, and 6 and every 8 weeks (n = 10) Placebo (n = 7) Week 14 if clinical inflammation persisted (joint synovitis with raised CRP): MTX was started Concomitant medication: No additional information

Result

TNF antagonist therapy provided modest short-term relief but did not prevent the development of RA in poor prognosis undifferentiated arthritis

Patients

17 patients with undifferentiated arthritis CRP > 10mg/l Disease duration < 12 months HAQ > 4

Authors

Saleem B, Mackie S, Quinn M, Nizam S, Hensor E, Jarrett S, Conaghan PG, Emery P

Publication

Ann Rheum Dis. 2008 Aug;67(8):1178–1180. Epub 2008 Jan 30

Follow up

54 weeks

Note

Week 52: Developed RA: 100% (IFX) 71%, (placebo) Change of (week 26): Pain VAS -24 (placebo), -12 (IFX) Patient’s global assessment -24 (placebo), -16 (IFX) Physician’s global assessment -20 (placebo), -16 (IFX) Fatigue VAS -37 (placebo), -2 (IFX) CRP -4 (placebo), -7 (IFX) Tender joint count 0 (placebo), -11 (IFX) Swollen joint count -1 (placebo), -5 (IFX) HAQ score -0.5 (placebo), -0.94 (IFX)

Rheumatoid Arthritis: Infliximab

261

Best-Trial

Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis BeSt: Behandelings strategie

Substance

Group 1 (sequential monotherapy, n = 126): Sequential 15 mg/week MTX Increased MTX to 25–30mg/week Change to 2000–3000mg/day SSZ Change to 20mg/dayLef Change to MTX + IFX Change to Gold + methylprednisolone Group 2 (step up, n = 121): Sequential 15mg/week MTX Increased MTX to 25–30mg/week + 2000–3000mg/day SSZ + 400mg/day HCQ + Prednisone Change to MTX + IFX Change to MTX + CSA + prednisone Change to 20mg/day Lef Group 3 (combination, n = 133): 7.5mg/week MTX + 2000mg/day SSZ + 400mg/day HCQ + 60mg/day prednisone Tapered to 7.5mg/day over 7 weeks Then increase of MTX to 25–30mg/week Change to MTX + CSA + prednisone Change to MTX + infliximab Change to leflunomide Change to gold + methylprednisolone Change to azathioprine + prednisone if DAS44 > 2.4 MTX with 2.5mg/kg/day ciclosporin A Group 4 (IFX, n = 128): 25–30mg/week MTX + 3mg/kg infliximab Increased to max. 10mg/kg Change to SSZ Change to leflunomide Change to MTX + CSA + prednisone Change to Gold + methylprednisolone Change to AZA + prednisone Treatment was changed: DAS44 > 2.4 If DAS44 £ 2.4 for 6 months treatment was reduced

Result

In patients with recent-onset active RA, drug-free remission was achieved in up to 18% of patients. DAS-driven treatment maintained clinical and functional improvement, independent of the treatment strategy. Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy

262

Rheumatoid Arthritis: Infliximab

Patients

508 patients with RA Disease duration £ 2years No prior DMARD therapy ³ 6 of 66, swollen joints ³ 6 of 68 tender joints, and ESR ³ 28 mm/h or a global health score of ³ 20 mm

Authors

van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Güler-Yüksel M, Zwinderman AH, Kerstens PJ, van der Lubbe PA, de Beus WM, Grillet BA, Ronday HK, Huizinga TW, Breedveld FC, Dijkmans BA, Allaart CF

Publication

Ann Rheum Dis. 2009 Jun;68(6):914–921. Epub 2008 Jul 28

Follow up

4 years

Note

DAS-remission (DAS44 < 1.6) 43% (all patients), 50% (Group 1), 41% (Group 2), 38% (Group 3), 42% (Group 4) Drug free remission: 14% (Group 1), 12% (Group 2), 8% (Group 3), 18% (Group 4) Received Prednisone therapy 6% (Group 1), 22% (Group 2), 99% (Group 3), 16% (Group 4) Cumulative Prednisone doses 177mg (Group 1), 1565mg (Group 2), 4116mg (Group 3), 588mg (Group 4) Change of: HAQ –0.8 (Group 1), 0.7 (Group 2), -0.8 (Group 3), -0.8 (Group 4) Progression of Sharp/van der Heijde score (Total score) +11.7 (Group 1), +9.7 (Group 2), +6.7 (Group 3), +5.4 (Group 4) Erosion score +6.0 (Group 1), +5.7 (Group 2), +3.0 (Group 3), +3.0 (Group 4) Narrowing score (SD) +5.7 (Group 1), +4.0 (Group 2), +3.7 (Group 3), +2.4 (Group 4) The absence of anti-cyclic citrullinated peptide antibodies, male gender and short symptom duration were independently associated with drug-free remission

Adverse events

Infections 25% (Group 1), 29% (Group 2), 18% (Group 3), 25% (Group 4) Gastrointestinal 14% (Group 1), 11% (Group 2), 13% (Group 3), 16% (Group 4) Dermal/mucosal 13% (Group 1), 13% (Group 2), 14% (Group 3), 9% (Group 4) Neurological 7% (Group 1), 9% (Group 2), 2% (Group 3), 13% (Group 4) Cardiovascular 4% (Group 1), 6% (Group 2), 10% (Group 3), 9% (Group 4) Infusion reactions n = 1 (Group 1), n = 0 (Group 2), n = 1 (Group 3), n = 2 (Group 4) Non-melanoma skin cancers n = 2 (Group 1), n = 0 (Group 2), n = 1 (Group 3), n = 3 (Group 4) Death n = 1 (Group 1), n = 3 (Group 2), n = 1 (Group 3), n = 3 (Group 4)

Rheumatoid Arthritis: Infliximab

Best-Trial

Clinical and radiological efficacy of initial vs. delayed treatment with Infliximab plus Methotrexate in patients with early rheumatoid arthritis BEST: Behandelings strategie

Substance

Group 1 (sequential monotherapy, n = 67): Sequential 15 mg/week MTX Increased MTX to 25–30 mg/week Change to 2000–3000mg/day SSZ Change to 20mg/day Lef Change to MTX + IFX Change to Gold + methylprednisolone Change to MTX + CSA + prednisone

263

Group 4 (IFX, n = 117): 25–30 mg/week MTX + 3 mg/kg infliximab Increased to max. 10mg/kg Change to SSZ Change to leflunomide Change to MTX + CSA + prednisone Change to Gold + methylprednisolone Change to AZA + prednisone Treatment was changed: DAS44 > 2.4 If DAS44 £ 2.4 for 6 months treatment was reduced Resul

Infliximab plus methotrexate as initial treatment for patients with recent onset RA was more effective than reserving infliximab plus methotrexate for patients who failed to respond sufficiently to traditional DMARDs

Patients

184 patients with RA Disease duration £ 2years No prior DMARD therapy ³ 6 swollen joints ³ 6 tender joints ESR ³ 28 mm/h Global health score of ³ 20 mm

Authors

van der Kooij SM, le Cessie S, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Zeben D, Kerstens PJ, Hazes JM, van Schaardenburg D, Breedveld FC, Dijkmans BA, Allaart CF

Publication

Ann Rheum Dis. 2009 Jul;68(7):1153–1158. Epub 2008 Oct 17

Follow up

3 years

Note

Stopped IFX and still DAS44 £ 2.4 56% (initial MTX), 29% (delayed MTX), Remained on MTX+IFX 19% (initial IFX), 40% (delayed IFX), Patients with radiological progression 26% (initial IFX), 50% (delayed IFX)

264

Rheumatoid Arthritis: Infliximab

Swefot-Trial

Addition of Infliximab compared with addition of Sulfasalazine and Hydroxychloroquine to Methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial Swefot: Swedish Pharmacotherapy

Substance

1st phase: 10 mg methotrexate/week (increased to 20mg/week) 2nd phase (after 3–4 months, if DAS28 > 3.2) HCQ, SSZ arm: + 2 × 1000mg sulfasalazine/day (max 3g/d) + 400mg hydroxychloroquine/day (n = 130) Ineffective: Exchange 1 substance to 2.5 mg ciclosporin A/day (increase to 5 mg/kg/d) IFX arm: + 3mg/kg infliximab (n = 128) Dose of IFX could be increased Ineffective: IFX replaced by 50 mg ETN/w Concomitant medication: No other DMARDs Occasional glucocorticoid injections into inflamed joints No low-dose oral glucocorticoids Previous medication: No DMARDs Prednisolone £ 10mg/d

Result

In patients with early RA in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy was clinically superior to addition of conventional disease-modifying antirheumatic drugs

Patients

487 early RA patients Symptom duration <1 year DAS28 > 3.2

Authors

van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Cöster L, Waltbrand E, Zickert A, Theander J, Thörner A, Hellström H, Teleman A, Dackhammar C, Akre F, Forslind K, Ljung L, Oding R, Chatzidionysiou A, Wörnert M, Bratt J

Publication

Lancet. 2009 Aug 8;374(9688):459–466

Follow up

24 months

ACR 20

Compared to inclusion 45% (HCQ, SSZ), 59% (IFX) Compared to randomization 28% (HCQ, SSZ), 42% (IFX)

ACR 50

Compared to inclusion 34% (HCQ, SSZ), 48% (IFX) Compared to randomization 15% (HCQ, SSZ), 25% (IFX)

ACR 70

Compared to inclusion 15% (HCQ, SSZ), 28% (IFX) Compared to randomization 7% (HCQ, SSZ), 12% (IFX)

Rheumatoid Arthritis: Infliximab

Note

Compared to inclusion EULAR good response 32% (HCQ, SSZ), 47% (IFX) Compared to randomization EULAR good response 25% (HCQ, SSZ), 29% (IFX) Compared to inclusion EULAR good response 58% (HCQ, SSZ), 71% (IFX) Compared to randomization EULAR good response 49% (HCQ, SSZ), 60% (IFX)

Adverse events

Total adverse events n = 48 (HCQ, SSZ), n = 32 (IFX) Number of patients with at least one adverse event 25% (HCQ, SSZ), 21% (IFX) Blood and lymphatic system n = 5 (HCQ, SSZ), n = 1 (IFX) Liver n = 1 (HCQ, SSZ), n = 5 (IFX) Infectiouns n = 0 (HCQ, SSZ), n = 5 (IFX) Skin and allergic reactions n = 3 (HCQ, SSZ), n = 11 (IFX) Gastrointestinal n = 15 (HCQ, SSZ), n = 1 (IFX) Respiratory system n = 2 (HCQ, SSZ), n = 2 (IFX) Hypertension n = 2 (HCQ, SSZ), n = 0 (IFX) Eyes n = 2 (HCQ, SSZ), n = 0 (IFX) Ears n = 1 (HCQ, SSZ), n = 0 (IFX) Central and peripheral nervous system n = 6 (HCQ, SSZ), n = 1 (IFX) Musculoskeletal n = 0 (HCQ, SSZ), n = 1 (IFX) Psychiatric n = 4 (HCQ, SSZ), n = 0 (IFX) General n = 2 (HCQ, SSZ), n = 3 (IFX) Neoplasm n = 0 (HCQ, SSZ), n = 0 (IFX) Abnormal blood test n = 1 (HCQ, SSZ), n = 1 (IFX) Unspecified n = 4 (HCQ, SSZ), n = 1 (IFX) Serious adverse events n = 1 (generalised symptoms), (HCQ, SSZ), n = 1 (persistent fever), (IFX)

265

266

Rheumatoid Arthritis: Infliximab vs. Etanercept

OPPOSITE-Trial Open-label, pilot protocol of patients with rheumatoid arthritis who switch to Infliximab after an incomplete response to Etanercept: the opposite study OPPOSITE: Open-label, pilot protocol of patients with rheumatoid arthritis who switch to Infliximab after an inadequate response to Etanercept Substance

Infliximab 3 mg/kg (n = 13), at weeks 0, 2, 6, 14 and 22 Etanercept 2 × 25 mg/week (n = 14) Concomitant medication: 7,5–25mg MTX/week was continued Other DMARDs stable dose ³ 1 month > 10 mg Prednisone at stable dose ³ 1 month NSAIDs at stable dose ³ 1 month Previous medication: Etanercept, no washout period Stable dose of 7,5–25mg MTX/w No Anakinra No Infliximab

Result

Established RA patients who had an incomplete response to etanercept showed a numerical trend favouring patients who switched to infliximab as compared to contineous treatment with etanercept

Patients

28 patients with an inadequate response to etanercept Disease duration >3 months ETN for min 2 months Tender joint count ³ 9 Swollen joint count ³ 6 Positive rheumatoid factor Negative tuberculin test

Authors

Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, Weisman M, Wallace DJ, Crues J, Khanna D, Eckel G, Yeilding N, Callegari P, Visvanathan S, Rojas J, Hegedus R, George L, Mamun K, Gilmer K, Troum O

Publication

Ann Rheum Dis. 2007 Jul;66(7):893–899. Epub 2007 Apr 5

Follow up

16 weeks

ACR 20

61.5% (IFX), 28.6% (ETN)

ACR 50

30.7% (IFX), 14.3% (ETN)

Rheumatoid Arthritis: Infliximab vs. Etanercept

Note

DAS28 4.0 (IFX), 5.2 (ETN) DAS28 < 2.6 15.4% (IFX), 7.1% (ETN) HAQ decrease >0.22 61.5% (IFX), 14.3% (ETN) HAQ decrease >0.4 38.5% (IFX), 0.0% (ETN) Change of: DAS28 –30.8% (IFX), –16.0% (ETN) Sharp van der Heijde score +1.0 (IFX), +0.4% (ETN) Total erosion score +0.1 (IFX), –0.1% (ETN) Joint space narrowing +0.9 (IFX), 0.6% (ETN)

Adverse events

Gastrointestinal disorders 0 (IFX), 21.4% (ETN) Musculoskeletal and connective tissue disorders 30.8% (IFX), 7.1% (ETN) Nervous system disorders 7.7% (IFX), 7.1% (ETN) Respiratory disorders 7.7% (IFX), 28.6% (ETN) Skin and subcutaneous disorders 38.5% (IFX), 7.1% (ETN) General disorders and site reactions 0% (IFX), 20% (ETN) Serious adverse events: Gastro intestinal disorder 0% (IFX), 20% (ETN) Cardiac disorder 0% (IFX), 7.1% (ETN) Mucosceletal disorder 7.7% (IFX), 0% (ETN) Nervous system disorder 0% (IFX), 7.1% (ETN) Respiratory disorder 0% (IFX), 7.1% (ETN)

267

268

Rheumatoid Arthritis: Anti-TNF

GISEA-Trial

Good clinical response, remission, and predictors of remission in rheumatoid arthritis patients treated with tumor necrosis factor-a blockers The GISEA Study: GISEA: gruppo italiano studio early arthritis

Substance

All patients received one TNF-alpha blocker (Ada 24%, ETN 27%, IFX 27%) Concomitant medication: 10–20 mg MTX/week DMARDs were continued Corticosteroids were continued Previous medication: DMARDs alone or in combination

Result

Only a minority of RA patients with longstanding disease achieved a good clinical response or remission upon anti-TNF therapy in this cohort study of RA. Baseline HAQ < 1.63, and RF negativity were possible identifiers of the best responders

Patients

1257 RA patients DAS 28 > 3.2 Despite DMARD therapy

Authors

Mancarella L, Bobbio-Pallavicini F, Ceccarelli F, Falappone PC, Ferrante A, Malesci D, Massara A, Nacci F, Secchi ME, Manganelli S, Salaffi F, Bambara ML, Bombardieri S, Cutolo M, Ferri C, Galeazzi M, Gerli R, Giacomelli R, Grassi W, Lapadula G, Cerinic MM, Montecucco C, Trotta F, Triolo G, Valentini G, Valesini G, Ferraccioli GF; GISEA group

Publication

J Rheumatol. 2007 Aug;34(8):1670–1673. Epub 2007 Jul 1

Follow up

6months

Note

DAS28 remission 24% (RF positive), 36% (RF-negative) Good EULAR response 37% (RF positive), 50% (RF-negative) Moderate EULAR response 54% (RF positive), 37% (RF-negative) HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male)

Adverse events

Total 14% Skin reactions 8% Infusion reactions 2% Others 4% (infections, hematologic, hepatic, gastrointestinal)

Rheumatoid Arthritis: Rituximab

Trial

Efficacy of B-cell-targeted therapy with Rituximab in patients with rheumatoid arthritis

Substance

³ 10 mg oral methotrexate/week (n = 40) 1000 mg rituximab on days 1 and 15 (n = 40) Rituximab + i.v. 750 mg cyclophosphamide (days 3 and 17, n = 41) Rituximab + methotrexate (n = 40) Stable doses or corticosteroids £ 12.5 mg prednisolone/day (or the equivalent)

269

Concomitant medication: 100 mg methylprednisolone before infusions of RTX, Cyc, or placebo 60 mg prednisone on days 2, 4–7 30 mg prednisone on days 8–14 10 mg leucovorin calcium (folinic acid) on day 1 2 mg granisetron 1h prior infusion NSAIDs were permitted Prednisolone £ 12.5mg/d No other DMARD No TNF antagonist Previous medication: ³ 10 mg oral methotrexate/w Result

A single course of two infusions of rituximab, alone or in combination with other DMARDs, in patients with active rheumatoid arthritis despite methotrexate treatment led to a significant improvement in disease symptoms

Patients

161 patients who had active rheumatoid arthritis Despite treatment with methotrexate ³ 8 swollen joints ³ 8 tender joints CRP ³ 15 mg/l ESR ³ 28 mm/h Morning stiffness > 45 min Rheumatoid factor ³ 20 IU/mL

Authors

Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T

Publication

N Engl J Med. 2004 Jun 17;350(25):2572–2581

Follow up

48 weeks

ACR 20

Week 24: 38% (MTX), 65% (RTX), 76% (RTX + Cyc), 73% (RTX + MTX) Week 48: 20% (MTX), 33% (RTX), 49% (RTX + Cyc), 65% (RTX + MTX)

ACR 50

Week 24: 13% (MTX), 33% (RTX), 41% (RTX + Cyc), 43% (RTX + MTX) Week 48: 5% (MTX), 15% (RTX), 27% (RTX + Cyc), 35% (RTX + MTX)

ACR 70

Week 24: 5% (MTX), 15% (RTX), 15% (RTX + Cyc), 23% (RTX + MTX) Week 48: 0% (MTX), 10% (RTX), 10% (RTX + Cyc), 15% (RTX + MTX)

270

Note

Rheumatoid Arthritis: Rituximab

Week 24: Moderate or good EULAR response 50% (MTX), 85% (RTX), 85% (RTX + Cyc), 83% (RTX + MTX) Change of (week 24): DAS28 -1.3 (MTX), -2.2 (RTX), -2.6 (RTX + Cyc), -2.6 (RTX + MTX)

Adverse events

Hypotension 18% (MTX), 30% (RTX), 29% (RTX, Cyc), 18% (RTX, MTX) Exacerbation of rheumatoid arthritis 40% (MTX), 15% (RTX), 15% (RTX, Cyc), 5% (RTX, MTX) Hypertension 15% (MTX), 15% (RTX), 7% (RTX, Cyc), 25% (RTX, MTX) Nasopharyngitis 15% (MTX), 10% (RTX), 5% (RTX, Cyc), 10 (RTX, MTX) Arthralgia 8% (MTX), 8% (RTX), 2% (RTX, Cyc), 10% (RTX, MTX) Rash 3% (MTX), 10% (RTX), 10% (RTX, Cyc), 3% (RTX, MTX) Back pain 5% (MTX), 10% (RTX), 7% (RTX, Cyc), 0% (RTX, MTX) Cough 0% (MTX), 13% (RTX), 2% (RTX, Cyc), 5% (RTX, MTX) Pruritus 0% (MTX), 10% (RTX), 10% (RTX, Cyc), 0% (RTX, MTX) Nausea 3% (MTX), 5% (RTX), 10% (RTX, Cyc), 0% (RTX, MTX) Dyspnoea 0% (MTX), 10% (RTX), 0% (RTX, Cyc), 0% (RTX, MTX)

Rheumatoid Arthritis: Rituximab

271

Dancer-Trial

The efficacy and safety of Rituximab in patients with active rheumatoid arthritis despite Methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial DANCER: Dose-Ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis

Substance

Placebo (n = 149) Rituximab 2 × 500 mg (n = 124) Rituximab 2 × 1000 mg (n = 192) Concomitant medication: Ongoing 10–25 mg MTX/week Prednisone £ 10 mg/day of or equivalent 10–25 mg Methotrexate/w Other DMARDs were discontinued ³ 4 weeks 100 mg Methylprednisolone before infusions of RTX 60 mg Prednisone on days 2–7 30 mg Prednisone on days 8–14 Prednisolone £ 10 mg/d Previous medication: 10–25 mg MTX/week Failed 1–5 DMARDs and/or TNF antagonists (other than MTX)

Result

Rituximab treatment of RA patients with a moderate or active disease led to a significant number of patients with ACR responses in a dose dependent manner

Patients

456 RA patients with moderate/active disease Despite treatment with Swollen joint count ³ 12 Tender joint count ³ 8 ESR ³ 28 mm/h CRP ³1.5 mg/dL

Authors

Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM; DANCER Study Group

Publication

Arthritis Rheum. 2006 May;54(5):1390–1400

Follow up

24 weeks

ACR 20

28% (placebo), 55% (RTX 2 × 500), 54% (RTX 2 × 1000)

ACR 50

13% (placebo), 33% (RTX 2 × 500), 34% (RTX 2 × 1000)

ACR 70

5% (placebo), 13% (RTX 2 × 500), 20% (RTX 2 × 1000)

Note

Change of: DAS28 -1.79 (RTX 2 × 500), -2.05 (RTX 2 × 1000), -0.67 (placebo) EULAR response: No response 63% (placebo), 28% (RTX 2 × 500), 34% (RTX 2 × 1000) Moderate 37% (placebo), 73% (RTX 2 × 500), 67% (RTX 2 × 1000) Good 4% (placebo), 14% (RTX 2 × 500), 28% (RTX 2 × 1000)

272

Adverse events

Rheumatoid Arthritis: Rituximab

Exacerb. of RA 30% (placebo), 17% (2 × 500 RTX), 14% (2 × 1000 RTX) Headache 13% (placebo), 11% (2 × 500 RTX), 11% (2 × 1000 RTX) Nausea 9% (placebo), 6% (2 × 500 RTX), 10% (2 × 1000 RTX) URI 6% (placebo), 8% (2 × 500 RTX), 6% (2 × 1000 RTX) Nasopharyngitis 5% (placebo), 6% (2 × 500 RTX), 5% (2 × 1000 RTX) Arthralgia 3% (placebo), 4% (2 × 500 RTX), 6% (2 × 1000 RTX) Diarrhoea 5% (placebo), 6% (2 × 500 RTX), 3% (2 × 1000 RTX) Fatigue 5% (placebo), 4% (2 × 500 RTX), 4% (2 × 1000 RTX) Hypertension 3% (placebo), 4% (2 × 500 RTX), 6% (2 × 1000 RTX) Rigors 2% (placebo), 4% (2 × 500 RTX), 7% (2 × 1000 RTX) Dizziness 4% (placebo), 3% (2 × 500 RTX), 5% (2 × 1000 RTX) Serious non-infection adverse events 1% (placebo), 7% (2 × 500 RTX), 5% (2 × 1000 RTX) Serious infections 1% (placebo), 0% (2 × 500 RTX), 2% (2 × 1000 RTX) Acute infusion reaction (first infusion): No Glucosteroids 14% (placebo), 32% (2 × 500 RTX), 37% (2 × 1000 RTX) + Glucosteroids 19% (placebo), 19% (2 × 500 RTX), 29% (2 × 1000 RTX) Acute infusion reaction (second infusion): No Glucosteroids 8% (placebo), 5% (2 × 500 RTX), 6% (2 × 1000 RTX) + Glucosteroids i.v. 7% (placebo), 2% (2 × 500 RTX), 8% (2 × 1000 RTX) + Glucosteroids p.o. + i.v. 16% (placebo), 12% (2 × 500 RTX), 9% (2 × 1000 RTX)

Rheumatoid Arthritis: Rituximab

Reflex-Trial

Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks, Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) REFLEX: Randomized Evaluation of Long-Term Efficacy of Rituximab in RA

Substance

Rituximab (2 × 1,000 mg, n = 311) Placebo (n = 209)

273

Concomitant medication: 10–25 mg MTX/week Folate ³ 5 mg/week + i.v. Methylprednisolone (100 mg 30 min before each infusion) + oral prednisone (60 mg on days 2–7; 30 mg on days 8–14) Prednisone £ 10 mg/d Continued NSAIDs if the dosage was stable for ³ 4 weeks Discontinue Ada (³ 8 weeks), ETN (³ 4 weeks) Previous medication: 10–25 mg MTX/week IFX (³3 mg/kg ³4 infusions), Ada (40 mg /2 weeks ³ 3 months), or ETN (2 × 25 mg/week ³ 3 months) Result

One single course of rituximab with concomitant methotrexate therapy resulted in significant improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies

Patients

Patients with active RA Inadequate response to ³ 1 anti-TNF agent Disease duration ³ 6 months ³ 8 swollen joints ³ 8 tender joints CRP ³ 1.5 mg/dL ESR ³ 28 mm/h Radiographic evidence ³ 1 joint erosion

Authors

Cohen SB, Emery P, Greenwald MW, Dougados M, Furies RA, Genovese MC, Keystone EC, Loveless JE, Burmester GR, Cravets MW, Hessen EW, Shaw T, Totalities MC; REFLEX Trial Group

Publication

Arthritis Rheum. 2006 Sep;54(9):2793–2806

Follow up

24 weeks

ACR 20

18% (placebo), 51% (RTX)

ACR 50

5% (placebo), 27% (RTX)

ACR 70

1% (placebo), 12% (RTX)

274

Note

Rheumatoid Arthritis: Rituximab

Moderate EULAR responses 20% (placebo), 50% (RTX) Good EULAR responses 2% (placebo), 15% (RTX) Low disease activity 2% (placebo), 15% (RTX) Remission 0% (placebo), 9% (RTX) Change of: Genant modified Sharp Score +1,2 (placebo), +0.6 (RTX) Joint space narrowing +0.5 (placebo), +0.2 (RTX) Total erosion score +0.8 (placebo), +0.4 (RTX) Worsening of erosions +60% (placebo), +66% (RTX) Swollen joint count -2.6 (placebo), -10.4 (RTX) Tender joint count -2.7 (placebo), -14.4 (RTX) Patient’s global assessment of disease activity (0–100-mm VAS) -5.3 (placebo), -26.0 (RTX) Physician’s global assessment of disease activity (0–100-mm VAS) -6.2 (placebo), -29.5 (RTX) HAQ -0.1 (placebo), -0.4 (RTX) Patient’s assessment of pain (0–100-mm VAS) -2.5 (placebo), -23.4 (RTX) CRP (mg/dL) 0 (placebo), -2.1 (RTX) ESR (mm/h) -4.1 (placebo), -18.5 (RTX)

Adverse events

Rheumatoid arthritis 42% (placebo), 21% (RTX) Headache 9% (placebo), 8% (RTX) Upper respiratory tract infection 7% (placebo), 8% (RTX) Nasopharyngitis 6% (placebo), 7% (RTX) Nausea 2% (placebo), 7% (RTX) Fatigue 6% (placebo), 7% (RTX) Hypertension 5% (placebo), 7% (RTX) Diarrhoea 8% (placebo), 6% (RTX) Arthralgia 5% (placebo), 6% (RTX) Pyrexia 3% (placebo), 5% (RTX) Dizziness 4% (placebo), 5% (RTX) Bronchitis 6% (placebo), 4% (RTX) Cough 5% (placebo), 3% (RTX) Sinusitis 5% (placebo), 3% (RTX) Urinary tract infection 8% (placebo), 3% (RTX) Acute infusion reaction (first infusion) 18% (placebo), 23% (RTX) Acute infusion reaction (second infusion) 11% (placebo), 8% (RTX)

Rheumatoid Arthritis: Rituximab

Trial

Safety and efficacy of additional courses of Rituximab in patients with active rheumatoid arthritis: an open-label extension analysis

Substance

2 infusions of 1,000 mg given 2 weeks apart Concomitant medication: Following premedication with 100 mg i.v. methylprednisolone + 60 mg/day oral glucocorticoids (days 2–7) + 30 mg/day oral glucocorticoids (days 8–13) 10–25 mg MTX/week Folate ³ 5 mg/week No other DMARDs Prednisone £ 10 mg/day NSAIDs were permitted at stable dose Previous medication: Previously treated with rituximab

Result

Repeated courses of rituximab had a sustained clinical response in RA patients. No new adverse events were detected

Patients

1039 RA patients Previously treated with Rituximab Min 20% reduction of tender/swollen joint count Swollen and tender joint count of ³ 8

Authors

Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, Dougados M, Baldassare A, Ferraccioli G, Chubick A, Udell J, Cravets MW, Agarwal S, Cooper S, Magrini F

Publication

Arthritis Rheum. 2007 Dec;56(12):3896–3908

Follow up

24 weeks

ACR 20

Course 1: 72% (anti TNF naive), 73% (TNF pre-treated) Course 2: 65% (anti TNF naive), 59% (TNF pre-treated)

ACR 50

Course 1: 42% (anti TNF naive), 37% (TNF pre-treated) Course 2: 33% (anti TNF naive), 27% (TNF pre-treated)

ACR 70

Course 1: 21% (anti TNF naive), 19% (TNF pre-treated) Course 2: 12% (anti TNF naive), 9% (TNF pre-treated)

Note

Moderate/good EULAR response Course 1: 88% (anti TNF naive), 86% (TNF pre-treated) Course 2: 79% (anti TNF naive), 74% (TNF pre-treated) Low disease activity Course 1: 25% (anti TNF naive), 26% (TNF pre-treated) Course 2: 13% (anti TNF naive), 19% (TNF pre-treated) Remission Course 1: 13% (anti TNF naive), 14% (TNF pre-treated) Course 2: 6% (anti TNF naive), 8% (TNF pre-treated)

Adverse events

26 malignancies were reported in 22 of 1,039 patients (2%) All AEs/100 patient years 396.4 (Course 1), 326.0 (Course 2), 383.0 (Course 3), 384.2 (Course 4) All SAE/100 patient years 19.3 (Course 1), 17.5 (Course 2), 20.3 (Course 3), 24.0 (19.3 (Course 4)) Infusion reactions (Course 1) 25.6% (1st infusion), 9.3% (2nd infusion) Infusion reactions (Course 2) 14.2% (1st infusion), 5.4% (2nd infusion) Infusion reactions (Course 3) 10.5% (1st infusion), 2.3% (2nd infusion) Infusion reactions (Course 4) 15.0% (1st infusion), 2.6% (2nd infusion)

275

276

Rheumatoid Arthritis: Rituximab

Trial

Rituximab use in everyday clinical practice as a first-line biologic therapy for the treatment of DMARD-resistant rheumatoid arthritis

Substance

2 × 1,000 mg Rituximab 2 weeks apart (n = 17) 2 × 500 mg Rituximab 2 weeks apart (n = 22) Concomitant medication: Following premedication with 100 mg i.v. methylprednisolone Chlorpheniramine at either 4 mg oral or 10 mg i.v. DMARDs were continued (n = 32 MTX, n = 2 LE F, n = 1 AZA, n = 2 stoped DMARDs) Previous medication: Failed DMARD therapy Failed TNF antagonists n = 3

Result

Rituximab was well tolerated and seemed to be effecitve

Patients

39 patients with active RA Failed at least one DMARD

Authors

McGonagle D, Tan AL, Madden J, Taylor L, Emery P

Publication

Rheumatology (Oxford). 2008 Jun;47(6):865–867. Epub 2008 Apr 4

Follow up

1 year

Note

DAS28 6,35 (baseline) 3,38 (3 months) 3,79 (6 months) 3.48 (9 months) 3,3 (12 months) EULAR response 87.9% (3 months) 75.8% (6 months) 75.9% (9 months) 76.7 (12 months) EULAR good response 39.4% (3 months) 36.4% (6 months) 34.5% (9 months) 50.0% (12 months) CRP 22 mg/L (baseline) 17 mg/L (3 months) 8 mg/L (6 months) 12.5 mg/L (9 months) 8 mg/L (12 months)

Rheumatoid Arthritis: Rituximab

REFLEX Trial

Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies REFLEX: Randomized Evaluation of Long-Term Efficacy of Rituximab in RA

Substance

Rituximab (2 × 1,000 mg, n = 311) Placebo (n = 209) Concomitant medication: 10–25 mg MTX/week Folate ³ 5 mg/week + i.v. methylprednisolone (100 mg 30 min before each infusion) + oral prednisone (60 mg on days 2–7; 30 mg on days 8–14) Prednisone £ 10 mg/day Continued NSAIDs if the dosage was stable for ³ 4 weeks Discontinue Ada (³ 8 weeks), ETN (³ 4weeks) Previous medication: 10–25 mg MTX/week IFX (³3 mg/kg ³4 infusions), Ada (40 mg /2 weeks ³ 3 months), or ETN (2 × 25 mg/week ³ 3 months)

Result

Rituximab treatment in RA patients with long-standing, active and treatment-resistant disease significantly inhibited the progression of structural joint damage

Patients

Patients with active RA Inadequate response to 1 or more anti-TNF agents Disease duration ³ 6 months ³ 8 swollen joints ³ 8 tender joints CRP ³ 1.5 mg/dL ESR ³ 28 mm/h Radiographic evidence ³ 1 joint erosion

Authors

Keystone E, Emery P, Peterfy CG, Tak PP, Cohen S, Genovese MC, Dougados M, Burmester GR, Greenwald M, Kvien TK, Williams S, Hagerty D, Cravets MW, Shaw T

Publication

Ann Rheum Dis. 2009 Feb;68(2):216–221. Epub 2008 Apr 3

Follow up

56 weeks

Note

Change of: Genant-modified Sharp score +1.0 (Rituximab), +2.31 (placebo) Erosion score +0.59 (Rituximab), +1.32 (placebo) Joint space narrowing score +0.41 (Rituximab), +0.99 (placebo)

277

278

Rheumatoid Arthritis: Tocilizumab

STREAM-Trial

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial STREAM: safety and efficacy of Tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in monotherapy

Substance

4 mg tocilizumab/kg/4 weeks (still called MRA in this study, n = 54) 8 mg tocilizumab/kg/4 weeks (n = 55) Placebo (n = 53) Concomitant therapy: NSAIDs were permitted Prednisolone £ 10 mg was permitted Previous therapy: Insufficient response to min. 1 DMARD No DMARDs £ 4 weeks No immunosuppressants £ 4 weeks No parenteral and/or intraarticular use of corticosteroids £ 4 weeks No plasma exchange £ 4 weeks

Result

Treatment of RA patients with tocilizumab was well tolerated and significantly reduced the disease activity

Patients

164 refractory RA patients Active disease > 6 months Despite DMARD therapy ³ 6 swollen joints ³ 6 tender joints ESR ³ 30 mm CRP > 1 mg/L Prednisolone < 10 mg/day

Authors

Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T

Publication

Arthritis Rheum. 2004 Jun;50(6):1761–1769

Follow up

12 weeks

ACR 20

11.3% (placebo), 57.4% (4 mg Toc), 78.2% (8 mg Toc)

ACR 50

1.9% (placebo), 25.9% (4 mg Toc), 40.0% (8 mg Toc)

ACR 70

0.0% (placebo), 20.4% (4 mg Toc), 16.4% (8 mg Toc)

Note

Good EULAR response 0.0% (placebo), 5.6% (4mg Toc), 18.2% (8mg Toc) Good or moderate EULAR response 18.9% (placebo), 72.7% (4mg Toc), 90.9% (8mg Toc)

Adverse events

Common cold 13.0% (placebo), 16.7% (4 mg Toc), 9.1% (8 mg Toc) Headache 1.9% (placebo), 3.7% (4 mg Toc), 5.5% (8 mg Toc) Pruritus 5.6% (placebo), 5.6% (4 mg Toc), 3.6% (8 mg Toc) Skin eruption 1.9% (placebo), 3.7% (4 mg Toc), 5.5% (8 mg Toc) Stomatitis 3.7% (placebo), 5.6% (4 mg Toc), 7.3% (8 mg Toc) Fever 1.9% (placebo), 5.6% (4 mg Toc), 5.5% (8 mg Toc)

Rheumatoid Arthritis: Tocilizumab

CHARISMATrial

Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, Tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to Methotrexate CHARISMA Chugai Humanized Anti-Human Recombinant Interleukin-6 Monoclonal Antibody

Substance

Tocilizumab 2 mg/kg monotherapy (n = 53) Tocilizumab 4 mg/kg monotherapy (n = 54) Tocilizumab 8 mg/kg monotherapy (n = 52) Tocilizumab 2 mg/kg + MTX (n = 52) Tocilizumab 4 mg/kg + MTX (n = 49) Tocilizumab 8 mg/kg + MTX (n = 50) Placebo + MTX (n = 49)

279

Concomitant therapy: Prednisolone £ 10 mg/day was permitted 10–25 mg MTX/week or MTX placebo each week 5mg folic acid/w NSAIDs were permitted Previous therapy: MTX ³ 6 months No DMARDs £ 4 weeks No TNF antagonists £ 12 weeks Result

Targeted blockade of IL-6 signalling was a highly efficacious in patients with activity in RA

Patients

359 patients with active Response to MTX was inadequate ³ 6 tender joints ³ 6 swollen joints ESR ³ 30 mm/h CRP ³ 20 mg/L £ 10 mg Prednisolone or equivalent for 4 weeks

Authors

Maini RN, Taylor PC, Szechinski J, Pavelka K, Bröll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T; CHARISMA Study Group

Publication

Arthritis Rheum. 2006 Sep;54(9):2817–2829

Follow up

16 weeks

ACR 20

31% (2 mg/kg Toc), 61% (Toc 4mg/kg), 63% (8 mg/kg Toc), 64% (2 mg/kg Toc + MTX), 63% (4 mg Toc + MTX), 74% (8 mg Toc + MTX), 41% (Placebo + MTX)

ACR 50

6% (2 mg/kg Toc), 28% (Toc 4mg/kg), 41% (8 mg/kg Toc), 32% (2 mg/kg Toc + MTX), 37% (4mg Toc + MTX), 53% (8mg Toc + MTX), 29% (Placebo + MTX)

ACR 70

2% (2 mg/kg Toc), 6% (Toc 4mg/kg), 16% (8 mg/kg Toc), 14% (2 mg/kg Toc + MTX), 12% (4 mg Toc + MTX), 37% (8 mg Toc + MTX), 16% (Placebo + MTX)

280

Rheumatoid Arthritis: Tocilizumab

Note

Remission 17% (8 mg/kg Toc), 34% (8 mg Toc + MTX), 8% (Pacebo + MTX) Change of: DAS28: -2.9 (8 mg/kg Toc + MTX)

Adverse events

Infections (most frequent, no percentages) Mucosceletal disorders (no percentages) Gastrointestinal disorders (no percentages) Infective arthritis n = 1 (Toc) Sepsis n = 2 (Toc) Anaphylactic. shock + hypersensitivity. n = 4 (2-mg/kg Toc), n = 1 (4-mg/kg Toc) AST and ALT augmented in all patients (Toc) AST and ALT >3x upper normal limits 2% (Toc) Bilirubin levels ³21 µmoles/L n = 21 (Toc) Total cholesterol, high-density lipoprotein cholesterol, and triglycerides levels increased initially and then stabilized Increased, neutrophil reduction n = 40 (Toc)

Rheumatoid Arthritis: Tocilizumab

281

Radiate-Trial

IL-6 Receptor inhibition with Tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-TNF biologics: results from a 24-week multicentre Randomised Placebo Controlled Trial RADIATE: The Research on Actemra Determining efficacy after Anti-TNF failurE

Substance

8mg Tocilizumab (n = 175) 4mg Tocilizumab (n = 163) Placebo (n = 160) Rescue therapy at week 16 if £ 20% improvement in both swollen and tender joint count: 8 mg/kg Tocilizumab + MTX Concomitant therapy: Prednisone £ 10 mg/day was permitted or equivalent 10–25 mg MTX/week 5mg Folic acid/week NSAIDs were permitted Previous therapy: MTX ³ 12 weeks No other DMARDs £ 4 weeks No ETN < 2 weeks, IFX or Ada < 8 weeks, Lef < 12 weeks

Result

Tocilizumab and methotrexate combination therapy in patients with an inadequate response to TNF antagonists achieved rapid and sustained clinical improvements

Patients

499 RA patients with inadequate response to ³ 1 TNF-antagonist > 6 months active disease ³ 6 swollen joints ³ 8 tender joints CRP ³ 10mg/l ESR ³ 28mm MTX ³ 12 months MTX at baseline

Authors

Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J

Publication

Ann Rheum Dis. 2008 Nov;67(11):1516–1523. Epub 2008 Jul 14

Follow up

24 weeks

ACR 20

50.0% (8 mg tocilizumab), 30.4% (4 mg tocilizumab), 10.1% (placebo)

ACR 50

28.8% (8 mg tocilizumab), 16.8% (4 mg tocilizumab), 3.8% (placebo)

ACR 70

12.4% (8 mg tocilizumab), 5.0% (4 mg tocilizumab), 1.3% (placebo)

282

Note

Rheumatoid Arthritis: Tocilizumab

Remission (DAS28 < 2.6) 30.1% (8 mg tocilizumab), 7.6% (4 mg tocilizumab), 1.6% (placebo) Low disease activity (DAS28 < 3.2) 51.2% (8mg tocilizumab), 15.2% (4 mg tocilizumab), 4.9% (placebo) Good or moderate EULAR responses 67.7% (8 mg tocilizumab), 46.5% (4 mg tocilizumab), 16.5% (placebo) Change of: Swollen joint count -7.8 (8 mg tocilizumab), -6.8 (4 mg tocilizumab), -0.5 (placebo) Tender joint count -14.8 (8 mg tocilizumab), -10.5 (4 mg tocilizumab), -0.3 (placebo) HAQ -0.39 (8 mg tocilizumab), -0.31 (4 mg tocilizumab), -0.05 (placebo)

Adverse events

Death 0.0% (8 mg tocilizumab), 0.0% (4 mg tocilizumab), 0.0% (placebo) Infections 49.1% (8 mg tocilizumab), 46.6% (4 mg tocilizumab), 41.3% (placebo) Gastrointestinal 36.6% (8 mg tocilizumab), 32.5% (4 mg tocilizumab), 19.4% (placebo) Skin and subcutaneous tissue 21.7% (8 mg tocilizumab), 30.7% (4 mg tocilizumab), 14.4% (placebo) Mucosceletal 15.4% (8 mg tocilizumab), 20.9% (4 mg tocilizumab), 21.3% (placebo) Nervous system 18.3% (8 mg tocilizumab), 19.6% (4 mg tocilizumab), 16.9% (placebo) General administrative 12.0% (8 mg tocilizumab), 16.0% (4 mg tocilizumab), 14.4% (placebo) Respiratory 12.0% (8 mg tocilizumab), 14.7% (4 mg tocilizumab), 13.1% (placebo) Injuries 10.9% (8 mg tocilizumab), 6.7% (4 mg tocilizumab), 10.0% (placebo) Laboratory investigations 8.0% (8mg tocilizumab), 12.3% (4mg tocilizumab), 5.6% (placebo) Vascular 8.0% (8 mg tocilizumab), 11.0% (4 mg tocilizumab), 5.0% (placebo) Psychiatric 7.4% (8 mg tocilizumab), 9.8% (4 mg tocilizumab), 3.8% (placebo) Eye 6.3% (8 mg tocilizumab), 6.7% (4 mg tocilizumab), 1.9% (placebo) Metabolism 5.1% (8 mg tocilizumab), 4.3% (4 mg tocilizumab), 4.4% (placebo) Haematological 5.1% (8 mg tocilizumab), 2.5% (4 mg tocilizumab), 2.5% (placebo) Total cholesterol (mmol/L) 1.25% (8 mg tocilizumab), 1.09% (4 mg tocilizumab), 1.07% (placebo) High-density lipoprotein elevation to ³ 60 mg/dL 16.6% (8 mg tocilizumab), 13.5% (4 mg tocilizumab), 3.8% (placebo) Low-density lipoprotein elevation to ³ 160 mg/dL 12.0% (8 mg tocilizumab), 15.3% (4 mg tocilizumab), 3.8% (placebo)

Rheumatoid Arthritis: Tocilizumab

283

SAMURAI-Trial Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an X ray reader-blinded randomised controlled trial of Tocilizumab SAMURAI: Study of active controlled monotherapy used for rheumatoid arthritis Substance

Tocilizumab monotherapy 8 mg/kg every 4 weeks (n = 158) DMARDs (n = 148) Concomitant therapy: Prednisone £ 10 mg/day was permitted or equivalent No intraarticular corticosteroid injections Effective contraception NSAIDs were permitted DMARDs were discontinued (Toc-group) from the start of the study Previous therapy: Min. 1 DMARD No anti-TNF agents and Lef £ 3 months

Result

Tocilizumab monotherapy was well tolerated and provided radiographic benefit in patients with RA

Patients

306 patients with active RA of < 5 years disease duration Inadequate response to ³ 1 DMARD Anti-TNF agents or leflunomide not allowed within 3 months ³ 6 tender ³ 6 swollen joints ESR ³ 30mm CRP ³ 20mg/l

Authors

Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Murata N, van der Heijde D, Kishimoto T

Publication

Ann Rheum Dis. 2007 Sep;66(9):1162–1167. Epub 2007 May 7

Follow up

52 weeks

ACR 20

34% (DMARD), 78% (8mg tocilizumab)

ACR 50

13% (DMARD), 64% (8mg tocilizumab)

ACR 70

6% (DMARD), 44% (8mg tocilizumab)

284

Note

Rheumatoid Arthritis: Tocilizumab

Remission DAS > 2.6 3% (DMARD), 59% (8mg tocilizumab) Change of: Total Sharp score change +6.1 (DMARD), +2.3 (tocilizumab) Erosion score change +3.2 (DMARD), +0.9 (tocilizumab) Joint space narrowing score change +2.9 (DMARD), +1.5 (tocilizumab) HAQ 40% (DMARD), 68% (8mg tocilizumab)

Adverse events

Nasopharyngitis 32.4% (DMARD), 35.7% (8 mg tocilizumab) Rash 4.1% (DMARD), 10.8% (8 mg tocilizumab) Diarrhoea 9.0% (DMARD), 8.3% (8 mg tocilizumab) Headache 2.1% (DMARD), 7.0% (8 mg tocilizumab) Stomatitis 9.0% (DMARD), 5.7% (8 mg tocilizumab) Eczema 4.1% (DMARD), 5.7% (8 mg tocilizumab) Nausea 1.4% (DMARD), 5.7% (8 mg tocilizumab) Pruritus 1.4% (DMARD), 5.7% (8 mg tocilizumab) Paronychia 0.7% (DMARD), 5.7% (8 mg tocilizumab) Vomiting 3.4% (DMARD), 5.1% (8 mg tocilizumab) Vertebral compression fracture 5.5% (DMARD), 1.9% (8 mg tocilizumab)

Rheumatoid Arthritis: Tocilizumab

285

OPTION-Trial

Effect of interleukin-6 receptor inhibition with Tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial OPTION: tOcilizumab Pivotal Trial in Methotrexate Inadequate respONders

Substance

Tocilizumab 8 mg/kg (n = 205) every 4 weeks Tocilizumab 4 mg/kg (n = 214) every 4 weeks Placebo (n = 204) every 4 weeks Concomitant therapy: Prednisone £ 10 mg/day or equivalent was permitted NSAIDs were permitted, stable dose ³ 6 weeks 10–25 mg MTX/week was continued Folic acid 5mg/w All other DMARDs were discontinued: Lef ³ 12 weeks, colestyramine ³ 4, anakinra ³ 1 week, ETN ³ 2 weeks, IFX or Ada ³ 8 weeks Previous therapy: 10–25 mg MTX/week ³ 12 weeks

Result

Tocilizumab was effective in patients with moderately to severely active RA

Patients

623 patients with moderate to severe active RA Despite MTX therapy ³ 6 tender joints ³ 8 swollen joints ESR ³ 28mm/h CRP ³ 10mg/l

Authors

Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R; OPTION Investigators

Publication

Lancet. 2008 Mar 22;371(9617):987–997

Follow up

24 weeks

ACR 20

48% (4 mg/kg Toc), 59% (8 mg/kg Toc), 26% (placebo)

ACR 50

31% (4 mg/kg Toc), 44% (8 mg/kg Toc), 11% (placebo)

ACR 70

12% (4 mg/kg Toc), 22% (8 mg/kg Toc), 2% (placebo)

286

Note

Rheumatoid Arthritis: Tocilizumab

DAS28 < 2.6 13% (4 mg/kg Toc), 27% (8 mg/kg Toc), 0.8% (placebo) EULAR good response 21% (4 mg/kg Toc), 38% (8 mg/kg Toc), 3% (placebo) EULAR moderate response 41% (4 mg/kg Toc), 41% (8 mg/kg Toc), 32% (placebo) EULAR no response 38% (4 mg/kg Toc), 20% (8 mg/kg Toc), 65% (placebo) Change of: Swollen joint count –8.5 (4 mg/kg Toc), –10.5 (8 mg/kg Toc), –4.3 (placebo) Tender joint count –14.5 (4 mg/kg Toc), –17.1 (8 mg/kg Toc), –7.4 (placebo) Patient pain VAS (mm) –25.0 (4 mg/kg Toc), –29.8 (8 mg/kg Toc), –14.0 (placebo) Patient global VAS (mm) –28.8 (4 mg/kg Toc), –32.7 (8 mg/kg Toc), –17.8 (placebo) Physician global VAS (mm) –38.3 (4 mg/kg Toc), –41.6 (8 mg/kg Toc), –32.7 (placebo) CRP (mg/L) –16.6 (4 mg/kg Toc), –25.1 (8 mg/kg Toc), –3.5 (placebo) ESR (mm/h) –25.5 (4 mg/kg Toc), –39.5 (8 mg/kg Toc), –7.1 (placebo) HAQ –0.52 (4 mg/kg Toc) –0.55 (8 mg/kg Toc), –0.34 (placebo) RF concentration (U/mL) –8.5 (8 mg/kg Toc), –65.1 (8 mg/kg Toc), +17.1 (placebo) FACIT-Fatigue score +7.3 (8 mg/kg Toc), +8.6 (8 mg/kg Toc), +4.0 (placebo) SF36 score (physical) +9.7 (8 mg/kg Toc), +9.5 (8 mg/kg Toc), +5.0 (placebo) SF36 score (mental) +5.7 (8 mg/kg Toc), +7.3 (8 mg/kg Toc), +2.7 (placebo)

Adverse events

Infection 31% (4 mg/kg Toc), 32% (8 mg/kg Toc), 27% (placebo) Musculoskeletal 14% (4 mg/kg Toc), 12% (8 mg/kg Toc), 16% (placebo) Gastrointestinal 22% (4 mg/kg Toc), 23% (8 mg/kg Toc), 22% (placebo) Nervous system 12% (4 mg/kg Toc), 15% (8 mg/kg Toc), 13% (placebo) Any skin and subcutaneous disorder 13% (4 mg/kg Toc), 18% (8 mg/kg Toc), 7% (placebo) Any laboratory variable12% (4 mg/kg Toc), 15% (8 mg/kg Toc), 5% (placebo) Raised alanine aminotransferase 6% (4 mg/kg Toc), 5% (8 mg/kg Toc), 1% (placebo) Raised aspartate aminotransferase 0.5% (4 mg/kg Toc), 1% (8 mg/kg Toc), 0.5% (placebo) Any respiratory, thoracic, or mediastinal disorder 7% (4 mg/kg Toc), 8% (8 mg/kg Toc), 5% (placebo) Cough 3% (4 mg/kg Toc), 1% (8 mg/kg Toc), 1% (placebo) Pharyngeal pain 0.9% (4 mg/kg Toc), 2% (8 mg/kg Toc), 1% (placebo) Dyspnoea 1% (4 mg/kg Toc), 1% (8 mg/kg Toc), 0% (placebo) Any vascular disorder 8% (4 mg/kg Toc), 6% (8 mg/kg Toc), 5% (placebo) Hypertension 3% (4 mg/kg Toc), 4% (8 mg/kg Toc), 4% (placebo) Fatigue 1% (4 mg/kg Toc), 3% (8 mg/kg Toc), 2% (placebo) Peripheral oedema 2% (4 mg/kg Toc), 2% (8 mg/kg Toc), 1% (placebo) Pyrexia 0.9% (4 mg/kg Toc), 0.5% (8 mg/kg Toc), 2% (placebo) Administration site reaction 9% (4 mg/kg Toc), 11% (8 mg/kg Toc), 7% (placebo) Neoplasm 0% (4 mg/kg Toc), 0% (8 mg/kg Toc), 1% (placebo) Change from baseline (week 6): Total cholesterol (mmol/L) +0.9 (4 mg/kg Toc), +0.9 (8 mg/kg Toc), 0.0 (placebo) HDL cholesterol (mmol/L) +0.1 (4 mg/kg Toc), +0.1 (8 mg/kg Toc), -0.01 (placebo) LDL cholesterol (mmol/L) +0.5 (4 mg/kg Toc), +0.6 (8 mg/kg Toc), +0.03 (placebo)

Rheumatoid Arthritis: Tocilizumab

287

TOWARD-Trial

Interleukin-6 receptor inhibition with Tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the Tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study TOWARD: Tocilizumab in Combination With Traditional DMARD Therapy

Substance

8 mg tocilizumab (n = 805) Placebo (n = 415) Rescue therapy if < 20% improvement in tender/swolen joint count by week 16: Adjustment/change of the background DMARD Intraarticular/oral glucocorticoids Open-label tocilizumab 8 mg/kg every 4 weeks for up to 5 years. Concomitant therapy: Prednisone £ 10 mg/day or equivalent was permitted NSAIDs were permitted, stable dose ³ 6 weeks DMARD therapy was continued Methotrexate 75.8% (tocilizumab), 73.9% (placebo) Chloroquine/hydroxychloroquine 20.6% (tocilizumab), 19.8% (placebo) Sulfasalazine 13.1% (tocilizumab), 14.3% (placebo) Leflunomide 12.1% (tocilizumab), 15.5% (placebo) Parenteral gold 0.2% (tocilizumab), 0.7% (placebo) Azathioprine 2.2% (tocilizumab), 2.2% (placebo) Oral steroids 51.2% (tocilizumab), 54.6% (placebo) Folic acid 71.8% (tocilizumab), 70.0% (placebo) NSAIDs 71.4% (tocilizumab), 77.1% (placebo) Other 36.9% (tocilizumab), 34.5% (placebo) Previous therapy: Stable doses of DMARDs for ³ 8 weeks No anti-TNF or cytotoxic agents

Result

Combination therapy of tocilizumab with any of the DMARDs was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these DMARADs

Patients

1220 patients with active RA Swollen joint count ³ 6 Tender joint count ³ 8 CRP ³ 1 mg/dL ESR ³ 28 mm/h

Authors

Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, Woodworth T, Gomez-Reino JJ

Publication

Arthritis Rheum. 2008 Oct;58(10):2968–2980

Follow up

24 weeks

ACR 20

60.8% (Tocilizumab), 24.5% (placebo)

ACR 50

37.6% (Tocilizumab), 9.0% (placebo)

ACR 70

20.5% (Tocilizumab), 2.9% (placebo)

288

Note

Rheumatoid Arthritis: Tocilizumab

DAS28 < 2.6 30.2% (Toc), 3.4% (placebo) European League Against Rheumatism responses 79.7% (Toc), 37.6% (placebo) Change of: DAS28 -3.17 (Toc), -1.16 (placebo)

Adverse events

Death <1% (Toc), <1% (placebo) Infections and infestations 37.4% (Toc), 31.6% (placebo) Gastrointestinal disorders 20.8% (Toc), 14.7% (placebo) Musculoskeletal and connective tissue disorders 13.0% (Toc), 17.9% (placebo) Skin and subcutaneous tissue disorders 16.6% (Toc), 7.0% (placebo) Nervous system disorders 11.6% (Toc), 8.7% (placebo) Laboratory investigations 11.7% (Toc), 2.7% (placebo) General disorders and administration-site conditions 8.2% (Toc), 7.2% (placebo) Injury, poisoning, and procedural complications 7.9% (Toc), 7.0% (placebo) Respiratory, thoracic, and mediastinal disorders 8.6% (Toc), 5.1% (placebo) Vascular disorders 6.7% (Toc), 5.1% (placebo) Neutropenia: Grade 1 (> 1,500 cells/mm3) 18.8% (Toc), 4.3% (placebo) Grade 2 (< 1,500–1,000 cells/mm3) 11.6% (Toc), 0.5% (placebo) Grade 3 (< 1,000–500 cells/mm3) 3.7% (Toc), 0.0% (placebo) Grade 4 (< 500 cells/mm3) 0.0% (Toc), 0.0% (placebo) Alanine aminotransferase increase: < 3 ´ upper normal limit 41.4% (Toc), 14.0% (placebo) > 3 ´ upper normal limit 4.1% (Toc), 0.7% (placebo) Aspartate aminotransferase increase: < 3 ´ upper normal limit 35.7% (Toc), 11.8% (placebo) > 3 ´ upper normal limit 1.6% (Toc), 0.5% (placebo) Total Bilirubin increase: < 3 ´ upper normal limit 8.9% (Toc), 0.7% (placebo) > 3 ´ upper normal limit 0.2% (Toc), 0.0% (placebo) Total Cholesterol increase: No change 48.6% (Toc), 67.4% (placebo) ³ 240 mg/dL 23.0% (Toc), 5.5% (placebo) LDL Cholesterol increase: No change 56.6% (Toc), 66.5% (placebo) ³ 160 mg/dL 16.1% (Toc), 3.4% (placebo) HDL Cholesterol increase: No change 64.5% (Toc), 65.0% (placebo) ³ 60mg/dL 15.0% (Toc), 6.0% (placebo)

Rheumatoid Arthritis: Tocilizumab

289

STREAM-Trial

Long-term safety and efficacy of Tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study STREAM: safety and efficacy of Tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in monotherapy

Substance

8 mg tocilizumab/kg/4 weeks (open label extension, n =143, n = 94 after 5 years) After 12 weeks of: 4 mg tocilizumab/kg/4 weeks (n = 54) 8 mg tocilizumab/kg/4 weeks (n = 55) Placebo (n = 53) Concomitant therapy: NSAIDs were permitted Prednisolone £ 10 mg was permitted Previous therapy: Insufficient response to min. 1 DMARD No DMARDs £ 4 weeks No immunosuppressants £ 4 weeks No parenteral and/or intraarticular use of corticosteroids £ 4 weeks No plasma exchange £ 4 weeks

Result

In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile

Patients

143 refractory RA patients Active disease > 6 months ³ 6 swollen joints ³ 6 tender joints Insufficient response to min. 1 DMARD ESR ³ 30 mm CRP > 1 mg/L Prednisolone < 10 mg/day

Authors

Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J

Publication

Ann Rheum Dis. 2009 Oct;68(10):1580–1584. Epub 2008 Nov 19

Follow up

5 years

ACR 20

84.0%

ACR 50

69.1%

ACR 70

43.6%

Note

DAS28 < 2.6 55.3% Decreased their corticosteroid dose 88.6% Discontinued corticosteroids 31.8%

290

Adverse events

Rheumatoid Arthritis: Tocilizumab

Any serious adverse events 27.5 events/100 patient-years (53.8%) Serious infections 5.7/100 patient-years (17.5%) Joint surgery 14% Pneumonia 6.3% Herpes zoster 4.9% Tendon rupture 3.5% Humerus fracture 2.8% Spinal osteoarthritis 2.1% Femoral neck fracture 2.1% Joint dislocation 1.4% Back pain 1.4% Lumbar spinal stenosis 1.4% Acute bronchitis 1.4% Pyelonephritis 1.4% Drain stem infarction 1.4% Cataract 1.4% Pneumothorax 1.4% Liver function abnormality 1.4%

Rheumatoid Arthritis: Tocilizumab

SATORI-Trial

Study of active controlled Tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to Methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy SATORI: Study of active controlled Tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to Methotrexate

Substance

Tocilizumab 8 mg/kg every 4 weeks (n = 61) MTX 8 mg/week (n = 66) Concomitant therapy: Prednisolone £ 10 mg/day NSAIDs and switching of NSAIDs was permitted Intraarticular injections of corticosteroid and hyaluronate preparations were allowed No iother DMARDs No intravenous or intramuscular corticosteroids No plasmapheresis Previous therapy: 8 mg MTX for min 8 weeks No DMARDs other than MTX £ 2 weeks No prior TNF antagonists No leflunomide £ 12 weeks

Result

Tocilizumab monotherapy of RA patients suffering from active disease despite methotrexate treatment was well tolerated and provided clinical benefit

Patients

125 RA patients Disease duration > 6 months ³ 6 tender joints ³ 6 swollen joints ESR ³ 30 mm CRP ³ 10 mg/l

Authors

Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, Kishimoto T

Publication

Mod Rheumatol. 2009;19(1):12–19. Epub 2008 Nov 1

Follow up

24 weeks

ACR 20

25.0% (MTX), 80.3% (tocilizumab)

ACR 50

10.9% (MTX), 49.2% (tocilizumab)

ACR 70

6.3% (MTX), 29.5% (tocilizumab)

Note

Change of: Vascular endothelial growth factor -74.0 (placebo), -346.9 (tocilizumab) DAS28 < 3.2 3.2% (placebo), 65.5% (tocilizumab) DAS28 3.2–5.2 39.7% (placebo), 96.6% (tocilizumab) DAS28 < 2.4 1.6% (placebo), 43.1% (tocilizumab) MHAQ ³ 0.22 34% (placebo), 67% (tocilizumab)

291

292

Adverse events

Rheumatoid Arthritis: Tocilizumab

Total adverse events 71.9% (placebo), 91.8% (tocilizumab) Nasopharyngitis 10.9% (placebo), 18.0% (tocilizumab) Stomatitis 0% (placebo), 11.5% (tocilizumab) Hyperlipidaemia 1.6% (placebo), 6.6% (tocilizumab) Headache 3.1% (placebo), 6.6% (tocilizumab) Rash 3.1% (placebo), 6.6% (tocilizumab) Diarrhoea 1.6% (placebo), 6.6% (tocilizumab) Upper respiratory tract infections 6.3% (placebo), 4.9% (tocilizumab)

Rheumatoid Arthritis: Tocilizumab

293

AmbitionTrial

Comparison of Tocilizumab monotherapy versus Methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. Ambition: (Actemra versus Methotrexate double-Blind Investigative Trial In mONotherapy) AMBITION: Actemra versus Methotrexate double-Blind Investigative Trial In Monotherapy

Substance

Tocilizumab 8 mg/kg every 4 weeks (n = 288) 7.5 mg methotrexate/w, titrated to 20 mg/week within 8 weeks, dose reduction to 10 mg/week because of safety reasons was permitted (n = 284) Rescue therapy after 8 weeks: Placebo was switched to tocilizumab if swollen/tender joint count worsend by 20% Concomitant therapy: Prednisone £ 10 mg/day NSAIDs were permitted at stable doses ³ 6 weeks Folate ³ 5 mg/week Previous therapy: No unsuccessfull treatment with anti-TNF agent No methotrexate £ 6 months

Result

Tocilizumab monotherapy led to a rapid improvement of RA in patients who had not previously failed methotrexate or biologic treatment. It was superior to methotrexate monotherapy

Patients

673 RA patients Severe disease ³ 3 months ³ 6 swollen joints ³ 8 tender joints CRP ³ 1 mg/dL ESR ³ 28 mm/h ³ 3 months

Authors

Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, Siri DA, Tomsic M, Alecock E, Woodworth T, Genovese MC

Publication

Ann Rheum Dis. 2010 Jan;69(1):88–96

ACR 20

All patients 69.9% (Toc), 52.1% (MTX) MTX naive patients 68.6% (Toc), 53.7% (MTX)

ACR 50

All patients 44.1% (Toc), 33.5% (MTX) MTX naive patients 45.0% (Toc), 32.2% (MTX)

ACR 70

All patients 28.0% (Toc), 15.1% (MTX) MTX naive patients 27.2% (Toc), 14.2% (MTX)

294

Note

Rheumatoid Arthritis: Tocilizumab

EULAR Remission (DAS28 < 2.6) 33.6% (Toc), 12.1% (MTX) Good + moderate EULAR response 82.2% (Toc), 64.8% (MTX) Change of: DAS28 -3.31 (Toc), -2.05 (MTX) Swollen joint count -11.7 (Toc), -8.2 (MTX) Tender joint count -17.2 (Toc), -13.9 (MTX) Patient’s global VAS (mm) -34.5 (Toc), -30.7 (MTX) Physician’s global VAS (mm) -41.3 (Toc), -31.7 (MTX) Patient’s pain VAS (mm) -31.9 (Toc), -29.9 (MTX) CRP (mg/dL) -2.8 (Toc) -1.9 (MTX) ESR (mm/h) -37.3 (Toc) -16.1 (MTX) HAQ-DI -0.7 (Toc) -0.5 (MTX)

Adverse events

Infections 34.4% (Toc), 37.3% (MTX) Nasopharyngitis 6.9% (Toc), 6.0% (MTX) Upper respiratory tract infection 7.3% (Toc), 5.3% (MTX) Gastrointestinal disorders 29.9% (Toc), 31.3% (MTX) Nausea 6.3% (Toc), 12.0% (MTX) Diarrhoea 5.2% (Toc), 5.3% (MTX) Skin and subcutaneous disorders 14.6% (Toc), 11.3% (MTX) Musculoskeletal and connective tissue disorders 11.5% (Toc), 11.3% (MTX) Nervous system disorders 12.8% (Toc), 6.3% (MTX) Headache 7.3% (Toc), 2.5% (MTX) General disorders and administration site conditions 7.3% (Toc), 8.5% (MTX) Respiratory, thoracic and mediastinal 9.0% (Toc), 6.7% (MTX), vascular disorders 8.3% (Toc), 4.6% (MTX) Hypertension 5.6% (Toc), 2.1% (MTX) Psychiatric disorders 6.9% (Toc), 3.9% (MTX) Injury, poisoning and procedural complications 4.9% (Toc), 5.3% (MTX) Eye disorders 5.2% (Toc), 3.2% (MTX) Neoplasms benign, malignant and unspecified 0.3% (Toc), 1.1% (MTX) Infections 1.4% (Toc), 0.7% (MTX) Sepsis 0.0% (Toc), 0.4% (MTX) Pneumonia 0.7% (Toc), 0.4% (MTX) Sinusitis 0.3% (Toc), 0.0% (MTX) Sialoadenitis 0.3% (Toc), 0.0% (MTX)

Rheumatoid Arthritis: Tocilizumab

Neutropenia: Grade 1 (> 1,500 cells/mm3) 17.7% (Toc), 7.7% (placebo) Grade 2 (< 1,500–1,000 cells/mm3) 10.4% (Toc), 2.1% (placebo) Grade 3 (< 1,000–500 cells/mm3) 3.1% (Toc), 0.4% (placebo) Grade 4 (< 500 cells/mm3) 0.0% (Toc), 0.0% (placebo) Alanine aminotransferase increase: < 3 ´ upper normal limit 31.6% (Toc), 30.6% (placebo) > 3 ´ upper normal limit 1.0% (Toc), 2.5% (placebo) > 5 ´ upper normal limit 0.7% (Toc), 1.1% (placebo) Aspartate aminotransferase increase: < 3 ´ upper normal limit 20.5% (Toc), 23.6% (placebo) > 3 ´ upper normal limit 0.3% (Toc), 1.1% (placebo) > 5 ´ upper normal limit 0.7% (Toc), 0.4% (placebo) Total Bilirubin increase: < 3 ´ upper normal limit 7.6% (Toc), 0.7% (placebo) > 3 ´ upper normal limit 0.0% (Toc), 0.0% (placebo) > 5 ´ upper normal limit 0.0% (Toc), 0.0% (placebo) Total Cholesterol increase: No change 23.6% (Toc), 45.8% (placebo) ³ 240 mg/dL 13.2% (Toc), 0.4% (placebo) LDL Cholesterol increase: No change 11.1% (Toc), 21.8% (placebo) ³ 160 mg/dL 3.1% (Toc), 0% (placebo)

295

Ankylosing Spondylitis

Methylprednisolone

Trial

Intravenous methylprednisolone pulse therapy in ankylosing spondylitis

Substance

1,000 mg methylprednisolone high-dose (n = 8) 375 mg methylprednisolone low-dose (n = 9) Concomitant therapy: Exercise therapy NSAIDs were discontinued on day 0 Previous therapy: NSAIDs No pulse methylprednisolone £12 months No systemic or local corticosteroid £3 months

Result

Therapy with high or low dose methylprednisolone showed no statistically significant differences in ankylosing spondylitis patients with respect to pain relief and spinal mobility. There was a trend toward the high dose with a greater and longer lasting improvement

Patients

17 patients with active ankylosing spondylitis Despite NSAID treatment No pulse methylprednisolone in 12 months No systemic or intraarticular steroids for 3 months No lumbar spine syndesmophytes No total ankylosis

Authors

Peters ND, Ejstrup L

Publication

Scand J Rheumatol. 1992;21(3):134–138

Follow up

12 months

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_2, © Springer-Verlag London Limited 2011

297

298

Ankylosing Spondylitis: Methylprednisolone

Note

Pain VAS improved markedly in high dose patients Morning stiffness improved markedly in both groups, effect diminished rapidly Chin manubrium distance improved on day 3 (similar in both groups) Thorax expansion improved markedly in high dose patients Lumbar mobility improve in both groups similar Finger to floor distance decreased in both groups Re-institution of NSAIDs day 8 (low dose) day 25 (high dose)

Adverse events

Flushing n = 9 (low dose) n = 8 (high dose) Dizziness n = 1 (low dose), n = 2 (high dose) Bitter taste n = 0 (low dose), n = 1 (high dose) Insomnia n = 0 (low dose), n = 1 (high dose) Palpitation n = 0 (low dose), n = 1 (high dose) Irritability n = 1 (low dose), n = 0 (high dose) Dry mouth n = 1 (low dose), n = 1 (high dose) Sexual dysfunction n = 1 (low dose), n = 0 (high dose)

Ankylosing Spondylitis: Cyclophosphamide

Trial

Cyclophosphamide in the treatment of ankylosing spondylitis, a study on 66 cases

Substance

50–400 mg/day cyclophosphamide p.o. Continued after initiation in the hospital Previous medications were continued: Phenylbutazon Oxyphenylbutazon Indometazin Ibuprofen Corticosteroids Other NSAIDs

Result

Cyclophosphamide appeared to be effective in AS patients

Patients

66 patients with ankylosing spondylitis Peripheral arthritis n = 53

Authors

Demetriades P, Wesiroglou G, Mitseas C, Kontomerkos A

Publication

Z Allgemeinmed. September 10, 1973;49(25):1182–1186

Note

9% stable disease 63% significant improvement 21% marked improvement 7% doubtful improvement

Adverse events

Hair loss 26% Gastrointestinal disorders 20% Non bacterial cystitis 10% Nausea 9% Leucopenia <4000 ccm 3%

299

300

Ankylosing Spondylitis: Leflunomide

Trial

6 months open label trial of leflunomide in active ankylosing spondylitis

Substance

20 mg leflunomide/day (loading dose 100 mg for 3 days) Concomitant therapy: Steroids £7.5 mg/day at stable dose ³1 month Previous therapy: No DMARDs NSAIDs

Result

Patients with active AS and peripheral arthritis improved significantly with leflunomide treatment. There was no effect on axial symptoms

Patients

20 AS-patients Insufficient response to NSAIDs BASDAI ³3

Authors

Haibel H, Rudwaleit M, Braun J, Sieper J

Publication

Ann Rheum Dis. January 2005;64(1):124–126

Follow up

6 months

BASDAIimprovement

Change of: BASDAI 25% improvement: 25% of the patients BASDAI 50% improvement: 20% of the patients Absolute BASDAI did not change significantly over the 6-month study (4.9 at baseline 4.3 at week 24) No significant change: BASFI, BASMI, patient’s, and physician’s global assessment, SF-36 mental component, CRP Peripheral arthritis patients (n = 10, change from baseline): Inflamed joints 1.7 => 0.2 BASDAI 5.0 => 3.6

Adverse events leading to withdrawal

Patient 1: systemic allergic skin reaction Patient 2: diarrhea, nausea, hair loss, impotence, tachycardia Patient 3: skin allergy, diarrhea Patient 4: increase of liver enzymes Patient 5: nausea, dizziness, dyspepsia Patient 6: diarrhea, nausea, vomiting

Ankylosing Spondylitis: Leflunomide

Trial

Double-blind, randomized, placebo-controlled study of leflunomide (n = 30), in the treatment of active ankylosing spondylitis

Substance

100 mg leflunomide loading dose on days 1, 8, 15 Followed by 20 mg leflunomide every other day for 2 weeks Followed by 20 mg leflunomide every day (n = 30) Placebo (n = 15)

301

Concomitant therapy: NSAIDs were permitted if stable ³30 days Prednisone £15 mg if stable ³30 days No DMARDs No TNF antagonists Contraception was required for both sexes Previous therapy: No DMARDs £30 days No TNF blocking agents £30 days Result

Leflunomide treatment did not result in a significant improvement of the ASAS 20% response in patients suffering from active ankylosing spondylitis

Patients

45 patients with active ankylosing spondylitis BASDAI of ³4 Pain of ³4 on (VAS 0–10)

Authors

van Denderen JC, van der Paardt M, Nurmohamed MT, de Ryck YM, Dijkmans BA, van der Horst-Bruinsma IE

Publication

Ann Rheum Dis. December 2005;64(12):1761–1764. Epub 2005 May 18

Follow up

24 weeks

Note

ASAS 20%, 27% (leflunomide), 20% (placebo) Change of: Bath ankylosing spondylitis global score last week (0–10) -0.6 (placebo), -1.3 (leflunomide) Bath ankylosing spondylitis global score last 6 months -1.5 (placebo), -0.7 (leflunomide) Pain (0–10) -0.5 (placebo), -1.4 (leflunomide) BASFI (0–10) -0.4 (placebo), 0.0 (leflunomide) BASDAI (0–10) -0.3 (placebo), -1.1 (leflunomide) BASMI (0–10) +0.3 (placebo), 0.0 (leflunomide) Swollen joint count (0–44) -0.2 (placebo), +0.2 (leflunomide) Global physician’s assessment (0–10) -0.7 (placebo), -0.5 (leflunomide) ESR (mm/h) -1.9 (placebo), +8.4 (leflunomide) C reactive protein (mg/L) -6.1 (placebo), +6.5 (leflunomide)

Adverse events

Gastrointestinal disorders 57% (leflunomide), 33% (placebo) Respiratory tract infections 17% (leflunomide), 27% (placebo) Prurigo 13% (leflunomide), 13% (placebo) Fatigue 0% (leflunomide), 13% (placebo)

302

Ankylosing Spondylitis: Methotrexate

Trial

Methotrexate in severe ankylosing spondylitis: an open study

Substance

7.5 MTX/week after week 12 ³ 15 mg MTX/week Concomitant therapy: NSAIDs were continued at stable doses If MTX was judged effective NSAID dose was reduced Adequate contraception during and 6 months after MTX therapy Previous therapy: NSAIDs and SSZ

Result

Methotrexate appeard to have a beneficial effect in patients with ankylosing spondylitis

Patients

11 patients with ankylosing spondylitis Despite NSAID and SSZ therapy Stable NSAID dose ³4 weeks +³2 out of: Morning stiffness ³30 min Disturbance of sleep due to pain and stiffness Peripheral arthritis CRP ³20 mg/L, ESR ³20 mm/h, or IgA ³3.9 mg/L Spinal pain Stiffness and pain of the thorax during movement Pain in both buttocks during the night

Authors

Creemers MC, Franssen MJ, van de Putte LB, Gribnau FW, van Riel PL

Publication

J Rheumatol. June 1995;22(6):1104–1107

Follow up

36 weeks

Note

CRP and ESR improved equally Iridocyclitis not influenced Improvement of (no. of patients): Spinal pain n = 6 Chest pain n = 5 General well being n = 6 Tiredness n = 4 Morning stiffness n = 5 Occiput to wall distance n = 5, not applicable n = 5 Finger to floor distance n = 3 Chest expansion n = 5 Schober’s 10 cm test n = 6 Ritchie articular index n = 5, not applicable n = 3 Number of swollen joints n = 3, not applicable n = 6 Enthesitis index n = 5, not applicable n = 1 Dutch functional index n = 4 ESR n = 4, not applicable n = 2

Adverse events

Abdominal discomfort n = 2 Nausea n = 1 Transient oral ulcer n = 1 Reversible liver function elevations n = 3

Ankylosing Spondylitis: Methotrexate

Title

Efficacy of methotrexate in the treatment of ankylosing spondylitis: a 3-year open study

Substance

7.5 mg methotrexate/week (week 12: increased to 10 mg/week) Concomitant therapy: Stable 100 mg indomethacin/day was required SSZ discontinued No systemic or intraarticular steroid application No folic acid Previous therapy: NSAIDs and SSZ

Result

Methotrexate treatment was useful in patients with ankylosing spondylitis Peripheral arthritis and iridocyclitis did not improve

Patients

17 patients suffering from ankylosing spondylitis HLA B27 pos. Non-responders to treatment with 2–3 g sulfasalazine Lumbosacral and/or thoracolumbal junction involvement n = 12 Radiologic signs of acroiliitis n = 17 No psoriasis or inflammatory bowel disease Active disease if ³3 out of: Disturbed sleep due to pain and stiffness Peripheral arthritis n = 6 Spinal pain Thoracic stiffness and pain during normal movement/breathing Pain in both buttocks during the night or day ESR ³30 mm/h CRP ³20 mg/L

Authors

Biasi D, Carletto A, Caramaschi P, Pacor ML, Maleknia T, Bambara LM

Publication

Clin Rheumatol. 2000;19(2):114–117

Follow up

36 months

Note

Change of: VAS (night pain) 57.2 (baseline), 0 (36 months) VAS (general wellbeing), 62.6 (baseline), 3.7 (36 months) Schober’s Test 2.0 (baseline), 4.9 (36 months) Occiput wall 11.6 (baseline), 5.0 (36 months) Fingertip floor 33.0 (baseline), 7.1 (36 months) Number of peripheral swollen joints 5.0 (baseline), 2.1 (36 months) Number of tender swollen joints 8.2 (baseline), 3.3 (36 months) ESR (mm/h) 37.4 (baseline), 11.8 (36 months) CRP (mg/L) 37.8 (baseline), 4.2 (36 months) Dose of indomethacin (mg/day) 100 (baseline), 15 (36 months)

Adverse events

Transitory elevation of transaminases n = 4 Hypogammaglobulinaemia n = 1

303

304

Ankylosing Spondylitis: Methotrexate

Trial

Efficacy of methotrexate in ankylosing spondylitis: a randomized, double-blind, placebo-controlled trial

Substance

7.5 mg methotrexate (MTX)/week, dose was kept stable (n = 17) Placebo (n = 18) Concomitant therapy: NSAID were continued I.m. diclofenac 2 × 75 mg/day for 3 days (episodes of peripheral arthritis) Analgetic application for pain was permitted Folic acid was permitted Appropriate anticonception Previous therapy: No prior MTX treatment No intravenous methylprednisolone No oral corticosteroids or immunosuppressive drugs

Result

Methotrexate was safe and effective for patients with ankylosing spondylitis

Patients

Active ankylosing spondylitis patients Disease activity ³30 (VAS 0–100) Inflammatory back pain +³1 out of: Morning stiffness ³45 min Presence of peripheral arthritis

Authors

Gonzalez-Lopez L, Garcia-Gonzalez A, Vazquez-Del-Mercado M, Muñoz-Valle JF, Gamez-Nava JI

Publication

J Rheumatol. August 2004;31(8):1568–1574

Follow up

24 weeks

Note

Composite index for AS 20% response 53% (MTX), 17% (placebo) Change of: Morning stiffness -9 min (MTX), +2 min (placebo) Physical well being -6 (MTX), -8 (placebo) BASDAI -1.6 (MTX), -0.9 (placebo) BASFI -1.3 (MTX), -0.4 (placebo) Physical global assessment -32 (MTX), 0 (placebo) Patient global assessment -13 (MTX), -12 (placebo) HAQ -0.2 (MTX), 0 (placebo)

Adverse events

Mild headache 53% (MTX), 44% (placebo) Oral ulcerations 53% (MTX), 28% (placebo) Upper abdominal pain 29% (MTX), 28% (placebo) Nausea and vomiting 12% (MTX), 39% (placebo) Not severe, transitory diarrhea 12% (MTX), 28% (placebo) Transitory liver function abnormalities 12% (MTX), 11% (placebo) Loss of hair 5.9% (MTX), 0% (placebo) Mild infections 5.9% (MTX), 5.6% (placebo) Withdrawals 5.9% (MTX), 5.6% (placebo)

Ankylosing Spondylitis: Methotrexate

Trial

No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial

Substance

15 mg methotrexate (MTX) increased to 20 mg/week after 4 weeks No DMARDs £4 weeks Steroids ³7.5 mg/day not permitted (discontinued for 4 weeks) Concomitant therapy: No other DMARDs Steroids £7.5 mg/day NSAID were continued Previous therapy: NSAIDs

Result

Methotrexate did not show any benefit for axial manifestations in patients with active ankylosing spondylitis beyond the expected placebo response

Patients

20 patients with active AS Despite NSAID treatment BASDAI ³4

Authors

Haibel H, Brandt HC, Song IH, Brandt A, Listing J, Rudwaleit M, Sieper J

Publication

Ann Rheum Dis. March 2007;66(3):419–421. Epub 2006 Aug 10

Follow up

16 weeks

Note

ASAS 20 25% ASAS 40 10% ASAS 70 0% BASDAI 20 30% BASDAI 50 10% BASDAI 70 5% Change of: CRP 1 mg/dL (baseline), 0.8 mg/dL (16 weeks) Number of swollen joints 4.7 (baseline), 1.2 (16 weeks) Enthesitic sites 2.2 (baseline), 1.9 (16 weeks)

Adverse events

Nausea (n = 7) Infections of the upper respiratory tract (n = 6) NSAID-associated gastrointestinal bleeding (n =1)

305

306

Ankylosing Spondylitis: Pamidronate

Title

A 6-month randomized, controlled, double-blind, dose-response comparison of intravenous Pamidronate (60 mg versus 10 mg), in the treatment of non-steroidal anti-inflammatory drug-refractory ankylosing spondylitis

Substance

Pamidronate monthly at 60 mg i.v. (n = 41) Pamidronate monthly at 10 mg i.v. (n = 41) Concomitant therapy: DMARDs were continued NSAIDs were continued Previous therapy: NSAID (maximum tolerable dose, stable for 1 month) No intraarticular corticosteroid injections £3 months No i.v. infusion with methylprednisolone £3 months

Result

Pamidronate had a therapeutic effect in ankylosing spondylitis. This effect was more profound in patients treated with 60 rather than 10 mg pamindronate

Patients

84 AS patients Active disease ³6 months Despite stable NSAID therapy (maximum tolerable dose, stable for 1 month) BASDAI ³4 Morning stiffness of ³45 min

Authors

Maksymowych WP, Jhangri GS, Fitzgerald AA, LeClercq S, Chiu P, Yan A, Skeith KJ, Aaron SL, Homik J, Davis P, Sholter D, Russell AS

Publication

Arthritis Rheum. March 2002;46(3):766–773

Follow up

6 months

Note

BASDAI reduction ³25% 63.4% (60 mg), 30.2% (10 mg) BASDAI reduction ³50% 39% (60 mg), 16.3% (10 mg) BASDAI reduction ³70% 17% (60 mg), 4.7% (10 mg) BASFI reduction ³25% 63.4% (60 mg), 20.9% (10 mg) Change of: BASDAI -34.5% (60 mg), -15.0% (10 mg) Axial pain (VAS) -2.58 (60 mg), -1.01 (10 mg) BASFI -1.69 (60 mg), -0.15 (10 mg) Differences in ESR/CRP were not significant

Adverse events

Withdrawals 20.9% (10 mg), 7.3% (60 mg) Transient arthralgias/myalgias 68.3% (60 mg), 46.5% (10 mg)

Ankylosing Spondylitis: Sulfasalazine

307

Trial

Sulfasalazine in ankylosing spondylitis

Substance

1 g sulfasalazine/d (SSZ) for 1 week, dose was increased to 3 g/day (n = 14) Placebo (n = 15) Concomitant therapy: NSAIDs were allowed as a pain reliever Previous therapy: No information provided

Result

Sulfasalazine treatment of ankylosing spondylitis was effective and safe

Patients

37 patients with ankylosing spondylitis HLA B27 pos. ESR >30 mm/h Raised haptoglobin ³2 g/L Raised orosomucoid ³1.2 g/L Morning stiffness >30 min Disturbed sleep due to pain or stiffness

Authors

Feltelius N, Hällgren R

Publication

Ann Rheum Dis. May 1986;45(5):396–399

Follow up

12 weeks

Note

Change of: ESR change -3.5 (SSZ), -2.2 (placebo) Haptoglobin (g/L) -0.80 (SSZ), +0.06 (placebo) Orosomucoid (g/L) -0.16 (SSZ), +0.12 (placebo) Morning stiffness, stiffness, pain chest expansion, Schober’s test, sleep disturbance, sacroiliac pain improved in SSZ treated patients

Adverse events

Gastrointestinal symptoms n = 5 (SSZ), n = 3 (placebo) Nausea n = 1 (SSZ), n = 2 (placebo) Rash n = 2 (SSZ), n = 1 (placebo)

308

Ankylosing Spondylitis: Sulfasalazine

Trial

Sulfasalazine in ankylosing spondylitis: a double-blind controlled study in 60 patients

Substance

2 g sulfasalazine (SSZ)/day (n = 30) Placebo (n = 30) Concomitant therapy: NSAIDs were continued Previous therapy: NSAID

Result

Sulfasalazine treatment for spondylitis in ankylosing spondylitis was safe and effective

Patients

60 patients with active ankylosing spondylitis Despite NSAID treatment No peripheral arthritis

Authors

Dougados M, Boumier P, Amor B

Publication

Br Med J (Clin Res ed). October 11, 1986;293(6552):911–914

Follow up

6 months

Note

Patients considered treatment as: Success n = 6 (placebo), n = 15 (SSZ) Failure n = 24 (placebo), n = 15 (SSZ) Change of: Pain (VAS) -6.5 mm (placebo), -9.0 (SSZ) Joint index 0.0 (placebo), -1.0 (SSZ) No. of nocturnal awakenings 0.0 (placebo), 0.0 (SSZ) Functional index -2.3 (placebo), -4.0 (SSZ) Schobers test +0.5 (placebo), +0.5 (SSZ) Hand-ground distance (cm) 0.0 (placebo), -3.0 (SSZ) Chest expansion (cm) +1.0 (placebo), +1.0 (SSZ) ESR (mm/h) -2.0 (placebo), -2.0 (SSZ)

Adverse events

Nausea n = 0 (placebo), n = 3 (SSZ) Epigastric pain n = 1 (placebo), n = 0 (SSZ) Rash n = 1 (placebo), n = 0 (SSZ) Increased serum aspartate transaminase n = 0 (placebo), n = 1 (SSZ) Anemia n = 1 (placebo), n = 0 (SSZ) Abdominal pain n = 0 (placebo), n = 1 (SSZ)

Ankylosing Spondylitis: Sulfasalazine

Title

Sulfasalazine in the treatment of ankylosing spondylitis. A 26-week, placebo-controlled clinical trial

Substance

2 × 500 mg sulfasalazine (increased weekly to mean 2.5 g/day, n = 43) Placebo (n = 42) Concomitant therapy: NSAIDs were continued Previous therapy: NSAID

Result

Sulfasalazine treated patients with ankylosing spondylitis improved in morning stiffness, chest expansion, and ESR

Patients

85 patients with active ankylosing spondylitis 55 patients with peripheral arthritis ESR ³30 mm/h CRP ³20 mg/L Morning stiffness ³30 min

Authors

Nissilä M, Lehtinen K, Leirisalo-Repo M, Luukkainen R, Mutru O, Yli-Kerttula U

Publication

Arthritis Rheum. September 1988;31(9):1111–1116

Follow up

26 weeks

Note

Change of: Duration of morning stiffness -31 min (SSZ), –11 min (placebo) Severity of morning stiffness (VAS) -17 (SSZ), -5 (placebo) Severity of pain (VAS) -14 (SSZ), -8 (placebo) Chest expansion +12 cm (SSZ), +14 cm (placebo) Schober’s test +0.3 cm (SSZ), +0.4 cm (placebo) Finger tips to floor -3.0 cm (SSZ), -3.4 cm (placebo) Occiput to wall -0.1 cm (SSZ), 0 cm (placebo) Painful joints -0.2 (SSZ), -0.5 (placebo) Swollen joints -0.2 (SSZ), -0.3 (placebo) General well being (VAS) -6 (SSZ), -5 (placebo) ESR (mm/h) -19 (SSZ), -4 (placebo) CRP -11 (SSZ), -8 (placebo) Change of (only SSZ treated patients): Duration of morning stiffness -19 min (axial type), -39 min (peripheral type) Chest expansion (cm) +11 (axial type), +13 (peripheral type) Schober’s test +0.4 (axial type), +0.2 (peripheral type) ESR (mm/h) –17 (axial type), –19 (peripheral type) CRP (g/L) –8 (axial type), –12 (peripheral type)

Adverse events

Rash n = 2 (SSZ), n = 2 (placebo) Pruritus n = 0 (SSZ), n = 1 (placebo) Abdominal symptoms n = 6 (SSZ), n = 3 (placebo) Dizziness n = 1 (SSZ), n = 4 (placebo) Elevation of hepatic enzymes n = 0 (SSZ), n = 1 (placebo)

309

310

Ankylosing Spondylitis: Sulfasalazine

Trial

Sulfasalazine therapy in ankylosing spondylitis: its effect on disease activity, immunoglobulin A and the complex immunoglobulin A-alpha-1-antitrypsin

Substance

500 mg sulfasalazine (SSZ) day increased every 5 days to 2 g/day (n = 15) Placebo (n = 13) Concomitant therapy: NSAIDs continued, changes of substance or dose were not allowed Previous therapy: NSAID

Result

Sulfasalazine treated patients improved in clinical and laboratory measures of ankylosing spondylitis

Patients

28 patients with active AS ESR >30 mm/h CRP >20 mg/L IgA >272 IU/mL Morning stiffness >10 min Sleep disturbance due to pain/stiffness No fused sacroiliitic joints

Authors

Davis MJ, Dawes PT, Beswick E, Lewin IV, Stanworth DR

Publication

Br J Rheumatol. October 1989;28(5):410–413

Follow up

3 months

Note

Study completed 53% (SSZ), 47% (placebo) Change of: VAS stiffness -1 (placebo), -3 (SSZ) VAS pain 0 (placebo), -3 (SSZ) Occiput wall (inches), +0.1 (placebo), -0.6 (SSZ) Finger foot (inches), +0.94 (placebo), +0.3 (SSZ) Sleep disturbance -3 (placebo), -7 (SSZ) ESR (mm/h), –0.8 (placebo), -6.2 (SSZ) CRP (mg/L), +11 (placebo), -16 (SSZ)

Ankylosing Spondylitis: Sulfasalazine

Title

A controlled trial of Sulfasalazine treatment of chronic ankylosing spondylitis: Failure to demonstrate a clinical effect

Substance

500 mg sulfasalazine/d (SSZ) increased by 500 mg every week to 2 g/day (n = 32) Placebo (n = 30)

311

Concomitant therapy: NSAIDs were continued Access to physiotherapy was free Previous therapy: NSAID No SSZ No immunosuppressant or corticosteroids Result

Sulfasalazine therapy of long-standing active ankylosing spondylitis was not effective

Patients

62 patients with long standing, symptomatic ankylosing spondylitis Requiring daily NSAIDs No prior SSZ therapy

Authors

Corkill MM, Jobanpurta P, Gibson T, Macfarlain DG

Publication

Br J Rheumatol. 1990;29:41–45

Follow up

48 weeks

Note

Changes of: VAS spinal pain -4.0 mm (SSZ), +3.8 mm (placebo) Spinal stiffness -9.0 mm (SSZ), +0.8 mm (placebo) Peripheral joint pain +0.1 mm (SSZ), +6.1 mm (placebo) Schober’s index -0.17 cm (SSZ), +0.30 cm (placebo) Chest expansion -0.13 cm (SSZ), –0.47 cm (placebo) Cervical flexion -4.1° (SSZ), –5.9° (placebo) Cervical rotation -0.7° (SSZ), +1° (placebo) ESR –5.8 mm/h (SSZ), -5.7 mm/h (placebo)

Adverse events

Mild gastrointestinal problems 37.5% (SSZ), 20% (placebo) Mild headaches 15.6% (SSZ), 6.3% (placebo) Mild depression 3.3% (SSZ), 6.3% (placebo) Gastrointest. leading to withdrawal 15.6% (SSZ), 26.7% (placebo) Headaches leading to withdrawal 15.6% (SSZ), 0% (placebo) Depression leading to withdrawal 3.1% (SSZ), 0% (placebo) Leucopoenia 3.1% (SSZ), 0% (placebo)

312

Ankylosing Spondylitis: Sulfasalazine

Trial

Sulfasalazine in ankylosing spondylitis. A radiological, clinical, and laboratory assessment

Substance

500 mg sulfasalazine (SSZ)/day, increased every 4 days to 2 g/day (n = 20) Placebo (n = 20) Concomitant therapy: NSAIDs were continued, dose reduction was permitted Access to physiotherapy was free Previous therapy: NSAIDs: Indomethacin n = 13 Naproxen n = 10 Furbiprofen n = 4 Diclophenac n = 3 Piroxicam n = 2 Phenylbutazone n = 2

Result

Sulfasalazine was not superior to placebo treatment of ankylosing spondylitis patients

Patients

40 patients with ankylosing spondylitis requiring NSAIDs Morning stiffness >10 min Sleep disturbance because of pain ESR >30 mm/h CRP >20 mg/L IgA >272 IU/mL Not ³3 bridging syndesmophytes on the lateral lumbar spine

Authors

Taylor HG, Beswick EJ, Dawes PT

Publication

Clin Rheumatol. March 1991;10(1):43–48

Follow up

12 months

Note

Change of: Pain -2.43 (SSZ), -0.56 (placebo) Stiffness (VAS 1–10) -1.44 (SSZ), -0.09 (placebo) Sleep disturbance -29% (SSZ), -24% (placebo) Occiput wall distance (inches) +0.01(SSZ), +0.06 (placebo) Spinal flexion (inches) +0.17 (SSZ), +0.38 (placebo) finger-floor distance (inches) -2.39 (SSZ), -1.63 (placebo) Chest expansion (inches) 0.0 (SSZ), -0.2 (placebo)

Adverse events

Headache and dizziness n = 2 (SSZ), n = 0 (placebo) Gastrointestinal upset n = 0 (SSZ), n = 2 (placebo)

Ankylosing Spondylitis: Sulfasalazine

Trial

The course of established ankylosing spondylitis and the effects of Sulfasalazine over 3 years

Substance

500 mg sulfasalazine (SSZ) increased every week to maximum 2 g/day (n = 44) Placebo (n = 45) Concomitant therapy: NSAIDs were continued Previous therapy: NSAIDs

Result

Sulfasalazine was not superior to placebo in the treatment of ankylosing spondylitis patients

Patients

89 patients with established AS (including radiological sacroiliitis) No clear definition of the cohort studied

Authors

Kirwan J, Edwards A, Huitfeldt B, Thompson P, Currey H

Publication

Br J Rheumatol. August 1993;32(8):729–733

Follow up

3 years

Note

Both groups improved in spinal mobility tests Arthritic episodes 0.392/year (placebo), 0.298/year (SSZ)

Adverse events

Indigestion n = 0 (placebo), n = 1 (SSZ) Rash n = 0 (placebo), n = 1 (SSZ) Low white blood cells n = 0 (placebo), n = 1 (SSZ) Mouth ulcers n = 0 (placebo), n = 1 (SSZ) Diarrhea n = 0 (placebo), n = 1 (SSZ) Abnormal liver function tests n = 0 (placebo), n = 1 (SSZ) In anticipation of pregnancy n = 0 (placebo), n = 1 (SSZ) Light-headedness n = 1 (placebo), n = 0 (SSZ) Urinary frequency n = 1 (placebo), n = 0 (SSZ) New back pain n = 1 (placebo), n = 0 (SSZ) Chest pain n = 2 (placebo), n = 0 (SSZ) No specific symptoms n = 9 (placebo), n = 12 (SSZ)

313

314

Ankylosing Spondylitis: Sulfasalazine

Title

Sulfasalazine in the treatment of spondylarthropathy

Substance

500 mg (SSZ)/day, increased every week to 3 g/day (n = 179) Placebo (n = 172) Concomitant therapy: NSAIDs were continued if stable ³1 month Previous therapy: NSAIDs No DMARDs £3 months

Result

Sulfasalazine was slightly superior to placebo treatment in patients suffering from spondylarthropathies, most prominent in a subgroup analysis of patients with psoriatic arthritis

Patients

351 patients Ankylosing spondylitis (n = 134) Psoriatic arthritis (n = 136) Reactive arthritis (n = 81) No pre-exposure to SSZ Stable NSAIDS ³4 weeks Physicians global assessment: moderate/severe/very severe disease activity Pain VAS ³20/100 mm Morning stiffness ³30 min ³1 of the following criteria: Distal interphalangeal involvement Peripheral asymmetric arthritis Symmetric polyarthritis Sacroiliac involvement

Authors

Dougados M, van der Linden S, Leirisalo-Repo M, Huitfeldt B, Juhlin R, Veys E, Zeidler H, Kvien TK, Olivieri I, Dijkmans B, Bertouch J, Brooks P, Edmonds J, Major G, Amor B, Calin A

Publication

Arthritis Rheum. 1995;38:618–627

Study duration

6 months

Ankylosing Spondylitis: Sulfasalazine

Note

Change of: Physicians global assessment -43.8% (placebo), -60.1% (SSZ) Physicians global assessment +11.6% (placebo), +8.3% (SSZ) Pain (VAS 0-100 mm) -12 mm (placebo), -19 mm (SSZ) Patients global assessment improved 43.8% (placebo), 60.1% (SSZ) Patients global assessment worsened 11.1% (placebo), 8.3% (SSZ) Physicians global assessment improved 46.8% (placebo), 57% (SSZ) Physicians global assessment worsened 7% (placebo), 5.6% (SSZ) Morning stiffness (min) -45 (placebo), -26 (SSZ) Functional index –2.5 (placebo), –4.0 (SSZ) ESR (mm/h) –6 (placebo), –13 (SSZ) Tender joint count –2.1 (placebo), –5.3 (SSZ) Tender joint score –4.0 (placebo), –8.8 (SSZ) Swollen joint count –1.6 (placebo), –4.4 (SSZ) Swollen joint score –2.2 (placebo), –7.7 (SSZ) Dactylitis –0.1 (placebo), –0.5 (SSZ)

Adverse events

Nausea n = 13 (placebo), n = 36 (SSZ) Abdominal pain n = 15 (placebo), n = 14 (SSZ) Diarrhea n = 10 (placebo), n = 9 (SSZ) Stomatitis n = 2 (placebo), n = 1 (SSZ) Duodenal ulcers n = 0 (placebo), n = 1 (SSZ) Pruritus n = 4 (placebo), n = 6 (SSZ) Eruptions n = 7 (placebo), n = 11 (SSZ) Dizziness n = 10 (placebo), n = 8 (SSZ) Headache n = 8 (placebo), n = 24 (SSZ) Neuropathy n = 0 (placebo), n = 1 (SSZ) Haemoglobin decrease >2 mg/dL n = 10 (placebo), n = 28 (SSZ) White blood cell count <3.5 10E/L n = 6 (placebo), n = 6 (SSZ) Increase liver enzymes >2 × normal level n = 0 (placebo), n = 2 (SSZ) Myalgia n = 1 (placebo), n = 0 (SSZ) Anxiety n = 1 (placebo), n = 0 (SSZ)

315

316

Ankylosing Spondylitis: Sulfasalazine

Title

Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis

Substance

500 mg sulfasalazine/d (SSZ), increased over 4 weeks to 2 g (n = 131) Placebo (n = 133) Concomitant therapy: NSAIDs were continued at stabile doses No phenylbutazone No oral, intraarticular, or parenteral glucosteroids Previous therapy: NSAIDs No SSZ

Result

2 g sulfasalazine were well tolerated and a little more effective than placebo

Patients

264 AS patients with an active disease Active spondylitis Failed NSAIDs Morning stiffness ³45 min Inflammatory back pain Physician’s global assessment moderate or higher Failed to minimum 1 NSAID

Authors

Clegg DO, Reda DJ, Weisman MH, Blackburn WD, Cush JJ, Cannon GW, Mahowald MI, Schumacher HR, Taylor T, Budiman.mak E, Cohen MR, Vasey FB, Luggen ME, Mejias M, Silverman SL, Makkena R, Alepa FP, Buxbaum RJ, Ward JR, Henderson WG

Publication

Arthritis Rheum. December 1996;39(12):2004–2012

Follow up

36 weeks

Ankylosing Spondylitis: Sulfasalazine

Note

Response rate 38.2% (SSZ), 36.1% (placebo) Physician’s global assessment (% with improvement) 53.4% (SSZ), 55.6% (placebo) Patient’s global assessment (% with improvement) 40.5% (SSZ), 42.1% (placebo) Morning stiffness (% with improvement) 48.9% (SSZ), 44.4% (placebo) Back pain (% with improvement) 23.7% (SSZ), 27.1% (placebo) Change of: Chest expansion (cm) –0.4 (SSZ), 0 (placebo) Occiput to wall (cm) 0 (SSZ), 0.2 (placebo) Fingers to floor (cm) –1.8 (SSZ), –1.3 (placebo) ESR (mm/h) –5.3 (SSZ), –1.7 (placebo) CRP (mcg/mL) –0.28 (SSZ), –0.23 (placebo) Morning stiffness –0.5 (SSZ), –0.7 (placebo) Back pain (number) –6.1 (SSZ), –5.3 (placebo) Spondylitis functional index –0.7 (SSZ), –0.5 (placebo) Joint pain/tenderness score (number) –0.6 (SSZ), +0.3 (placebo) Joint swelling score (number) –0.2 (SSZ), –0.2 (placebo) Dactylitis score +0.1 (SSZ), 0.0 (placebo) Enthesopathy index (number) –1.4 (SSZ), –1.6 (placebo) Spondylitis articular index (number) –1.6 (SSZ), –1.6 (placebo) Chest expansion (cm) –0.4 (SSZ), 0.0 (placebo) Modified Schober’s test (cm) +0.1 (SSZ), +0.2 (placebo) Occiput to wall test (cm) 0.0 (SSZ), +0.2 (placebo) Finger to floor test (cm) –1.8 (SSZ), –1.3 (placebo)

Adverse events

Intercurrent illness 0.8% (SSZ), 2.2% (placebo) Adverse drug reactions (gastrointestinal, dermatological, pruritus, oral ulcers, alopecia, headache), 8.4% (SSZ), 4.4% (placebo) Gastrointestinal 3.8% (SSZ), 1.6% (placebo) Dermatological 1.5% (SSZ), 2.2% (placebo) Central nervous system 1.5% (SSZ), 0.8% (placebo) Fever 0.8% (SSZ), 0% (placebo) Increase of liver enzymes 0.8% (SSZ), 0% (placebo)

317

318

Ankylosing Spondylitis: Sulfasalazine

Trial

Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study

Substance

2 g sulfasalazine (SSZ)/day (n = 249) Placebo (n = 359) Concomitant therapy: NSAIDs were continued at stable doses No oral, intraarticular, or parenteral corticosteroids No phenylbutazone Previous therapy: NSAIDs stable dose ³4 weeks No SSZ

Result

Peripheral articular manifestations of spondylarthropathies responded better to treatment with sulfasalazine than axial manifestations. Sulfasalazine was safe and well tolerated in spondylarthropathy patients

Patients

618 spondylarthropathy patients (AS, PsoA, Reactive arthritis) Active or responsive disease Morning stiffness ³45 min Joint swelling capable of showing improvement Axial arthritis (n = 187) Peripheral arthritis (n = 432)

Authors

Clegg DO, Reda DJ, Abdellatif M

Publication

Arthritis Rheum. November 1999;42(11):2325–2329

Follow up

36 weeks

Note

Axial arthritis response: Overall response 40.2% (SSZ), 43.3% (placebo) Physician global assessment 54.6% (SSZ), 58.9% (placebo) Patient global assessment 41.2% (SSZ), 44.4% (placebo) Morning stiffness 50.5% (SSZ), 46.7% (placebo) Back pain 25.8% (SSZ), 30% (placebo) Peripheral arthritis response: Overall response 59% (SSZ), 42.7% (placebo) Physician global assessment 48.6% (SSZ), 43.2% (placebo) Patient global assessment 47.2% (SSZ), 39.5% (placebo) Joint pain 56.6% (SSZ), 45.9% (placebo) Joint swelling 63.2% (SSZ), 52.7% (placebo)

Adverse events

Total AE, leading to withdrawal 27% (SSZ), 18% (placebo) Peripheral arthritis, leading to withdrawal 29% (SSZ), 21% (placebo)

Ankylosing Spondylitis: Sulfasalazine

319

Trial

Sulfasalazine in the prevention of anterior uveitis associated with ankylosing spondylitis

Substance

2 × 500 mg sulfasalazine (SSZ)/day, increased daily by 1 to 3–4 g/day (n = 10) No treatment (n = 12) Concomitant therapy: No NSAIDs No eyedrops for iridic attacks

Result

Sulfasalazine reduced relapses and the severity of anterior uveitis associated with ankylosing spondylitis in some cases

Patients

22 AS patients with anterior uveitis ³2 attacs during the last year No glucose 6 phosphate dehydrogenase deficiency HLA B27 pos. Sacroiliitis grade III/IV

Authors

Benitez-Del-Castillo JM, Garcia-Sanchez J, Iradier T, Bañares A

Publication

Eye (Lond). June 2000;14(Pt 3A):340–343

Follow up

36 months

Note

Blood aqueous barrier permeability Acute attacks 31.3 × 10-4 min-1 (SSZ) 66.2 × 10-4 min-1 (no treatment) Disease free period 3.8 × 10-4 min-1 (SSZ) 5.3 × 10-4 min-1 (no treatment) Chronic intestinal inflammation at the end of the study n = 3 (SSZ) n = 7 (no treatment) No. of attacks/year: 1st year 0.5 (SSZ), 1.33 (no treatment) 2nd year 0.6 (SSZ), 0.83 (no treatment) 3rd year 0.3 (SSZ), 1.0 (no treatment)

320

Ankylosing Spondylitis: Sulfasalazine

Trial

Sulfasalazine in ankylosing spondylitis: a prospective, randomized, double-blind placebo-controlled study and comparison with other controlled studies

Substance

500 mg sulfasalazine (SSZ)/day increased to 3 g/day over 6 weeks (n = 34) Placebo (n = 36) Concomitant therapy: NSAIDs were continued Change of NSAIDs was permitted Previous therapy: No corticosteroids £6 weeks NSAIDs

Result

Sulfasalazine was beneficial in peripheral joint involvement of some ankylosing spondylitis patients. However, Sulfasalazine had no clinically relevant benefit in the whole patient cohort analyzed. Adverse effects leading to drop out of patients was high with a daily dose of 3 g

Patients

70 patients with established diagnosis of ankylosing spondylitis Mean disease duration of 16.7 years Negative Rheumatoid factor Morning stiffness ³20 min Spinal pain (VAS 0–100) ³25 mm No glucose 6 phosphate dehydrogenase deficiency

Authors

Schmidt WA, Wierth S, Milleck D, Droste U, Gromnica-Ihle E

Publication

Z Rheumatol. April 2002;61(2):159–167

Follow up

26 weeks

Note

Spinal Pain (VAS 0–100) -1.9 (placebo), -4.2 (SSZ) Nocturnal awakening because of pain -5.4 (placebo), -5.6 (SSZ) Pain (VAS) -1.7 (placebo), -1.1 (SSZ) Morning stiffness (VAS 0–100) -8.4 (placebo), -31.9 (SSZ) Swollen joint count -0.1 (placebo), -0.0 (SSZ) Tender joint count 0 (placebo), 0.1 (SSZ) Patient’s assessment very good improvement 17.1% (placebo), 33.3% (SSZ) Physicians assess. very good improvement 17.6% (placebo), 38.5% (SSZ) Schober-Test (cm) 0 (placebo), +0 (SSZ) Distance finger-floor (cm) -1 (placebo), -1 (SSZ) Distance Occiput-wall (cm) +0.5 (placebo), +1.2 (SSZ) Distance chin-sternum (cm) -0.5 (placebo), -0.5 (SSZ) Thorax-excursion (cm) +0.6 (placebo), +0.9 (SSZ) ESR (mm/h) -3.8 (placebo), -6.9 (SSZ) CRP -3.5 mg/L (placebo), -6.0 mg/L (SSZ) IgA (normal: 0.9–4.5 g/L) +0.3 (placebo), -1.7 (SSZ) IgG (normal: 8–18 g/L) +2.2 (placebo), -0.3 (SSZ) IgM (normal: 0.6–2.8 g/L) 0.0 (placebo), -0.3 (SSZ)

Adverse events

Gastro intestinal 47% (placebo), 44% (SSZ) Skin 11% (placebo), 27% (SSZ) Cerebral 31% (placebo), 38% (SSZ) Hematological 6% (placebo), 18% (SSZ) Kidney 33% (placebo), 27% (SSZ) Liver 8% (placebo), 12% (SSZ) Other 8% (placebo), 21% (SSZ) All 72% (placebo), 85% (SSZ)

Ankylosing Spondylitis: Sulfasalazine

Trial

Efficacy of Sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicenter randomized controlled trial

Substance

500 mg sulfasalazine (SSZ)/day, increased to 2 g/day (n = 120) Placebo (n = 122)

321

Concomitant therapy: NSAIDs were continued, dose was decreased, if possible Previous therapy: No DMARDs £4 weeks No corticosteroids £4 weeks Result

Treatment success of undifferentiated spondarthropathies was no better with sulfasalazine than with placebo. Sulfasalazine was more effective than placebo in a subgoup analysis of patients with inflammatory back pain and no peripheral arthritis

Patients

Ankylosing spondylitis patients With inflammatory or predominantly lower-limb synovitis +1 other feature of SpA of the European Spondyloarthropathy Study Group Symptom duration >3 months and <5 years BASDAI >3

Authors

Braun J, Zochling J, Baraliakos X, Alten R, Burmester G, Grasedyck K, Brandt J, Haibel H, Hammer M, Krause A, Mielke F, Tony HP, Ebner W, Gömör B, Hermann J, Zeidler H, Beck E, Baumgaertner M, Sieper J

Publication

Ann Rheum Dis. September 2006;65(9):1147–1153. Epub 2006 Apr 10

Follow up

24 weeks

Note

Change of: BASDAI score -1.76 (SSZ), -1.52 (placebo) BASFI score (0–10) -0.46 (SSZ), -0.28 (placebo) WOMAC Index, pain -0.48 (SSZ), -0.49 (placebo) WOMAC Index, stiffness -0.63 (SSZ), -0.71 (placebo) WOMAC Index, physical function -0.45 (SSZ), -0.27 (placebo) Schober’s test (cm) +0.19 (SSZ), +0.26 (placebo) Chest expansion (cm) +0.07 (SSZ), + 0.14 (placebo) CRP (mg/dL) in patients with raised CRP >10 mg/dL at baseline -3.05 (SSZ), -7.84 (placebo) ESR (mm/h) in patients with ESR >15 mm/h at baseline -9.25 (SSZ), -7.02 (placebo)

322

Adverse events

Ankylosing Spondylitis: Sulfasalazine

Headache 17% (SSZ), 14.4% (placebo) Nausea 15.2% (SSZ), 9.3% (placebo) Abdominal pain 14.3% (SSZ), 13.6% (placebo) Rhinitis 13.4% (SSZ), 15.3% (placebo) Asthenia 13.4% (SSZ), 4.2% (placebo) Diarrhea 8.9% (SSZ), 12.7% (placebo) Vertigo 8.9% (SSZ), 2.5% (placebo) Back pain 8.0% (SSZ), 4.2% (placebo) Vomiting 8.0% (SSZ), 3.4% (placebo) Arthralgia 7.1% (SSZ), 6.8% (placebo) Pain 7.1% (SSZ), 5.9% (placebo) Rash 7.1% (SSZ), 5.1% (placebo) Bronchitis 6.3% (SSZ), 7.6% (placebo) Pruritus 5.4% (SSZ), 10.2% (placebo) Pharyngitis 5.4% (SSZ), 8.5% (placebo)

Ankylosing Spondylitis: Pred., Cyc., 5FU, MTX, MMF

323

COPCORD

Excellent endpoints from step-down bridge combination therapy of five immuno-suppressants in NSAID-refractory ankylosing spondylitis: 6-year international study in Asia – WHO-ILAR COPCORD stage II treatment of the autoimmune diseases COPCORD: Community Oriented Program for Control of Rheumatic Disease

Substance

Low-dose iv methylprednisolone +1.5 mg/kg/body weight i.v. cyclophosphamide (maximum 100 mg) 5×/week +25–100 mg 5-fluorouracil (FU) 5×/week +0.2 mg/kg (maximum 12.5 mg) methotrexate (MTX)/week (first 6 months) If ESR ³ 20 mm (men ³ 10 mm): Low-dose oral 1,500 mg mycophenolate mofetil (MMF) 100–150 mg/day ciclosporin were prescribed for at least 2 years ESR £ 20 mm (men £ 10 mm): MMF 1,000–1,500 mg and/or ciclosporin 100–150 mg/day 5-FU + ciclosporin is continued 5×/week ESR £ 10 mm (men £ 5 mm): 5-FU + ciclosporin appliocations were decreased to 3-2-1-weekly, fortnightly, monthly, and terminated at 1–2-monthly Concomitant weekly intraarticular injections with 40 mg triamcinolone + 2% lignocaine + 5 mg dexamethasone

Result

Combination therapy of five immuno-suppressants followed by a step down protocol achieved remission in the majority of patients with NSAIDrefractory ankylosing spondylitis

Patients

79 AS patients Refractory to NSAIDs Refractory to physical therapy

Authors

Darmawan J, Nasution AR, Chen SL, Haq SA, Zhao D, Zeng Q, Davatchi F

Publication

J Rheumatol. December 2006;33(12):2484–2492

Follow up

288 weeks

324

Note

Ankylosing Spondylitis: Pred., Cyc., 5FU, MTX, MMF

Dropouts n = 15 64/79 patients achieved ASAS 20, ASAS 50, and ASAS 70 Disease remission n = 60 at 6 months Change of BASRI £ 2, n = 44: ESR (female) –71.9 mm/h ESR (male) –80.7 mm/h CRP –133.8 mg% BASDAI –5.89 BASFI –5.05 BAS-G –6.7 BASMI –7.11 BASRI-spine –1.4 BASRI-hip –1.5 Change of BASRI ³2, n = 20: ESR (female) –93.4 mm/h ESR (male) –106.6 mm/h CRP –222 mg% BASDAI –7.46 BASFI –7.4 BAS–G –6.9 BASMI –6.56 BASRI-spine 0 BASRI-hip 0 Cumulative doses of: Cyclophosphamide 1,281.2 mg (BASRI <2), 1,942.7 mg (BASRI ³2) MMF 748.3 mg (BASRI <2), 1,304.8 mg (BASRI ³2) MTX 748.3 mg (BASRI <2), 152.3 mg (BASRI ³2) i.v. corticosteroids 105.8 mg (BASRI <2), 152.3 mg (BASRI ³2) i.a. 9 mg triamcinolone + dexamethasone 1.4 mg (BASRI <2), 13.4 mg Triamcinolone ± 2.8 mg dexamethasone (BASRI ³2)

Adverse events

Gastrointestinal side effects n = 20 No liver, renal, cardiovascular, and hematologic adverse effects were observed

Ankylosing Spondylitis: Adalimumab

325

ATLAS-trial

Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial ATLAS: adalimumab Trial Evaluating Long-term Efficacy and Safety for Ankylosing Spondylitis

Substance

40 mg adalimumab every 2nd week (n = 208) Placebo (n = 107) Concomitant therapy: Continued sulfasalazine £3 g/day Continued hydroxychloroquine £400 mg/day Continues methotrexate £25 mg/week Continued prednisone equivalent £10 mg/day Continue NSAIDs at stable doses Previous therapy: No previous anti-TNF therapy, ciclosporin, azathioprine No intraarticular injections with corticosteroids within 4 weeks ³1 NSAIDs or DMARD No corticosteroid injections £4 weeks

Result

Adalimumab treatment of akylosing spondylitis patients led to a significant and sustained reduction of disease activity

Patients

315 AS patients BASDAI ³4 Total back pain score ³4 by VAS (0–10) Morning stiffness ³1 h Inadequate response or intolerance to ³1 NSAIDs or DMARD

Authors

van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, Braun J, Dougados M, Reveille JD, Wong RL, Kupper H, Davis JC Jr; ATLAS Study Group

Publication

Arthritis Rheum. July 2006;54(7):2136–2146

Follow up

24 weeks

326

Note

Ankylosing Spondylitis: Adalimumab

Week 12: ASAS 5/6 Response: 13.1% (placebo), 48.6% (Ada) ASAS 20 Response: 20.6% (placebo), 58.2% (Ada) ASAS 40 Response: 13.1% (placebo), 39.9% (Ada) Partial remission: 3.7% (placebo), 20.7% (Ada) Week 24: ASAS 5/6 Response: 12.1% (placebo), 44.7% (Ada) ASAS 20 Response: 13.1% (placebo), 39.4% (Ada) Partial remission: 5.6% (placebo), 22.1% (Ada) ASAS 40 Response: 13.1% (placebo), 39.4% (Ada) Partial remission: 5.6% (placebo), 22.1% (Ada) Change of (week 24): Patient’s global assessment of disease activity (0–10-cm VAS) +8.7 (placebo), -37.8 (Ada) Total back pain (0–10-cm) VAS –10.0 (placebo), -42.4 (Ada) BASFI (0–10-cm VAS) -8.5 (placebo), -37.7 (Ada) Inflammation (mean of questions 5 and 6 of the BASDAI, 0–10-cm VAS) -12.5 (placebo), -42.9 (Ada) BASDAI (0–10-cm VAS) -0.8 (placebo), -2.6 (Ada) C-reactive protein (mg/dL) -0.1 (placebo), -1.3 (Ada) BASMI (range 0–10) 0.0 (placebo), -0.6 (Ada) Tragus-to-wall -0.1 (placebo), -0.4 (Ada) Anterior lumbar flexion -0.1 (placebo), +0.3 (Ada) Lumbar side flexion 0.0 (placebo), +2.1 (Ada) Intermalleolar distance +1.0 (placebo), +7.4 (Ada) Cervical rotation -1.0 (placebo), +3.6 (Ada) Chest expansion +0.4 (placebo), +0.3 (Ada) MASES (range 0–13) -1.6 (placebo), -3.2 (Ada) BAS-G (0–10-cm VAS) -0.8 (placebo), -2.7 (Ada) Nocturnal pain (0–10-cm VAS) -0.9 (placebo), -2.7 (Ada) Physician’s global assessment of disease activity (0–10-cm VAS) -1.0 (placebo), -2.5 (Ada) Swollen joint count (range 0–44 joints) -0.4 (placebo), -0.4 (Ada) Tender joint count (range 0–46 joints) -0.3 (placebo), -0.9 (Ada)

Adverse events

Patients with any adverse event 59.8% (placebo), 75.0% (Ada) Patients with any serious adverse event 2.8% (placebo), 2.9% (Ada) Patients with any Injection-site reaction 2.8% (placebo), 10.1% (Ada) Patients with any infection 21.5% (placebo), 31.7% (Ada) Patients with any serious infection 0.9% (placebo), 0% (Ada) Nasopharyngitis 7.5% (placebo), 12.5% (Ada) Headache 8.4% (placebo), 9.6% (Ada)

Ankylosing Spondylitis: Adalimumab

Trial

Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: a multicenter, randomized, double-blind, placebo-controlled study

Substance

40 mg adalimumab/2 weeks (n = 38) Placebo (n = 44)

327

Concomitant therapy: Continued sulfasalazine £3 g/day Continued hydroxychloroquine £400 mg/day Continued methotrexate £25 mg/week Continued prednisone equivalent £10 mg/day Continued NSAIDs at stable doses Previous therapy: No previous anti-TNF therapy, ciclosporine, azathioprine No intraarticular injections with corticosteroids within 4 weeks ³1 NSAIDs or DMARD No corticosteroid injections £4 weeks Result

Adalimumab significantly reduced spinal and sacroiliac joint inflammation in patients with active ankylosing spondylitis after 12 weeks of treatment. Improvement was maintained for up to 52 weeks

Patients

82 patients with spinal and sacroiliac joint inflammation by MRI Unsuccessful treatment with ³1 NSAIDs Failed to respond to ³1 DMARD Active AS 2 of the following three criteria: BASDAI score ³ 4 Total back pain VAS (0–100) ³40 Morning stiffness of ³1 h

Authors

Lambert RG, Salonen D, Rahman P, Inman RD, Wong RL, Einstein SG, Thomson GT, Beaulieu A, Choquette D, Maksymowych WP

Publication

Arthritis Rheum. December 2007;56(12):4005–4014

Follow up

24-week double-blind period total 52 weeks

Note

Change of: Spine SPARCC score +9.4% (placebo), 53.6% (Adalimumab) Sycroiliic joint SPARCC –12.7% (placebo), 52.9% (Adalimumab) % Change in spine SPARCC score: ASAS20 Responders –52.8% (Adalimumab), +4.7% (placebo) ASAS20 Nonresponders –54.2% (Adalimumab), +10.9% (placebo) ASAS40 Responders –56.2% (Adalimumab), –17.0% (placebo) ASAS40 Nonresponders –51.7% (Adalimumab), +11.5% (placebo) ASAS5/6 Responders –54.7% (Adalimumab), +33.8% (placebo) ASAS5/6 Nonresponders –52.7% (Adalimumab), +5% (placebo) % Change in sacroiliac joint SPARCC score: ASAS20 Responders –46.7% (Adalimumab), –19.4% (placebo) ASAS20 Nonresponders –60.2% (Adalimumab), –9.2% (placebo) ASAS40 Responders –46.7% (Adalimumab), –36.4% (placebo) ASAS40 Nonresponders –60.2% (Adalimumab), –8.9% (placebo) ASAS5/6 Responders –42.2% (Adalimumab), –28.5% (placebo) ASAS5/6 Nonresponders –63.5% (Adalimumab), –8.6% (placebo)

328

Ankylosing Spondylitis: Adalimumab

Title

Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: Results of a 12-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week 52

Substance

Open-label extension for 52 weeks after 12 weeks of: 40 mg adalimumab s.c./2 weeks (n = 22) Placebo (n = 24) Concomitant therapy: Continue NSAIDs Previous therapy: No DMARDs ³1 month No prednisone ³7.5 mg/day (or equivalent) ³1 month NSAIDs

Result

Adalimumab was effective and safe for treatment of patients with axial spondylarthropathies without radiographically defined sacroiliitis

Patients

Patients with active axial SpA (n = 46) Disease duration ³3 months Refractory to NSAIDs BASDAI ³ 4 No sacroiliitis Axial SpA required the presence of three of six diagnostic criteria Inflammatory back pain HLA–B27 positivity MRI showing active inflammation of the spine or sacroiliac joints History of a good response to NSAID treatment Presence ³1 extraspinal manifestations (anterior uveitis, peripheral arthritis, or enthesitis) Family history of SpA

Authors

Haibel H, Rudwaleit M, Listing J, Heldmann F, Wong RL, Kupper H, Braun J, Sieper J

Publication

Arthritis Rheum. June 24, 2008;58(7):1981–1991

Follow up

12 weeks + 40 weeks open label extension

Ankylosing Spondylitis: Adalimumab

Note

Week 12: ASAS 20 68.2% (Ada), 25% (placebo) ASAS40 54.5% (Ada), 12.5% (placebo) ASAS part. Remission 22.7% (Ada), 0% (placebo) Week 52: ASAS 20 54.5% (Ada), 66.7% (Placebo ³ Ada) ASAS40 45.5% (Ada), 54.2% (Placebo ³ Ada) ASAS part. Remission 18.2% (Ada), 37.5% (Placebo ³ Ada) After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo Change of: BASDAI (numeric rating scale: NRS 0–10) -2.7 (Ada), -1.2 (placebo) Morning stiffness (NRS 0–10) -2.8 (Ada), -1.0 (placebo) BASFI (range 0–10) -2.4 (Ada), -0.8 (placebo) BASMI (range 0–10) 0 (Ada), +0.4 (placebo) CRP (mg/L) -3.2 (Ada), -1.8 (placebo) Patient’s global assessment (0–10 NRS) -2.7 (Ada), -1.2 (placebo) Physician’s global assessment (0–10 NRS) -2.3 (Ada), -0.8 (placebo) General pain (0–10 VAS) –2.8 (Ada), –1.2 (placebo) Nocturnal pain (0–10 VAS) -3.0 (Ada), -1.1 (placebo) No. of swollen joints -0.3 (Ada), -1.5 (placebo) Maastricht Ankylosing Spondylitis Enthesitis Score (range 0–13) -0.5 (Ada), +0.3 (placebo) SF-36 mental component summary score (range 0–100) +3.3 (Ada), +0.3 (placebo) SF-36 physical component summary score (range 0–100) +10.0 (Ada), +4.2 (placebo) EuroQol Index (range 0–1) +0.2 (Ada), +0.14 (placebo)

329

330

Ankylosing Spondylitis: Adalimumab

ATLAS-Trial

Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial ATLAS: adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS

Substance

Open Label adalimumab after 24 weeks of ATLAS trial After: 40 mg adalimumab every 2nd week (n = 208) Placebo (n = 107) Concomitant therapy: Continue sulfasalazine £3 g/day Continue hydroxychloroquine £400 mg/day Continue methotrexate £25 mg/week Continue prednisone equivalent £10 mg/day Continue NSAIDs at stable doses Previous therapy: No previous anti-TNF therapy, ciclosporine, azathioprine No intraarticular injections with corticosteroids within 4 weeks ³1 NSAIDs or DMARD No corticosteroid injections £4 weeks

Result

Adalimumab reduced the clinical manifestations of ankylosing spondylitis and induced partial remission for up to 2 years. The long-term safety profile was similar to the short-term safety profile

Patients

315 AS patients BASDAI ³4 Total back pain score ³4 by VAS (0–10) Morning stiffness ³1 h Inadequate response or intolerance to ³1 NSAIDs or DMARD

Authors

van der Heijde D, Schiff MH, Sieper J, Kivitz AJ, Wong RL, Kupper H, Dijkmans BA, Mease PJ, Davis JC Jr; ATLAS Study Group

Publication

Ann Rheum Dis. June 2009;68(6):922–929. Epub 2008 Aug 13

Follow up

24 months after 24 weeks of ATLAS Trial

Ankylosing Spondylitis: Adalimumab

Note

Improvements in ASAS responses observed in ATLAS were sustained during long-term treatment (200/310) ASAS20 64.5% ASAS40 50.6% ASAS-defined partial remission 35.5% (157/310) BASDAI -3.9 BASFI -2.3

Adverse events

Nasopharyngitis 25.7% (Ada) Upper respiratory tract infection 17.0% (Ada) Headache 15.4% (Ada) Arthralgia 10.6% (Ada) Sinusitis 9.6% (Ada) Fatigue 8.0% (Ada) Diarrhea 9.6% (Ada) Nausea 8.7% (Ada) Influenza 7.4% (Ada) Cough 8.4% (Ada) Back pain 7.4% (Ada) Hypertension 7.4% (Ada) Pharyngolaryngeal pain 7.1% (Ada) Bronchitis 6.4% (Ada) Viral infection 6.1% (Ada) Injection-site reaction 4.8% (Ada) Pharyngitis 6.1% (Ada) Rash 5.5% (Ada)

331

332

Ankylosing Spondylitis: Adalimumab

ATLAS-Trial

Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis ATLAS: adalimumab Trial Evaluating Long-term Efficacy and Safety for AS

Substance

40 mg adalimumab every 2nd week (n = 6) Placebo (n = 5) Concomitant therapy: Continue sulfasalazine £3 g/day Continue hydroxychloroquine £400 mg/day Continue methotrexate £25 mg/week Continue prednisone equivalent £10 mg/day Continue NSAIDs at stable doses Previous therapy: No previous anti-TNF therapy, ciclosporine, azathioprine No intraarticular injections with corticosteroids within 4 weeks ³1 NSAIDs or DMARD No corticosteroid injections £4 weeks

Result

In patients with total spinal ankylosis, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. adalimumab’s effectiveness and safety were sustained for at least 2 years

Patients

315 patients with active AS Two out of three criteria: BASDAI ³4 VAS ³4 Morning stiffness ³1 h

Authors

van der Heijde D, Pangan AL, Schiff MH, Braun J, Borofsky M, Torre J, Davis JC Jr, Wong RL, Kupper H, Collantes E; ATLAS Study Group

Publication

Ann Rheum Dis. September 2008;67(9):1218–1221. Epub 2007 Dec 4

Follow up

24 weeks followed by open-label adalimumab for up to 5 years

Note

Investigator defined total spine ankylosis ASAS20 72.7% (1 year), 75.0% (2 years) ASAS40 36.4% (1 year), 62.5% (2 years) ASAS 5/6 54.5% (1 year), 37.5% (2 years) ASAS partial remission 9.1% (1 year), 0% (2 years) BASDAI 45.5% (1 year), 62.5% (2 years) Stage V total spine ankylosis ASAS20 62.5% (1 year), 60.0% (2 years) ASAS40 37.5% (1 year), 40.0% (2 years) ASAS 5/6 37.5% (1 year), 20.0% (2 years) ASAS partial remission 12.5% (1 year), 0% (2 years) BASDAI 50.0% (1 year), 60.0% (2 years)

Adverse events

No cases of opportunistic infections, tuberculosis, malignancies, congestive heart failure, demyelinating disorders, or lupus-like syndromes, or death during open label extension

Ankylosing Spondylitis: Adalimumab

333

ATLAS-Trial

Physical function, disease activity, and health-related quality-of-life outcomes after 3 years of adalimumab treatment in patients with ankylosing spondylitis ATLAS: The adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS

Substance

Open lable adalimumab after 24 weeks of: 40 mg adalimumab every 2nd week (n = 208) Placebo (n = 107) Concomitant therapy: Continue sulfasalazine £3 g/day Continue hydroxychloroquine £400 mg/day Continue methotrexate £25 mg/week Continue prednisone equivalent £10 mg/day Continue NSAIDs at stable doses Previous therapy: No previous anti-TNF therapy, ciclosporine, azathioprine No intraarticular injections with corticosteroids within 4 weeks ³1 NSAIDs or DMARD No corticosteroid injections £4 weeks

Result

Adalimumab treatment of ankylosing spondylitis patients significantly improved disease activity, patient-reported physical function, and quality of life

Patients

315 AS patients BASDAI ³4 Total back pain score ³4 by VAS (0–10) Morning stiffness ³1 h Inadequate response or intolerance to ³1 NSAIDs or DMARD

Authors

van der Heijde DM, Revicki DA, Gooch KL, Wong RL, Kupper H, Harnam N, Thompson C, Sieper J; ATLAS Study Group

Publication

Arthritis Res Ther. 2009;11(4):R124. Epub August 17, 2009

Follow up

156 weeks

Note

Response as compared to 24 week status: SF-36 physical component score (³three-point reduction) 81.9% BASFI responder (³21% reduction) 81.1% ASQOL responder (³1.8-point reduction) 79.7% Change of (week 156): BASDAI (0–10 cm) –3.9 BASFI (0–10 cm) –3.0 SF-36 physical component score (0–50) +11.6 SF-36 mental component score (0–50) +5.6 SF-36 physical function +23.3 SF-36 role–physical +37.8 SF-36 bodily pain +31.7 SF-36 general health +12.7 SF-36 vitality +20.1 SF-36 social function +22.3 SF-36 role–emotional +20.0 SF-36 mental health +10.5 ASQOL (0–18) +5.4

334

Ankylosing Spondylitis: Etanercept

Trial

6-month results of a double-blind, placebo-controlled trial of Etanercept treatment in patients with active ankylosing spondylitis

Substance

ETN group: 2 × 25 mg etanercept (ETN)/week for 12 weeks Patients were followed for 12 weeks after stopping ETN (n = 14) Placebo group: Placebo for 6 weeks (n = 16) Followed by 2 × 25 mg etanercept/week for 12 weeks Patients were followed for 12 weeks after stopping ETN (n = 16) Concomitant therapy: NSAID treatment could be continued at stable doses Continue NSAIDs, dose reduction was permitted Previous therapy: No DMARDs £4 weeks No corticosteroids £4 weeks No TNF antagonists

Result

AS patients with active disease despite DMARD and NSAID therapy were effectively treated with etanercept. After cessation of therapy, almost all patients experienced a relapse within a few weeks

Patients

30 patients with active AS BASDAI ³4 Spinal pain of ³4 (0–10 VAS)

Authors

Brandt J, Khariouzov A, Listing J, Haibel H, Sörensen H, Grassnickel L, Rudwaleit M, Sieper J, Braun J

Publication

Arthritis Rheum. June 2003;48(6):1667–1675

Follow up

24 weeks (ETN), 30 weeks (placebo)

Note

Week 6: 50% BADAI Improvement 57% (ETN), 6% (placebo), 56% (placebo => ETN, week 12) 20% BADAI Improvement 85.7% (ETN), 31.3% (placebo) ASAS 20% 78.6% (ETN), 25% (placebo) ASAS 50% 42.9% (ETN), 12.5% (placebo) Reduced NSAID dose by 50% 62%(ETN), 7% (placebo) Stop NSAIDs 38%(ETN), 13% (placebo) Change of: BASDAI -3.0 (ETN), -0.8 (placebo) BASFI -1.9 (ETN), -0.2 (placebo) Mean change of BASDAI -3 (ETN), -0.8 (placebo) BASMI -1.5 (ETN), -0.3 (placebo)

Adverse events

No serious adverse reactions at the injection-site Minor infections n = 6 (ETN), n = 6 (placebo) Injection-site reaction n = 2 (ETN), n = 0 (placebo)

Ankylosing Spondylitis: Etanercept

Trial

Recombinant human tumor necrosis factor receptor (Etanercept), for treating ankylosing spondylitis: a randomized, controlled trial

Substance

2 × 25 mg etanercept (ETN)/week (n = 138) Placebo (n = 139)

335

Concomitant therapy: Continue hydroxychloroquine, sulfasalazine and methotrexate at stable dosages No other DMARDs £4 weeks Prednisone £10 mg/day or the equivalent Continue NSAIDs at stable doses £2 weeks Analgesics were permitted: acetaminophen, codeine, hydrocodone, oxycodone, and tramadol in standard dosages Previous therapy: No other DMARDs than MTX, SSZ, HCQ £4 weeks No corticosteroids £4 weeks No TNF antagonists Result

Etanercept treatment in AS patients with active disease was highly effective and well-tolerated

Patients

277 AS patients with moderate to severe active disease Morning stiffness of ³30 mm (maximum 100 mm VAS) Patient’s global assessment of ³30 mm (maximum 100 mm VAS) Back pain of ³30 mm (maximum 100 mm VAS) BASFI of ³30 mm (maximum 100 mm VAS)

Authors

Davis JC Jr, Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, Kivitz A, Fleischmann R, Inman R, Tsuji W; Enbrel Ankylosing Spondylitis Study Group

Publication

Arthritis Rheum. November 2003;48(11):3230–3236

Follow up

24 weeks

336

Note

Ankylosing Spondylitis: Etanercept

Week 12: ASAS20 59% (ETN), 28% (placebo) Week 24: ASAS20 57% (ETN), 22% (placebo) Partial remission 17% (ETN), 4% (placebo) Change of: Patient’s global assessment (100-mm VAS) -6.6 (placebo), -26.9 (ETN) Back pain (100-mm VAS) -5.7 (placebo), -24.0 (ETN) BASFI -1.6 (placebo), -15.7 (ETN) CRP (mg/dL) -0.1 (placebo), -1.3 (ETN) ESR (mm/h) +0.5 (placebo), -14.7 (ETN) Modified Schober test (cm) -0.09 (placebo), +0.28 (ETN) Occiput-to-wall (cm) +0.68 (placebo), -1.06 (ETN) BASDAI -4.5 (placebo), -23.6 (ETN)

Adverse events

Injection-site reaction 9% (placebo), 30% (ETN) Injection-site bruising 17% (placebo), 21% (ETN) Upper respiratory tract infection 12% (placebo), 20% (ETN) Headache 12% (placebo), 14% (ETN) Accidental injury 4% (placebo), 12% (ETN) Diarrhea 9% (placebo), 8% (ETN) Rash 6% (placebo), 8% (ETN) Rhinitis 6% (placebo), 6% (ETN) Abdominal pain 5% (placebo), 6% (ETN) Dizziness 2% (placebo), 6% (ETN) Flu syndrome 7% (placebo), 4% (ETN)

Ankylosing Spondylitis: Etanercept

Trial

Outcomes of a multicentre randomized clinical trial of Etanercept to treat ankylosing spondylitis

Substance

2 × 25 mg etanercept (ETN, n = 45) Placebo (n = 39)

337

Concomitant therapy: Prednisone £10 mg/day or the equivalent Stable NSAID doses were permitted No used multiple NSAIDs Continue hydroxychloroquine, sulfasalazine and methotrexate at stable dosages No other DMARDs £4 weeks Previous therapy: No corticosteroids £4 weeks No TNF antagonists Result

Etanercept was well-tolerated and effective for reducing clinical symptoms of ankylosing spondylitis

Patients

84 AS patients Active disease Spinal inflammation ³30 (VAS 0–100) +2 times VAS ³30 for Back pain Patient global assessment of disease activity Physical function No complete ankylosis (fusion) of the spine

Authors

Calin A, Dijkmans BA, Emery P, Hakala M, Kalden J, Leirisalo-Repo M, Mola EM, Salvarani C, Sanmartí R, Sany J, Sibilia J, Sieper J, van der Linden S, Veys E, Appel AM, Fatenejad S

Publication

Ann Rheum Dis. December 2004;63(12):1594–1600. Epub 2004 Sept 2

Follow up

12 weeks

338

Note

Ankylosing Spondylitis: Etanercept

At week 12: ASAS 20 60.0% (ETN), 23.1% (placebo) ASAS 50 48.9% (ETN), 10.3% (placebo) ASAS 70 24.4% (ETN), 10.3% (placebo) Composite BASDAI score 50.1 (ETN) 33.8 (placebo) Fatigue BASDAI score 54.8 (ETN) 38.4 (placebo) Change of: C reactive protein (mg/L) –114 (ETN), +20 (placebo) Erythrocyte sedimentation rate (mm/1st h) –21 (ETN), +3 (placebo) Schober’s test of spinal flexion (cm) -0.1 (ETN), +0.5 (placebo) Chest expansion (cm) +0.5 (ETN), +0.2 (placebo) Occiput to wall distance (cm) -1.1 (ETN), -0.6 (placebo) ASAS: Spinal inflammation -43.3% (ETN), -15.9% (placebo) ASAS: Nocturnal and total pain –43.1% (ETN), -6.2% (placebo) ASAS: Patient global assessment –37.0% (ETN), -12.6% (placebo) BASFI -35.4% (ETN), -3.4% (placebo) BASDAI -43.6% (ETN), -13.6% (placebo) BASDAI: Fatigue score -42.6% (ETN), -4.9% (placebo)

Adverse events

Injection-site reactions 15% (placebo), 33% (ETN) Hemorrhage, injection-site 10% (placebo), 18% (ETN) Headache 10% (placebo), 13% (ETN) Nausea 10% (placebo), 7% (ETN) Asthenia 3% (placebo), 11% (ETN) Vertigo 8% (placebo), 0% (ETN) Diarrhea 5% (placebo), 4% (ETN) Pruritus 5% (placebo), 4% (ETN) Pain, abdomen 5% (placebo), 2% (ETN) Paraesthesia 5% (placebo), 2% (ETN) Arthralgia 5% (placebo), 0% (ETN) Hemorrhage, gastrointestinal 5% (placebo), 0% (ETN) Injury accidental 5% (placebo), 0% (ETN) Pain, back 5% (placebo), 0% (ETN) Throat irritation 5% (placebo), 0% (ETN)

Ankylosing Spondylitis: Etanercept

Trial

Long-term efficacy and safety of Etanercept after readministration in patients with active ankylosing spondylitis

Substance

2 × 25 mg etanercept (ETN)/week Concomitant therapy: NSAIDs at stable dosage Previous therapy: No corticosteroids £4 weeks No DMARDs £4 weeks Etanercept was withdrawn

Result

Etanercept was efficacious and safe after readministration over 1 year in patients with active ankylosing spondylitis not taking DMARDs or steroids

Patients

26 AS patients Etanercept for a mean of 26.8 weeks BASDAI ³ 4 Spinal Pain (VAS 0–10) ³4

Authors

Brandt J, Listing J, Haibel H, Sörensen H, Schwebig A, Rudwaleit M, Sieper J, Braun J

Publication

Rheumatology (Oxford). March 2005;44(3):342–348

Follow up

54 weeks

Note

50% improvement of BASDAI 57.7% Partial remission 31% ASAS 20 73.1% ASAS 40 62.5% ASAS 5/6 65.0% NSAIDs stopped 83% Change of: BASDAI -3.4 BASFI -2.5 BASMI -0.8 CRP -8.1 mg/L ESR -13.3 mm/h

Adverse events

Upper respiratory tract infection n = 17 (severe n = 1) Bronchitis n = 5 Diarrhea n = 4 (severe n = 1) Cough n = 3 Sinusitis n = 2 Headache n = 2 Rhinitis n = 2 Conjunctivitis n = 2 Chest discomfort n = 1 Renal colic n = 1 Cohn’s disease n = 1 Chest discomfort n = 1

339

340

Ankylosing Spondylitis: Etanercept

OASIS-Trial

Sustained durability and tolerability of Etanercept in ankylosing spondylitis for 96 weeks OASIS: Outcome Assessment in Ankylosing Spondylitis International Study

Substance

Etanercept 25 mg (ETN, n = 138) Placebo (n = 139) Concomitant therapy: Continue hydroxychloroquine, sulfasalazine and methotrexate at stable dosages No other DMARDs £4 weeks NSAIDs were continued Prednisone £10 mg/day or the equivalent stable for 2 weeks

Result

Etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis over 2 years

Patients

Patients with AS Morning stiffness (VAS 0–100) ³30 mm Spinal pain (VAS 0–100) ³30 mm +2 of the following 3 variables: Patient global assessment (VAS 0–100) ³30 mm Back pain (nocturnal and total back pain, VAS 0–100) ³30 mm BASFI VAS (0–100) ³30 mm

Authors

Davis JC, van der Heijde DM, Braun J, Dougados M, Cush J, Clegg D, Inman RD, Kivitz A, Zhou L, Solinger A, Tsuji W

Publication

Ann Rheum Dis. November 2005;64(11):1557–1562. Epub 2005 Apr 20

Follow up

24 + 72 weeks open label follow up

Note

Change of: Occiput to wall measure -1.4 cm (ETN => ETN), -0.4 cm (placebo => ETN) Chest expansion +0.6 cm (ETN => ETN), +0.3 cm (placebo => ETN) Modified Schober’s Index +0.4 (ETN => ETN), +0.2 cm (placebo => ETN) ASAS 40 62% (ETN => ETN), 60% (placebo => ETN) ASAS 5/6 Responders 52% (ETN => ETN), 41% (placebo => ETN) Patient global assessment (0–100) -36.7 (ETN => ETN), -34.9 (placebo => ETN) Back pain (0–100) -36.6 (ETN => ETN), -36.2 (placebo => ETN) BASFI (0–100) -25.7 (ETN => ETN), -24.5 (placebo => ETN) Inflammation (BASDAI questions 5 and 6, 0–100) -38.1 (ETN => ETN), -37.3 (placebo => ETN) CRP -1.3 (ETN => ETN), -1.3 (placebo => ETN)

Adverse events

Injection-site reaction 21% Headache 15% Injection-site bruising 13% Diarrhea 12% Abdominal pain 12% Accidental injury 11% Rash 11% Pain (body as a whole) 8% Asthenia 7% Rhinitis 7% Conjunctivitis 7% Depression 7% Hypertension 7% Nausea 7% Uveitis 6% Arthralgia 5% Dizziness 5%

Ankylosing Spondylitis: Etanercept

Trial

Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis

Substance

50 mg etanercept (ETN)/week (n = 155) 2 × 25 mg etanercept/week (n = 150) Placebo (n = 51) Concomitant therapy: NSAIDs were continued Corticosteroids £10 mg/day stable ³2 weeks Continue hydroxychloroquine, sulfasalazine and methotrexate at stable dosages ³4 weeks No other DMARDs £4 weeks Previous therapy: No TNF antagonists

Result

Clinical outcomes and safety were similar in patients with ankylosing spondylitis treated with etanercept 50 mg once weekly or with 25 mg twice weekly

Patients

356 patients with active ankylosing spondylitis Duration and intensity of morning stiffness (VAS) ³30 +³2 of the following: Patient’s global assessment of disease activity VAS score >30 Nocturnal and total pain (VAS) ³ 30 BASFI ³30

Authors

van der Heijde D, Da Silva JC, Dougados M, Geher P, van der Horst-Bruinsma I, Juanola X, Olivieri I, Raeman F, Settas L, Sieper J, Szechinski J, Walker D, Boussuge MP, Wajdula JS, Paolozzi L, Fatenejad S; Etanercept Study 314 Investigators

Publication

Ann Rheum Dis. December 2006;65(12):1572–1577. Epub 2006 Sept 12

Follow up

12 weeks

Note

Patients discontinuing therapy 9.0% (ETN 50), 9.3% (ETN 25), 13.7% (placebo) ASAS 20 74.2% (ETN 50), 71.3% (ETN 25), 37.3% (placebo) ASAS 40 response 58.1% (ETN 50), 53.3% (ETN 25), 21.6% (placebo) ASAS 5/6 response 70.3% (ETN 50), 72.0% (ETN 25), 27.5% (placebo)

Adverse events

Any adverse event 35.5% (ETN 50), 44% (ETN 25), 35.3% (placebo) Injection-site reactions 20.7% (ETN 50), 22.7% (ETN 25), 11.8% (placebo) Back pain 0.6% (ETN 50), 0.7% (ETN 25), 5.9% (placebo) Abdominal pain 3.2% (ETN 50), 4% (ETN 25), 2% (placebo) Nausea 1.9% (ETN 50), 3.3% (ETN 25), 3.9% (placebo) Overdose 3.9% (ETN 50), 2.7% (ETN 25), 2.0% (placebo) Headache 3.9% (ETN 50), 2.7% (ETN 25), 0% (placebo) Diarrhea 3.9% (ETN 50), 2.7% (ETN 25), 0% (placebo) Any infection 22.6% (ETN 50), 22.0% (ETN 25), 23.5% (placebo) Upper respiratory infection 7.7% (ETN 50), 8% (ETN 25), 13.7% (placebo) Pharyngitis or laryngitis 3.9% (ETN 50), 2.0% (ETN 25), 0% (placebo)

341

342

Ankylosing Spondylitis: Etanercept

OASIS-Trial

Radiographic progression of ankylosing spondylitis after up to 2 years of treatment with Etanercept OASIS: Outcome Assessment in Ankylosing Spondylitis International Study

Substance

Etanercept 25 mg (n = 138) Placebo (n = 139) Concomitant therapy: Continue hydroxychloroquine, sulfasalazine and methotrexate at stable dosages No other DMARDs £4 weeks NSAIDs were continued Prednisone £10 mg/day or the equivalent stable for 2 weeks

Result

Structural progression in ankylosing spondylitis appeared to be independent of TNF

Patients

Patients with AS Morning stiffness (VAS 0–100) ³30 mm Pain (VAS 0–100) ³30 mm +2 of the following three variables: Patient global assessment (VAS 0–100) ³30 mm Back pain (average nocturnal back pain and total back pain, VAS) ³30 BASFI (VAS 0–100) ³30 OASIS (n = 175): Not treated with ETN OASIS meeting entry criteria (n = 76): never treated with TNF antagonists, but woul have met OASIS entry criteria ETN (n = 275) treated with ETN during OASIS trial, n = 139 only during open lable phase

Authors

van der Heijde D, Landewé R, Einstein S, Ory P, Vosse D, Ni L, Lin SL, Tsuji W, Davis JC Jr

Publication

Arthritis Rheum. May 2008;58(5):1324–1331

Follow up

24 + 72 weeks open label follow up

Note

Change of: mSASSS +0.95 (OASIS), +1.27 (OASIS meeting entry criteria), +0.91 (ETN) Cervical radiography score +0.42 (OASIS), +0.53 (OASIS meeting entry criteria), +0.49 (ETN) Lumbar radiography score +.53 (OASIS), +0.73 (OASIS meeting entry criteria), +0.42 (ETN)

Ankylosing Spondylitis: Infliximab vs. Etanercept

343

Trial

A 2-year comparative open label randomized study of efficacy and safety of Etanercept and Infliximab in patients with ankylosing spondylitis

Substance

Etanercept 50 mg/week (ETN, n = 25) Infliximab 5 mg/kg at week 0, 2, 6, and every 6 weeks (IFX, n = 25) Concomitant therapy: No information on background therapy Previous therapy: No TNF antagonists Naïve for DMARDs NSAIDs

Result

The efficacy and safety of both etanercept and infliximab in patients with ankylosing spondylitis was compared in a 2-year open label randomized study. The results were consistent with a significant more rapid clinical improvement in the infliximab treated group. Treatment with both etanercept and infliximab at the end of the study was effective, safe, and well tolerated

Patients

50 consecutive ankylosing spondylitis patients Non responder to NSAIDs No complete ankylosis (fusion) of the spine BASDAI >4 VAS for spinal pain score >4

Authors

Giardina AR, Ferrante A, Ciccia F, Impastato R, Miceli MC, Principato A, Triolo G

Publication

Rheumatol Int. October 23, 2009. Epub ahead of print

Follow up

102 weeks

Note

Week12: ASAS 20 75% (IFX), 60% (ETN) ASAS 40 55% (IFX), 43% (ETN) BASFI 3.5 (IFX), 5 (ETN) Change of: BASDAI -1.3 (IFX), -0.3 (ETN)

Adverse events

Injection-site/infusion reactions 4% (IFX), 25% (ETN) Headache 32% (IFX), 28% (ETN) Diarrhea 8% (IFX), 4% (ETN) Tachycardia 48% (IFX), 32% (ETN) Hypertension 16% (IFX), 8% (ETN) Abdominal pain 4% (IFX), 4% (ETN) Uveitis 4% (IFX), 8% (ETN) Optic neuritis 4% (IFX), 4% (ETN) Arthralgia 16% (IFX), 12% (ETN) Vertigo 4% (IFX), 8% (ETN) Severe infections 8% (IFX), 4% (ETN)

344

Ankylosing Spondylitis: Golimumab

GO-RAISE-Trial Efficacy and safety of Golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial Substance

Golimumab 50 mg/4 weeks (n = 138) Golimumab 100 mg/4 weeks (n = 140) Placebo (n = 78) Concomitant therapy: Continue hydroxychloroquine, sulfasalazine and methotrexate, corticosteroids, and NSAIDs at stable doses No other DMARDs NSAIDs were continued Previous therapy: Naïve for TNF blocking agents No alefacept or efalizumab £3 months No anti-TNF therapy, rituximab, natalizumab, or cytotoxic drugs

Result

Golimumab was effective and well tolerated in AS patients with ankylosing spondylitis

Patients

356 AS patients with active disease Despite NSAID or DMARDs treatment BASDAI ³4 Back pain (VAS) ³4

Authors

Inman RD, Davis JC Jr, Heijde D, Diekman L, Sieper J, Kim SI, Mack M, Han J, Visvanathan S, Xu Z, Hsu B, Beutler A, Braun J

Publication

Arthritis Rheum. November 2008;58(11):3402–3412

Ankylosing Spondylitis: Golimumab

Follow up

24 weeks

Note

ASAS 20 21.8% (placebo), 59.4% (50 mg Gol), 60% (100 mg Gol) ASAS 40 15.4% (placebo), 43.5% (50 mg Gol), 54.3% (100 mg Gol) BASDAI50 14.7% (placebo), 50.8% (50 mg Gol), 47.8% (100 mg Gol) Patients with -1 unit improvement in the BASMI 34.2% (placebo), 47.2% (50 mg Gol), 51.1% (100 mg Gol)

345

Change of (week 24): Patient’s global assessment of disease activity (0–10-cm VAS) -0.2 (placebo), -2.6 (50 mg Gol), -3.6 (100 mg Gol) Patient’s assessment of total back pain (0–10-cm VAS) -0.4 (placebo), -3.5 (50 mg Gol), -3.9 (100 mg Gol) Overall morning stiffness (0–10-cm VAS) -0.2 (placebo), -3.5 (50 mg Gol), -3.7 (100 mg Gol) BASFI (0–10 scale) +0.4 (placebo), -1.6 (50 mg Gol), -1.6 (100 mg Gol) Night back pain (0–10-cm VAS) -0.4 (placebo), -3.1 (50 mg Gol), -3.5 (100 mg Gol) C-reactive protein (g/dL) 0.0 (placebo), -0.7 (50 mg Gol), -0.5 (100 mg Gol) BASMI (0–10) 0.0 (placebo), 0.0 (50 mg Gol), -0.2 (100 mg Gol) Tragus-to-wall (cm) 0.0 (placebo), 0.0 (50 mg Gol), 0.0 (100 mg Gol) Lumbar flexion (cm) 0.0 (placebo), +0.5 (50 mg Gol), +0.3 (100 mg Gol) Cervical rotation 4.0° (placebo), +5.5° (50 mg Gol), +5.0° (100 mg Gol) Lumbar side flexion (cm) +1.0 (placebo), +2.0 (50 mg Gol), +1.0 (100 mg Gol) Intermalleolar distance (cm) –2.0 (placebo), +6.0 (50 mg Gol), +5.3 (100 mg Gol) Chest expansion (cm) 0.0 (placebo), +0.5 (50 mg Gol), +0.2 (100 mg Gol) SF 36, physical component summary score (0–50) 2.0 (placebo), 7.9 (50 mg Gol), 8.1 (100 mg Gol) SF 36, mental component summary score (0–50) -0.3 (placebo), 1.4 (50 mg Gol), 5.2 (100 mg Gol) Jenkins Sleep Evaluation Questionnaire (0–20) -1.0 (placebo), -3.0 (50 mg Gol), -4.0 (100 mg Gol) Adverse events

Injection-site reaction 2.6% (placebo), 7.2% (Gol) Any infection 36.4% (placebo), 45.1% (Gol) Any serious infection 1.3% (placebo), 0.6% (Gol) Any malignancy 1.3% (placebo), 0.3% (Gol) Nasopharyngitis 11.7% (placebo), 13.2% (Gol) Upper respiratory tract infection 7.8% (placebo), 12.2% (Gol) Fatigue 6.5% (placebo), 11.0% (Gol) Arthralgia 10.4% (placebo), 7.2% (Gol) Headache 2.6% (placebo), 6.9% (Gol) ALT level increased 2.6% (placebo), 6.0% (Gol) Cough 6.5% (placebo), 6.0% (Gol) Diarrhea 3.9% (placebo), 5.6% (Gol) Nausea 5.2% (placebo), 5.6% (Gol) AST level increased 1.3% (placebo), 5.3% (Gol) Injection-site erythema 0% (placebo), 4.7% (Gol) Pharyngolaryngeal pain 5.2% (placebo), 5.0% (Gol) Antibodies to Golimumab: not applicable (placebo), 3.5% (Gol)

346

Ankylosing Spondylitis: Infliximab

Trial

Treatment of active ankylosing spondylitis with Infliximab: a randomized controlled multicentre trial

Substance

5 mg/kg infliximab at weeks 0, 2, and 6 (IFX, n = 35) Placebo (n = 35) Concomitant therapy: No DMARDs £4 weeks No oral corticosteroids £4 weeks NSAIDs were continued, dose reduction was permitted

Result

Infliximab was effective in patients with active ankylosing spondylitis

Patients

70 patients with AS BASDAI ³4 VAS ³4 (maximum 10)

Authors

Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sörensen H, Zeidler H, Thriene W, Sieper J

Publication

Lancet. April 6, 2002;359(9313):1187–1193

Follow up

12 weeks

Note

BASDAI improvement >50% 53% (IFX), 9% (placebo) 50% reduction of NSAIDs 56% (IFX), 19% (placebo) NSAIDs stopped 41% (IFX), 13% (placebo) Change of: BASDAI -3.2 (IFX), -0.6 (placebo) BASMI -2.1 (IFX), -0.1 (placebo) Number of swollen joints -0.7 (IFX), -0.2 (placebo) Number of enthesitic regions -1.0 (IFX), -0.4 (placebo) C-reactive protein (mg/L) -18 (IFX), -3 (placebo) Erythrocyte sedimentation rate (mm/h) -23 (IFX), +4 (placebo) HAQ physical component score +15.0% (IFX) -1.6% (placebo) HAQ mental-component score +14.1% (IFX) +6.2% (placebo) Patient’s global assessment -3.6 (IFX) -0.6% (placebo) Physician’s global assessment -3.5% (IFX) -0.5 (placebo)

Adverse events

No infusion reactions or delayed-type hypersensitivity reactions arose Upper respiratory infections 51% (placebo), 35% (IFX) One patient developed systemic tuberculosis One patient bronchi-centric allergic Granulomatosis of the lung One patient developed transient leucopenia

Ankylosing Spondylitis: Infliximab

Trial

2-year maintenance of efficacy and safety of Infliximab in the treatment of ankylosing spondylitis

Substance

Infliximab 5 mg/kg every 6 weeks open label (n = 52) After 12 weeks randomized trial (Braun, Lancet. April 6, 2002; 359(9313):1187–1193)

347

Concomitant therapy: No DMARDs No oral corticosteroids NSAIDs were permitted at stable doses Result

Patients with ankylosing spondylitis treated for 2 years with infliximab (5 mg/kg) exhibited a good and durable clinical response

Patients

52 active AS patients BASDAI ³4 Spinal pain assessment score (VAS 0–10) ³4

Authors

Braun J, Brandt J, Listing J, Zink A, Alten R, Burmester G, Gromnica-Ihle E, Kellner H, Schneider M, Sörensen H, Zeidler H, Sieper J

Publication

Ann Rheum Dis. February 2005;64(2):229–234. Epub September 23, 2004

Follow up

102 weeks

Note

Change of: Arthritis n = -12 Enthesitis n = -16 Partial remission n = +13 Tragus wall distance >15 cm -4% Lumbar flexion >4 cm +15% Cervical rotation >70° +25% Lateral lumbar flexion >10 cm +18% Intermalleolar distance >100 cm +15% Patient’s Global disease assessment (VAS 0–10 cm) -4.3 Physician’s Global disease assessment (0–10 cm) -4.3 BASDAI -3.8 BASFI -2.2 BASMI -1.1 CRP (mg/L) -17.2 ESR (mm/h) -17.5 SF-36 Physical component +11.6 SF-36 Mental component +7.9

348

Adverse evens

Ankylosing Spondylitis: Infliximab

Upper respiratory tract infections 17% Rhinitis 13% Herpes simplex 12% Influenza-like symptoms 10% Pulmonary infection 10% Antinuclear factor test positive 8% Symptoms associated with infusion 8% Hepatic enzymes increased 8% Bronchitis 8% Headache 6% Fatigue 6% Dry eyes 6% Allergy 6% Accidental injury 6% Alanine aminotransferase increased 6% Menorrhagia 5% Fungal vaginitis 5%

Ankylosing Spondylitis: Infliximab

ASSERT-Trial

Efficacy and safety of Infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT) ASSERT: The ankylosing spondylitis study for the evaluation of recombinant Infliximab therapy

Substance

Infliximab (5 mg/kg/6 weeks, n = 201), loading at weeks 0, 2, and 6 Placebo (n = 78)

349

Concomitant therapy: Stable doses of NSAIDs Stable doses of acetaminophen (paracetamol) Stable doses of tramadol Previous therapy: No sulfasalazine or methotrexate £2 weeks No other DMARDs £6 months No cytotoxic drugs £12 months No systemic corticosteroids £1 month No anti-TNF therapy other than infliximab £3 months Result

Infliximab was a well tolerated and effective in the treatment of ankylosing spondylitis

Patients

279 patients with AS Disease duration >3 months BASDAI ³4 Spinal pain (VAS 0–10) ³4

Authors

van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, Braun J; Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group

Publication

Arthritis Rheum. February 2005;52(2):582–591

Follow up

24 weeks

Note

Change of: BASDAI score –0.4 (placebo), –2.9 (IFX) BASFI score (0–10) 0.0 (placebo), –1.7 (IFX) BASMI score (0–10) 0.0 (placebo), –1.0 (IFX) Tragus-to-wall 0.0 (placebo), –0.5 (IFX) Lumbar flexion +0.4 (placebo), +0.5 (IFX) Cervical rotation 0.0 (placebo), +5.0 (IFX) Lumbar side flexion +0.3 (placebo), +2.0 (IFX) Intermalleolar distance 0.0 (placebo), +3.5 (IFX) Chest expansion, cm 0.0 (placebo), +16.7 (IFX) Mander enthesis index (0–90) –3.0 (placebo), –3.0 (IFX) Swollen joint index (0–44) 0.0 (placebo), 0.0 (IFX) Night pain (0–10 VAS) –0.3 (placebo), –2.9 (IFX) Patient’s global assessment (0–10 VAS) +6.1 (placebo), +49.2 (IFX) CRP (mg/dL) 0.0 (placebo), –68.7 (IFX) SF-36 summary physical component +0.8 (placebo), +10.2 (IFX) SF-36 mental component +2.0 (placebo), +2.7 (IFX)

350

Adverse events

Ankylosing Spondylitis: Infliximab

Upper respiratory tract infection 14.7% (placebo), 13.9% (IFX) Pharyngitis 2.7% (placebo), 10.4% (IFX) ALT level increased 4% (placebo), 9.4% (IFX) Headache 8.0% (placebo), 8.9% (IFX) Rhinitis 2.7% (placebo), 7.4% (IFX) Diarrhea 5.3% (placebo), 5.4% (IFX) Pain 5.3% (placebo), 5.4% (IFX) AST level increased 2.7% (placebo), 5.4% (IFX) Fatigue 4.0% (placebo), 5.0% (IFX) Pruritus 6.7% (placebo), 4.0% (IFX) Nausea 10.7% (placebo), 3.5% (IFX) Arthritis 5.3% (placebo), 3.0% (IFX) Rash 5.3% (placebo), 2.5% (IFX)

Ankylosing Spondylitis: Infliximab

Trial

Persistent clinical response to the anti-TNF-alpha antibody Infliximab in patients with ankylosing spondylitis over 3 years

Substance

Infliximab (IFX) at 5 mg/kg every 6 weeks open label After 12 weeks of randomized trial (Braun, Lancet. April 6, 2002; 359(9313):1187)

351

Concomitant therapy: No DMARDs No oral corticosteroids NSAIDs were permitted at stable doses Result

3-year treatment of AS patients with infliximab showed a durable clinical response without loss of efficacy. The treatment was well tolerated

Patients

46 patients with AS BASDAI ³4 VAS ³4 (maximum 10)

Authors

Braun J, Baraliakos X, Brandt J, Listing J, Zink A, Alten R, Burmester G, Gromnica-Ihle E, Kellner H, Schneider M, Sörensen H, Zeidler H, Sieper J

Publication

Rheumatology (Oxford). May 2005;44(5):670–676. Epub March 9, 2005

Follow up

156 weeks

Note

Change of: Patient’s global assessment (0–10 cm) –4.0 Physician’s global assessment (0–10 cm) –4.5 BASDAI –3.7 Pain –4.2 BASFI –2.1 BASMI –0.9 CRP median (range) –20.0 mg/L ESR median (range) –16.0 mm/h SF-36 Physical component +12.0 SF-36 Mental component –193.7 Fatigue –3.1 Spinal pain –4.7 Peripheral joint pain –3.0 Entheseal pain –3.3 Morning stiffness –4.5 Tragus wall distance <15 cm –8.7% Lumbar flexion >4 cm +21.8% Cervical rotation >70° +17.4% Lateral lumbar flexion >10 cm +13.0% Intermalleolar distance >100 cm +10.9%

352

Adverse events

Ankylosing Spondylitis: Infliximab

Upper respiratory tract infections 37% Diarrhea 22% Rhinitis 20% Herpes labialis 13% Antinuclear factor test positive 13% Hepatic enzymes increased 13% Headache 13% Dry skin 9% Myalgia 9% Vertigo 9% Dry eyes 7% Accidental injury 7% Creatinine kinase increased 7% Vomiting 7% Cough 7% Pharyngitis 7% Bronchitis 7%

Ankylosing Spondylitis: Infliximab

Trial

Infliximab in combination with Methotrexate in active ankylosing spondylitis: a clinical and imaging study

Substance

5 mg/kg infliximab (IFX, n = 28, weeks 0, 2, 6, 14, 22) Placebo (n = 14)

353

Concomitant therapy: 7.5 mg methotrexate (MTX)/week, increased to 10 mg/week (both groups) Continue NSAIDs at stable dosis Continue corticosteroids at stable dosis No DMARDs £4 weeks No intraarticular or intramuscular injections of corticosteroids Previous therapy: NSAIDs 89% (IFX), 86% (placebo) Oral corticosteroids 18% (IFX), 25% (placebo) DMARDs 36% (IFX), 21% (placebo) Result

Infliximab in combination with methotrexate was a safe and efficacious treatment in ankylosing spondylitis over 6 months. Manifestations such as enthesitis/osteitis regressed as determined by MRI. Disease flares were reported 8 weeks after the last infusion

Patients

42 active AS patients Persistent inflammatory back pain VAS >3 (maximum 10)

Authors

Marzo-Ortega H, McGonagle D, Jarrett S, Haugeberg G, Hensor E, O’connor P, Tan AL, Conaghan PG, Greenstein A, Emery P

Publication

Ann Rheum Dis. November 2005;64(11):1568–1575. Epub April 13, 2005

Follow up

30 weeks

Note

Change of (median): BASDAI –1.85 (IFX + MTX), –0.83 (MTX) BASFI –1.64 (IFX + MTX), –0.32 (MTX) Early morning stiffness –30 min (IFX + MTX), +30 min (MTX) Pain (VAS) 27.5 (IFX + MTX), –7.5 (MTX) Night pain (VAS) –41.5 (IFX + MTX), –18.0 (MTX) Enthesopathy (VAS) –45.5 (IFX + MTX), –27 (MTX) Physician DAS –40 (IFX + MTX), –4.5 (MTX) ASQol –5.5 (IFX + MTX), +1 (MTX) CRP mg/L –22 (IFX + MTX), –4 (MTX) Bone mineral density (femoral neck) +2.52% (IFX + MTX), –1.34% (MTX) Bone mineral density (total hip) +1.88% (IFX + MTX), +0.11% (MTX) Bone mineral density (spine L2–4) +3.6% (IFX + MTX), –1.38% (MTX)

354

Adverse events

Ankylosing Spondylitis: Infliximab

Upper respiratory infections 7.1% (IFX + MTX), 14.3% (MTX) Sinusitis 3.6% (IFX + MTX), 0% (MTX) Sore throat 3.6% (IFX + MTX), 0% (MTX) Oral thrush 3.6% (IFX + MTX), 0% (MTX) Transient transaminase rise 7.1% (IFX + MTX), 0% (MTX) Chest infection 3.6% (IFX + MTX), 0% (MTX) Shingles 3.6% (IFX + MTX), 0% (MTX) Urticarial rash 3.6% (IFX + MTX), 0% (MTX) Iritis 3.6% (IFX + MTX), 0% (MTX) Infusion reactions 3.6% (IFX + MTX), 0% (MTX)

Ankylosing Spondylitis: Infliximab

ASSERT-Trial

Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with Infliximab: results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study. ASSERT: the ankylosing spondylitis study for the evaluation of recombinant Infliximab therapy

Substance

Infliximab (IFX, 5 mg/kg/6 weeks after loading phase at weeks 0–2–6, n = 194) Placebo (n = 72)

355

Concomitant therapy: Stable doses of NSAIDs, acetaminophen (paracetamol), or tramadol Previous therapy: No sulfasalazine or methotrexate £2 weeks No other DMARDs £6 months No cytotoxic drugs £12 months No systemic corticosteroids £1 month No anti-TNF therapy other than infliximab £3 months Result

Infliximab treated ankylosing spondylitis patients therapy showed a decrease in spinal inflammation as detected by MRI

Patients

279 patients with AS Disease duration >3 months BASDAI ³4 Spinal pain (VAS 0–10) ³4

Authors

Braun J, Landewé R, Hermann KG, Han J, Yan S, Williamson P, van der Heijde D; ASSERT Study Group

Publication

Arthritis Rheum. May 2006;54(5):1646–1652

Follow up

6 months

Note

MRI Activity Score 0 = no erosions or bone marrow edema 1 = minor bone marrow edema involving £25% of the vertebral unit 2 = moderate bone marrow edema involving >20% but £50% of the vertebral unit 3 = major bone marrow edema involving MRI score >1 at week 24 37.1% (IFX), 73.6% (placebo) Change of: MRI Activity Score –5.0 (IFX), –0.6 (placebo)

356

Ankylosing Spondylitis: Infliximab

Trial

Safety and Efficacy of Readministration of Infliximab After Long-term Continuous Therapy and Withdrawal in Patients with Ankylosing Spondylitis

Substance

Therapy was discontinued after continuous treatment with infliximab (5 mg/kg/6 weeks) Infliximab was re-administered if BASDAI if physician global assessment ³4 Concomitant therapy: No information on concomitant medication

Result

Readministration of infliximab was safe and efficacious after discontinuation of long-term treatment. Prolonged remission after discontinuation was rare

Patients

42 AS patients discontinued treatment after 3 years of effective treatment with 5 mg/kg Infliximab Each patient was re-infused with Infliximab if needed

Authors

Baraliakos X, Listing J, Rudwaleit M, Brandt J, Alten R, Burmester G, Gromnica-Ihle E, Haibel H, Schewe S, Schneider M, Sörensen H, Zeidler H, Visvanathan S, Sieper J, Braun J

Publication

J Rheumatol. March 2007;34(3):510–515. Epub February 1, 2007

Follow up

48 weeks after relapse occurred

Ankylosing Spondylitis: Infliximab

Note

357

Continued clinical remission without therapy for >1 year n = 1 Re-infused because of clinical relapse n = 41 No correlation between antibodies to IFX and clinical measures Change of: BASDAI 2.5 (TP1 = end of IFX), 6.0 (TP2, flair, readministration IFX), 2.7 (TP3, after 24 weeks), 2.6 (TP4, after 48 weeks) BASFI 2.9 (TP1), 5.7 (TP2), 3.2 (TP3), 3.2 (TP4) BASMI 2.6 (TP1), 3.4 (TP2), 3.0 (TP3), 2.7 (TP4) CRP (mg/L, median) 1.0 (TP1), 11.2 (TP2), 1.6 (TP3), 1.8 (TP4) ESR (median, mm/h) 8 (TP1), 24 (TP2), 6 (TP3), 11 (TP4) Patient’s global assessment 2.6 (TP1), 7.0 (TP2), 2.9 (TP3), 2.8 (TP4) Physician’s global assessment 1.6 (TP1), 6.3 (TP2), 1.9 (TP3), 2.0 (TP4) BASDAI 50% response 54% (TP1), 62.5% (TP3), 62.5% (TP4) ASAS 40 response 65% (TP1), 65.0% (TP3), 62.5% (TP4) ASAS 5/6 response 72.5% (TP1), 67.5% (TP3), 70.0% (TP4) Partial remission 35% (TP1), 25% (TP3), 30% (TP4)

Adverse events

Upper respiratory infections n = 10 Infections at any site n = 6 Gum infection n = 4 Herpes simplex n = 3 Dry skin with pruritus n = 2 Infusion reactions n = 1 Elevated liver enzymes n = 1 Nausea n = 1 Tachycardia n = 1 Swelling of fingers n = 1 Repeated local infections n = 1 Skin leishmaniosis after injury n = 1 Bicycle accident with subdural haematoma n = 1

358

Ankylosing Spondylitis: Infliximab

Trial

Maintenance of Infliximab treatment in ankylosing spondylitis: results of a 1-year randomized controlled trial comparing systematic versus on-demand treatment

Substance

5 mg infliximab (IFX)/kg every 6 weeks (n = 124, loading dose weeks 0 – 2- 6, dose could be increased to 7.5 mg/kg after week 40) On-demand treatment with infliximab (n = 123) Concomitant therapy: +2.5 mg methotrexate (MTX)/week, increased to maximum 12.5 mg/week (n = 61, on demand patients) Other DMARDs were discontinued ³4 weeks Stable NSAIDs and/or corticosteroids ³4 weeks

Result

Continuous treatment of ankylosing spondylitis with infliximab was more efficacious than on-demand treatment. The addition of methotrexate to infliximab was not significantly beneficial

Patients

247 AS patients, evidence of active inflammation 3 months prior to enrolment CRP level >2× the upper limit of normal Positive findings on MRI of the spine or sacroiliac joints Enthesitis demonstrated by power Doppler ultrasound BASDAI ³3 VAS axial pain ³3 (maximum 10)

Authors

Breban M, Ravaud P, Claudepierre P, Baron G, Henry YD, Hudry C, Euller-Ziegler L, Pham T, Solau-Gervais E, Chary-Valckenaere I, Marcelli C, Perdriger A, Le Loët X, Wendling D, Fautrel B, Fournié B, Combe B, Gaudin P, Jousse S, Mariette X, Baleydier A, Trape G, Dougados M; French Ankylosing Spondylitis Infliximab Network

Publication

Arthritis Rheum. January 2008;58(1):88–97

Follow up

58 weeks

Ankylosing Spondylitis: Infliximab

Note

ASAS 20: 75% (continuous treatment), 46% (on demand), 40% (on demand –MTX), 51% (on demand +MTX) ASAS 40: 51% (continuous treatment), 30% (on demand), 24% (on demand –MTX), 36% (on demand +MTX) Partial remission: 27% (continuous treatment), 7% (on demand), 5% (on demand –MTX), 10% (on demand +MTX) Change of: Patient’s assessment of pain VAS –3.1 (continuous treatment), –1.4 (on demand), –1 3 (on demand –MTX), –1.6 (on demand +MTX) Patient’s global assessment VAS –3.3 (continuous treatment), –2.0 (on demand), –2.1 (on demand –MTX), –2 9 (on demand +MTX) BASDAI –2.9 (continuous treatment), –1.7 (on demand), –1.8 (on demand –MTX), –1.6 (on demand +MTX) BASFI –2.4 (continuous treatment), –1.2 (on demand), –1.0 (on demand –MTX), –1.5 (on demand +MTX) Physical component of the SF–36 +6.0 (continuous treatment), +5.7 (on demand), +5.8 (on demand –MTX), +5.7 (on demand +MTX) Mental component of the SF–36 +7.8 (continuous treatment), +4.8 (on demand), +5.8 (on demand –MTX), +3.9 (on demand +MTX) ESR (mm/h) –18.6 (continuous treatment), –10.4 (on demand), –9.1 (on demand –MTX), –11.7 (on demand +MTX) CRP (mg/L) –20.2 (continuous treatment), –8.1 (on demand), –6.7 (on demand –MTX), –9.4 (on demand +MTX) Weight (kg) +2.4 (continuous treatment), +0.9 (on demand), +0.9 (on demand –MTX), +0.9 (on demand +MTX) Schober test (cm) +0.6 (continuous treatment), +0.3 (on demand), +0.2 (on demand –MTX), +0.3 (on demand +MTX) Fingers–to–floor distance (cm) –6.7 (continuous treatment), –2.9 (on demand), –1.6 (on demand –MTX), –4.2 (on demand +MTX) Occiput–to–wall distance (cm) –1.4 (continuous treatment), 0 (on demand), +0.1 (on demand –MTX), –0.2 (on demand +MTX) Chest expansion (cm) +0.7 (continuous treatment), +0.7 (on demand), +0.7 (on demand –MTX), +0.7 (on demand +MTX)

Adverse events

88.3% of the patients experienced adverse events, no significant difference between groups No. of infusions after week 10 (mean) 5.8 (continuous treatment), 3.5 (on demand), 3.7 (on demand –MTX), 3.3 (on demand +MTX) reactions to infusion 14.5% (continuous treatment), 6.5% (on demand), 9.7% (on demand –MTX), 3.3% (on demand +MTX) Patients requiring an increased dose 4.8% (continuous treatment), 4.9% (on demand), 6.5% (on demand –MTX), 3.3% (on demand +MTX) 66 serious events occurred in 57 patients One sudden death (myocardial infarction in the on–demand group + MTX) Two solid cancers (One in each group) Three serious infection (continuous treatment), four (on–demand) No cases of lymphoma, tuberculosis, or opportunistic infection

359

360

Ankylosing Spondylitis: Infliximab

Trial

Persistent clinical efficacy and safety of anti-tumor necrosis factor alpha therapy with Infliximab in patients with ankylosing spondylitis over 5 years: evidence for different types of response

Substance

Infliximab (5 mg/kg i.v. every 6 weeks, n = 42) After a 12 weeks clinical trial: Infliximab (5 mg/kg i.v. every 6 weeks, n = 34) Placebo (n = 35) Concomitant medication: No DMARDs No oral corticosteroids NSAIDs at stable doses

Result

Infliximab was safe and efficacious over 5 years in patients with ankylosing spondylitis. The majority of the patients had rather persistent levels of low disease activity and remained on treatment

Patients

69 patients with active AS BASDAI ³4 Spinal pain score ³4 and a of at least 4 weeks

Authors

Braun J, Baraliakos X, Listing J, Fritz C, Alten R, Burmester G, Krause A, Schewe S, Schneider M, Sörensen H, Zeidler H, Sieper J

Publication

Ann Rheum Dis. March 2008;67(3):340–345. Epub October 29, 2007

Follow up

5 years

Note

Partial clinical remission 34.2% Withdrawal 9.5% BASDAI 2.5 BASDAI <4: 78.9% BASDAI <3: 57.9% BASFI 3.0 BASMI 2.8 CRP 3.4 mg/L ASAS 20: 84.2% ASAS 40: 63.2% ASAS 5/6: 76.3%

Adverse events

94.7% reported at least one adverse event Common cold 41% Bronchitis 11% Increase of liver enzymes 6.5%

Psoriatic Arthritis

Chloroquine

Trial

Chloroquine therapy in psoriatic arthritis

Substance

250 mg chloroquine/day (n = 32) Control patients not treated with chloroquine (n = 24) Concomitant medication: Background NSAIDs

Result

Inflammatory activity in patients with psoriatic arthritis decreased subsequent to chloroquine treatment. Exacebation of cutaneous psoriasis was not increased as compared to untreated control patients

Patients

32 patients with psoriatic arthritis treated with NSAIDs

Authors

Gladman DD, Blake R, Brubacher B, Farewell VT

Publication

J Rheumatol. November 1992;19(11):1724–1726

Follow up

6 months

Note

>30% reduction of inflamed joint count 75% (chloroquine), 54% (controls) Increase of inflamed joint count 12% (chloroquine), 35% (controls) Exacerbation of cutaneous psoriasis n = 6 (chloroquine, n = 1 severe), n = 6 (controls)

Adverse events

Exacerbation of psoriasis 18.75% (chloroquine)

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_3, © Springer-Verlag London Limited 2011

361

362

Psoriatic Arthritis: Ciclosporin vs. Methotrexate

Trial

Comparison of Ciclosporin A and Methotrexate in the treatment of psoriatic arthritis: a 1-year prospective study

Substance

3 mg/kg ciclosporin A (CsA)/day (increased every 4 weeks by 1 mg/kg/day maximum 5 mg/kg/day, n = 17) 2.5 mg methotrexate (MTX)/day on 3 consecutive days/week (increased every 4 weeks by 7.5 mg/week to maximum 15 mg/week, n = 18) Concomitant medication: Stable NSAIDs ³1 month Previous medication: No CsA or MTX £3 months

Result

Low-dose ciclosporin A and methotrexate were both effective in the treatment of psoriatic arthritis

Patients

35 patients with PsoA Active Arthritis Despite NSAID treatment ³5 painful and/or swollen joints Disease duration >6 months

Authors

Spadaro A, Riccieri V, Sili-Scavalli A, Sensi F, Taccari E, Zoppini A

Publication

Clin Exp Rheumatol. September–October 1995;13(5):589–593

Follow up

12 months

Note

Change of: Painful joints –3.7 (CsA), –6.4 (MTX) Swollen joints –2.5 (CsA), –3.5 (MTX) Ritchie index –1.0 (CsA), –11.3 (MTX) Morning stiffness (min) –11.4 (CsA), –50.9 (MTX) Grip strength right (mmHg) +11 (CsA), +49 (MTX) Grip strength left (mmHg) +26 (CsA), +29 (MTX) Physician’s assessment (VAS), –14.7 (CsA), –30.3 (MTX) Patient’s assessment (VAS) –27.3 (CsA), –31.0 (MTX) PASI –5.4 (CsA), –2.3 (MTX) ESR (mm/h) –9.0 (CsA), –18.8 (MTX) CRP (mg/L) –10.6 (CsA), –11.2 (MTX)

Adverse events

Uncontrolled hypertension n = 3 (CsA), n = 0 (MTX) Abnormal renal function n = 1 (CsA), n = 0 (MTX) Gastrointestinal discomfort n = 1 (CsA), n = 2 (MTX) Unsatisfactory response n = 2 (CsA), n = 0 (MTX) Elevation of liver enzymes n = 0 (CsA), n = 1 (MTX) Intercurrent infection n = 0 (CsA), n = 1 (MTX) Withdrawals (12 months) 17.6% (CsA), 22.2% (MTX) Withdrawals (12 months) 41.2% (CsA), 27.8% (MTX)

Psoriatic Arthritis: Ciclosporine vs. Sulfasalazine

Trial

A comparison of Ciclosporine, Sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritis

Substance

3 mg/kg ciclosporin/day (increased to 5 mg/kg/day at weeks 4–8–12 if needed, n = 36) 2 × 500 mg sulfasalazine/day (increased to 3,000 mg/day at weeks 4–8–12 if needed, n = 32) Symptomatic therapy alone (NSAID/corticosteroids/analgesics, n = 31)

363

Concomitant medication: Prednisone £ 5 mg/day NSAIDs were continued at stable doses No intraarticular corticosteroids £3 weeks Previous medication: NSAIDs Previous DMARD therapy was permitted No photochemotherapy £4 weeks No retinoid therapy £3 months Result

Ciclosporin was more efficacious than symptomatic therapy or sulfasalazine in patients with psoriatic arthritis

Patients

99 patients with active PsoA despite NSAID treatment With or without axial involvement (sacroiliitis and/or spondylitis) ³3 swollen and tender joints ³30 min morning stiffness Pain (VAS) > 20 mm Patient global assessment of disease activity ³2 (VAS 0–5 point) PASI score £ 15

Authors

Salvarani C, Macchioni P, Olivieri I, Marchesoni A, Cutolo M, Ferraccioli G, Cantini F, Salaffi F, Padula A, Lovino C, Dovigo L, Bordin G, Davoli C, Pasero G, Alberighi OD

Publication

J Rheumatol. October 2001;28(10):2274–2282

Follow up

24 weeks

ACR 20

44.4% (CsA), 43.8% (SSZ), 35.5% (symptomatic therapy)

ACR 50

25.0% (CsA), 12.5% (SSZ), 3.2% (symptomatic therapy)

ACR 70

13.8% (CsA), 0% (SSZ), 0% (symptomatic therapy)

364

Note

Psoriatic Arthritis: Ciclosporine vs. Sulfasalazine

ASAS 20 47.2% (CsA), 40.0% (SSZ), 29.0% (symptomatic therapy) ASAS 50 16.6% (CsA), 12.5% (SSZ), 9.7% (symptomatic therapy) ASAS 70 5.5% (CsA), 0% (SSZ), 0% (symptomatic therapy) Change of: Pain score (VAS, mm) –27.2 (CsA), –17.3 (SSZ), –12.5 (symptomatic therapy) Swollen joint count –4.8 (CsA), –4.4 (SSZ), –1.8 (symptomatic therapy) Tender joint count –7.6 (CsA), –5.7 (SSZ), –3.5 (symptomatic therapy) Joint pain/tenderness score –6.9 (CsA), –4.8 (SSZ), –1.5 (symptomatic therapy) Morning stiffness, min –41.5 (CsA), –45.9 (SSZ), –37.1 (symptomatic therapy) Total AIMS test –9.2 (CsA), –4.8 (SSZ), –3.8 (symptomatic therapy) Spondylitis functional index –5.7 (CsA), –3.5 (SSZ), –0.9 (symptomatic therapy) Schober test (cm) +1.3 (CsA), –1.8 (SSZ), 0.0 (symptomatic therapy) Finger-to-floor test (cm) +1 (CsA), 0 (SSZ), +2.9 (symptomatic therapy) Cervical spine flexion test (mm) –2.9 (CsA), +1.8 (SSZ), +0.8 (symptomatic therapy) Cervical spine extension test (mm) +3.3 (CsA), –4.8 (SSZ), –1.2 (symptomatic therapy) Chest expansion (mm) +7.0 (CsA), 2.7 (SSZ), 3.3 (symptomatic therapy) PASI –3.6 (CsA), –2.3 (SSZ), –0.4 (symptomatic therapy) ESR (mm/h) –12.4 (CsA), –12.9 (SSZ), –0.9 (symptomatic therapy) CRP (mg/dL) –1.6 (CsA), –0.9 (SSZ), –0.1 (symptomatic therapy)

Adverse events

Impaired renal function n = 10 (CsA), n = 1 (SSZ), n = 1 (symptomatic therapy) GI intolerance n = 4 (CsA), n = 6 (SSZ), n = 4 (symptomatic therapy) Neurological disturbances n = 7 (CsA), n = 3 (SSZ), n = 3 (symptomatic therapy) Hypertrichosis n = 2 (CsA), n = 0 (SSZ), n = 0 (symptomatic therapy) Hypertension n = 5 (CsA), n = 1 (SSZ), n = 1 (symptomatic therapy) Gingival hyperplasia n = 2 (CsA), n = 0 (SSZ), n = 0 (symptomatic therapy) Increased liver enzymes n = 1 (CsA), n = 4 (SSZ), n = 1 (symptomatic therapy) Bacterial infections n = 1 (CsA), n = 0 (SSZ), n = 0 (symptomatic therapy) Altered blood cell counts n = 1 (CsA), n = 0 (SSZ), n = 0 (symptomatic therapy) Neoplasia n = 0 (CsA), n = 0 (SSZ), n = 0 (symptomatic therapy)

Psoriatic Arthritis: Ciclosporin ± Methotrexate

Trial

A randomized, double-blind, placebo-controlled, multicenter trial of combination therapy with Methotrexate plus Ciclosporin in patients with active psoriatic arthritis

Substance

2.5 mg/kg/day ciclosporin A (CsA, n = 38), increased every 4 weeks by 0.5 mg/kg/day to maximum 4 mg/kg/day Placebo (n = 34) Concomitant medication: Background ³15 mg/week MTX for ³3 months Prednisolone £ 10 mg/day NSAIDs were continued at stable doses No intraarticular corticosteroids £3 weeks Previous medication: NSAIDs Methotrexate (MTX)

Result

Combining ciclosporin and methotrexate treatment significantly improved the signs of inflammation but not pain or quality of life in patients with active psoriatic arthritis as compared to methotrexate monotherapy

Patients

72 patients with active PsoA with an incomplete response to ³15 mg MTX/week Disease duration ³24 weeks Evidence of skin and/or nail psoriasis Seronegative for rheumatoid factor Active PsoA: ³3 tender joints

Authors

Fraser AD, van Kuijk AW, Westhovens R, Karim Z, Wakefield R, Gerards AH, Landewé R, Steinfeld SD, Emery P, Dijkmans BA, Veale DJ

Publication

Ann Rheum Dis. June 2005;64(6):859–864. Epub November 4, 2004

Follow up

12 months

Note

Change of: Tender joint index –16.9 (Placebo + MTX), –12.0 (CsA + MTX) Tender joint count –8.6 (Placebo + MTX), –7.3 (CsA + MTX) Swollen joint count –3.8 (Placebo + MTX), –5.0 (CsA) ESR (mm/h) –1.6 (Placebo + MTX), +0.9 (CsA + MTX) CRP (mg/L) –2.8 (Placebo + MTX), –4.7 (CsA + MTX) PASI –0.3 (Placebo + MTX), –1.2 (CsA + MTX) Patient global pain (VAS) –0.2 (Placebo + MTX), –0.8 (CsA + MTX) Patient global disease activity (VAS) –0.5 (Placebo + MTX), –1.0 (CsA + MTX) HAQ –0.2 (Placebo + MTX), –0.1 (CsA + MTX) Percentage of joints with synovitis detectable by ultrasound –6% (Placebo + MTX), –33% (CsA + MTX) Larsen score +7.4 (Placebo + MTX), +1.6% (CsA + MTX)

Adverse events

Nausea 18% (Placebo + MTX), 39% (CsA + MTX) Headache 6% (Placebo + MTX), 24% (CsA + MTX) Burning sensations 0% (Placebo + MTX), 13% (CsA + MTX) Paresthesia 0% (Placebo + MTX), 11% (CsA + MTX) Muscle cramps 0% (Placebo + MTX), 11% (CsA + MTX) Hypertrichosis 0% (Placebo + MTX), 8% (CsA + MTX) Serious adverse events 3% (Placebo + MTX), 11% (CsA + MTX)

365

366

Psoriatic Arthritis: Leflunomide

TOPAS-Trial

Efficacy and safety of Leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial TOPAS: Treatment with Leflunomide in Psoriatic Arthritis

Substance

20 mg leflunomide/day (after 3-day100 mg/day loading dose, n = 98) Placebo (n = 92) Concomitant medication: No DMARDs £28 days No biologic agents £28 days Discontinue topical treatment for psoriasis ³14 days Continue NSAIDs at stable doses Prednisone f £ 10 mg/day or equivalent at stable doses Medically accepted contraceptive regimen Previous medication: Previous DMARD therapy 50.5% (placebo) 37 (Lef)

Result

Leflunomide was an effective treatment for PsoA, with regard to the ACR 20 response and cutaneous psoriasis

Patients

190 patients with active psoriatic arthritis and cutaneous psoriasis ³3 swollen and 3 painful joints Psoriasis ³3% of the total body surface + Distal interphalangeal involvement or Polyarticular involvement or Arthritis mutilans or Asymmetric oligoarticular arthritis or Ankylosing spondylitis–like arthritis

Authors

Kaltwasser JP, Nash P, Gladman D, Rosen CF, Behrens F, Jones P, Wollenhaupt J, Falk FG, Mease P; Treatment of Psoriatic Arthritis Study Group

Publication

Arthritis Rheum. June 2004;50(6):1939–1950

Follow up

6 months

ACR 20

20.0% (placebo), 36.6% (Lef)

Psoriatic Arthritis: Leflunomide

Note

PASI 50 18.9% (placebo), 30.4% (Lef) PASI 75 7.8% (placebo), 17.4% (Lef) Psoriatic Arthritis Response Criteria 30% (placebo), 59% (Lef) Improvement of: Physician’s global assessment 34.1% (placebo), 52.6% (Lef) Patient’s global self-assessment 30.8% (placebo), 31.6% (Lef) Patient pain assessment 35.6% (placebo), 46.7% (Lef) Deterioration of: Physician’s global assessment 22% (placebo), 10.5% (Lef) Patient’s global self-assessment 24.2% (placebo), 15.8% (Lef) Patient pain assessment 33.3% (placebo), 13.3% (Lef) Change of: Joint pain/tenderness score –4.6 (placebo), –9.1 (Lef) Joint swelling score –4.2 (placebo), –6.8 (Lef) Tender joint count –3 (placebo), –5.6 (Lef) Swollen joint count –2.7 (placebo), –4.4 (Lef) CRP level (mg/dL) –0.1 (placebo), –7.9 (Lef) HAQ total score –0.05 (placebo), –0.19 (Lef) PASI score –0.6 (placebo), –2.1 (Lef) DLQI total score –0.2 (placebo), –1.9 (Lef)

Adverse events

Diarrhea 13% (placebo), 24% (Lef) Aggravation reaction 22.8% (placebo), 17.7% (Lef) Involving PsoA 19.6% (placebo), 9.4% (Lef) Unrelated to PsoA 3.3% (placebo), 8.3% (Lef) Flu syndrome 13% (placebo), 12.5% (Lef) Increased ALT level 5.4% (placebo), 12.5% (Lef) Headache 7.6% (placebo), 11.5% (Lef) Nausea 8.7% (placebo), 9.4% (Lef) Rash 3.3% (placebo), 7.3% (Lef) Joint disorder 5.4% (placebo), 6.3% (Lef) Pruritus 4.3% (placebo), 6.3% (Lef) Gastrointestinal pain 6.5% (placebo), 6.3% (Lef) Tiredness/lethargy 1.1% (placebo), 6.3% (Lef) Skin disorder (other than rash and pruritus), 3.3% (placebo), 5.2% (Lef) ALT- elevation: ³2 times to <3 times the upper normal limit 0% (placebo), 8% (Lef) ³3 times to <5 times the upper normal limit 2% (placebo), 1% (Lef) ³5 times to <8 times the ULN 0% Placebo), 0% (Lef) ³8 times the upper normal limit 0% (placebo),1% (Lef)

367

368

Psoriatic Arthritis: Leflunomide

TOPAS-Trial

Leflunomide improves psoriasis in patients with psoriatic arthritis: an in-depth analysis of data from the TOPAS study TOPAS: Treatment with Leflunomide in Psoriatic Arthritis

Substance

Leflunomide (20 mg/day after 3-day100 mg/day loading dose, n = 98) Placebo (n = 92) Concomitant medication: No DMARDs £28 days No biologic agents £28 days Discontinue topical treatment for psoriasis ³14 days Continue NSAIDs at stable doses Prednisone f £ 10 mg/day or equivalent at stable doses Medically accepted contraceptive regimen Previous medication: Previous DMARD therapy 50.5% (placebo), 37 (Lef)

Result

Leflunomide was an effective treatment for PsoA and plaque psoriasis

Patients

190 patients with plaque psoriasis (³3% skin involvement) Active PsoA (³3% swollen and ³3% tender joints) Distal interphalangeal involvement or Polyarticular involvement or Arthritis mutilans or Symmetric oligoarticular arthritis or Ankylosing spondylitis–like arthritis

Authors

Nash P, Thaçi D, Behrens F, Falk F, Kaltwasser JP

Publication

Dermatology. 2006;212(3):238–249

Follow up

24 weeks

Psoriatic Arthritis: Leflunomide

Note

PASI 50 30.4% (Lef), 18.9% (placebo) PASI 75 17.4% (Lef), 7.8% (placebo) PASI 90 9.8% (Lef), 2.2% (placebo) Change of: Total PASI –2.1 (Lef), –0.6 (placebo) Erythema –0.7 (Lef), –0.2 (placebo) Infiltration –0.8 (Lef), –0.2 (placebo) Desquamation –0.7 (Lef), –0.3 (placebo) Target lesion response 46.4% (Lef), 25.3% (placebo) Combined skin and joint response 27.2 (Lef), 8.9% (placebo) Dermatology Life Quality Index improvement 1.9 (Lef), 0.2 (placebo) Change of SF36 mental component summary: Total score +3.4 (Lef), +0.1 (placebo) Physical functionin improvement +9 (Lef), +1.3 (placebo) Role – physical improvement +8.5 (Lef), –0.5 (placebo) Bodily pain improvement +10.6 (Lef), –1.6 (placebo) General health improvement +3 (Lef), –0.7 (placebo) Change of SF36 physical component summary: Total score +1 (Lef), –0.6 (placebo) Vitality +7.1 (Lef), +0.9 (placebo) Social functioning +3.5 (Lef), –4.5 (placebo) Emotional role +0.6 (Lef), +1.2 (placebo) Mental health + (Lef), 0.8 (placebo)

Adverse events

Diarrhea 24% (Lef), 13% (placebo) Elevated ALT levels (>2 times), 10% (Lef), 2% (placebo)

369

370

Psoriatic Arthritis: Leflunomide vs. Methotrexate

Trial

Leflunomide in psoriatic arthritis: a retrospective study of discontinuation rate in daily clinical practice compared with Methotrexate

Substance

Leflunomide 10–20 mg/day (n = 42, without loading dose) Methotrexate (MTX) 7.5–15 mg/week (n = 44) Concomitant medication: No other DMARDs No biologics Corticosteroids were continued NSAIDs were continued Previous medication: Previous DMARD therapy 38.1% (Lef), 40.9% (MTX) Previous NSAID therapy 38.1% (Lef), 40.9% (MTX)

Result

The rate of adverse events was lower among leflunomide treated patients. Discontinuation due to liver toxicity was lower among methotrexate treated patients in this study of adverse events and not of drug efficacy

Patients

86 PsoA patients with polyarticular involvement or Asymmetrical oligoarticular arthritis Satisfying ESSG criteria for the spondyarthropathies

Authors

Malesci D, Tirri R, Buono R, La Montagna G

Publication

Clin Exp Rheumatol. November–December 2007;25(6):881–884

Follow up

24 months

Note

Drug survival 54.9% (Lef), 57.0% (MTX) Discontinuation rate for toxicity 29.2% (Lef), 18.8 (MTX)

Adverse events

Nausea 4.8% (Lef), 6.8% (MTX) Diarrhea 4.8% (Lef), 0% (MTX) Hypertransaminasemia (>2 times ULN), 9.5% (Lef), 9.1% (MTX) Hypertension 9.5% (Lef), 0% (MTX) Leucopoenia 4.8% (Lef), 0% (MTX)

Psoriatic Arthritis: Methotrexate

Trial

Randomized, double-blind, placebo-controlled trial of low-dose pulse Methotrexate in psoriatic arthritis

Substance

2.5 methotrexate (MTX) 3 times every 12 h/week, increased to maximum 15 mg/week after 6 weeks (n = 16) Placebo (n = 21) Concomitant medication: No gold, anti-malerial, steroid treatment £3 months Ibuprofen (1,600–24,400 mg/day) or indomethacin (75–200 mg/day) Analgetics were permitted: acetaminophen, propoxyphene Previous medication: NSAIDs

Result

Arthritic disease improved better after methotrexate then after placebo treatment

Patients

37 PsoA patients Classic psoriatic arthritis involving distal interphalangeal joints or Seronegative symmetric polyarthritis and psoriasis or Arthritis mutilans and psoriasis Active disease despite NSAID treatment

Authors

Wilkens RF, Williams JW, Ward JR, Egger MJ, Reading JC, Clements PJ, Cathcart ES, Samuelson CO, Solsky MA, Kaplan SB, Guttadauria M, Halla JT, Weinstein A

Publication

Arthritis Rheum. 1984;27(4):376

Study duration

12 weeks

Note

Change of: Grip strength right +1 mmHg (placebo), –4 mmHg (MTX) Grip strength left –0 mmHg (placebo), –9 mmHg (MTX) Morning stiffness –30 min (placebo), –45 min (MTX) Physicians assessment (1–5) 0 (placebo), –1 (MTX) Patients physical assessment (1–5) 0 (placebo), –1 (MTX) Tender joints count –6 (placebo), –4 (MTX) Swollen joint count –1 (placebo), –3 (MTX) Joint swelling/tenderness score –10 (placebo), –9 (MTX) Joint swelling score –2 (placebo), –5 (MTX) ESR (mm/h) –3 (placebo), –19.0 (MTX) Affected surface area (cm2) 0 (placebo), –114 (MTX) Affected skin scaling (0–3) 0 (placebo), –1 (MTX) Affected skin induration (0–3) 0 (placebo), 0 (MTX) Affected skin erythema (0–3) 0 (placebo), –1 (MTX)

Adverse events

Gastrointestinal distress or stomatitis n = 3 (MTX)

371

372

Psoriatic Arthritis: Methotrexate

Trial

The effectiveness of a traditional therapeutical approach in early psoriatic arthritis: results of a pilot randomized 6-month trial with

Substance

Group A (n = 19): NSAID at full dosage for 3 months +10 mg/week MTX intramusculary for the remaining 3 months Group B (n = 16): 10 mg/week MTX intramusculary for the entire 6-month period NSAID therapy at full dosage Concomitant medication: No information provided Previous medication: NSAID therapy on demand before enrollment

Result

Methotrexate treatment of early psoriatic arthritis was more rapid and effective than NSAIDs in the control of signs and symptoms of the disease

Patients

25 patients with Early Psoriatic Arthritis Oligo-enthesoarthritis ³12 weeks Patients with established psoriatic arthritis

Authors

Scarpa R, Peluso R, Atteno M, Manguso F, Spanò A, Iervolino S, Di Minno MN, Costa L, Del Puente A

Publication

Clin Rheumatol. July 2008;27(7):823–826. Epub November 21, 2007

Follow up

6 months

Note

Change of (3 months): Swollen joint count –1.5 (group A), –2 (group B) Tender joint count –1 (group A), –1 (group B) Assessment of pain (VAS) –33 (group A), –30 (group B) ESR –14.5 mm/h (group A), –8 mm/h (group B) CRP –7.5 mg/L (group A), –1 mg/L (group B) Patient’s global assessment –1.5 (group A), –1 (group B) Physician’s global assessment –1 (group A), –1 (group B) Change of (6 months): Swollen joint count –2.5 (group A), –2 (group B) Tender joint count –3 (group A), –2 (group B) Assessment of Pain (VAS) –45 (group A), –60 (group B) ESR –19.5 mm/h (group A), –14 mm/h (group B) CRP –9 mg/L (group A), –3 mg/L (group B) Patient’s global assessment –2.5 (group A), –2 (group B) Physician’s global assessment –2 (group A), –2 (group B)

Adverse events

No adverse events No significant laboratory changes

Psoriatic Arthritis: Sulfasalazine

Trial

Sulfasalazine in the management of psoriatic arthritis

Substance

500 mg sulfasalazine/day, increased weekly to 40 mg/kg/day (n = 19) Placebo (n = 20) Concomitant medication: NSAIDs continued at stable doses Previous medication: NSAID

Result

Sulfasalazine was effective in psoriatic arthritis. However, also a partial response was observed in the placebo group

Patients

Patients with psoriatic arthritis Rheumatoid factor negative Asymmetric arthritis Cutaneous psoriasis ³3 painful and actively synovitic joints No DMARDs Treated with NSAIDs ³3 months

Authors

Fraser SM, Hopkins R, Hunter JA, Neumann V, Capell HA, Bird HA

Publication

Br J Rheumatol. October 1993;32(10):923–925

Follow up

24 weeks

Note

Change of (median): Pain (VAS) –235 (placebo), –400 (SSZ) Morning stiffness (min) 0 (placebo), –30 (SSZ) Global index –1 (placebo), 0 (placebo) Ritchie articular index –14 (placebo), –11 (SSZ) Grip +30 (placebo), +20 (SSZ) ESR –13 (placebo), –21 (SSZ)

Adverse events

Rash n = 2 (SSZ), n = 1 (placebo) Nausea n = 1 (SSZ), n = 0 (placebo) Lack of effect n = 1 (SSZ), n = 8 (placebo) Dyspepsia n = 1 (SSZ), n = 1 (placebo) Mouth ulcers n = 0 (SSZ), n = 1 (placebo)

373

374

Psoriatic Arthritis: Sulfasalazine

Trial

Sulfasalazine therapy for psoriatic arthritis: a double-blind, placebo-controlled trial

Substance

1,500 mg SSZ/day, increased to 3 g/day after 3 days (n = 10) Placebo (n = 14) Cross over after 8 weeks for non responding placebo patients Concomitant medication: NSAIDs continued at stable doses No oral or intraarticular corticosteroids were permitted £4 weeks Maximum 4 × 60 mg propoxyphene was used for treatment of increased arthralgia Previous medication: NSAID

Result

Sulfasalazine was effective in psoriatic arthritis

Patients

24 PsoA patients Seronegative, stable psoriasis Involvement of ³3 joints with active synovitis ³1 typical radiographic abnormality

Authors

Gupta AK, Grober JS, Hamilton TA, Ellis CN, Siegel MT, Voorhees JJ, McCune WJ

Publication

J Rheumatol. May 1995;22(5):894–898

Follow up

12 weeks

Note

Change of (week 8): Tender joint count –13 (SSZ), –2 (placebo) Swollen joint count –7 (SSZ), –6 (placebo) Joint pain/tenderness index –16 (SSZ), –3 (placebo) Joint swelling index –7 (SSZ), –6 (placebo) Grip strength right (mmHg) +15 (SSZ), –5 (placebo) Grip strength left (mmHg) +16 (SSZ), +3 (placebo) 50 ft walking time –0.3 s (SSZ), –0.5 (placebo) Morning stiffness duration –41 min (SSZ), +30 min (placebo) Physicians assessment –1.2 (SSZ), +0.3 (placebo) Patients assessment –1.1 (SSZ), +0.3 (placebo)

Psoriatic Arthritis: Sulfasalazine

Trial

Sulfasalazine in psoriatic arthritis: a randomized, multicenter, placebo-controlled study

Substance

500 mg sulfasalazine/day increased daily by 500 mg to 2 g/day (n = 64) Placebo (n = 53)

375

Concomitant medication: NSAIDs were continued at stable doses Analgetics were continued at stable doses Previous medication: No DMARDs £2 month prior study entry NSAID Result

2 g sulfasalazine/day was safe and effective for the pain variable but not with regard to joint symptoms

Patients

117 PsoA patients with active disease Disease duration ³3 months ³1 of the following: Pain and soft-tissue swelling of the distal interphalangeal joints of the hands and/or feet Peripheral asymmetrical oligoarthritis Symmetrical peripheral arthritis and absent rheumatoid factor or subcutaneous nodules Sacroiliac or spinal involvement

Authors

Combe B, Goupille P, Kuntz JL, Tebib J, Lioté F, Bregeon C

Publication

Br J Rheumatol. July 1996;35(7):664–668

Follow up

24 weeks

Note

Withdrawal due to inadequate response n = 4 (SSZ), n = 7 (placebo) Withdrawal due to adverse events n = 8 (SSZ), n = 12 (placebo) Change of: Morning stiffness (min) –35.3 (placebo), –32.8 (SSZ) Pain VAS (mm) –19.1 (placebo), –27.9 (SSZ) Number of tender joints –3.3 (placebo), –3.7 (SSZ) Ritchie’s index –6.0 (placebo), –5.6 (SSZ) ESR (mm/h) –6.5 (placebo), –12.0 (SSZ) CRP (mg/L) –6.6 (placebo), –12.6 (SSZ) Patient’s assessment of joint improvement: Worse 14% (placebo), 3% (SSZ) No effect 23% (placebo), 11% (SSZ) Slighly better 16% (placebo), 29% (SSZ) Clearly better 37% (placebo), 50% (SSZ) Healed 9% (placebo), 8% (SSZ)

Adverse events

Gastrointestinal 6.3% (placebo), 9.3% (SSZ) Edema 3.1% (placebo), 1.8% (SSZ) Skin reactions 3.1% (placebo), 0% (SSZ) Headache 0% (placebo), 1.8% (SSZ) Liver function abnormalities 1.6% (placebo), 0% (SSZ) Increased creatinine 1.6% (placebo), 0% (SSZ) Pruritus 1.6% (placebo), 0% (SSZ) Eosinophilia 1.6% (placebo), 0% (SSZ) Fever 0% (placebo), 1.8% (SSZ)

376

Psoriatic Arthritis: Sulfasalazine

Trial

Comparison of Sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study

Substance

500 mg sulfasalazine/day, increased weekly by 500 mg to 2 g/day (n = 109) Placebo (n = 112) Concomitant medication: NSAIDs were continued at stable doses No systemic or intraarticular steroids Previous medication: NSAID No sulfasalazine

Result

2 g sulfasalazine/day was more effective than placebo in the treatment of patients with psoriatic arthritis. It was well tolerated

Patients

221 patients with PsoA Psoriasis confirmed by dermatology consult or by skin biopsy Distal interphalangeal joint involvement Asymmetric peripheral arthritis, or symmetric polyarthritis ³3 joints with active arthritis (tenderness and joint swelling) Negative rheumatoid factor or ANA >1:80 Failed to respond to therapeutic doses of 1 of the NSAIDs

Authors

Clegg DO, Reda DJ, Mejias E, Cannon GW, Weisman MH, Taylor T, Budiman-Mak E, Blackburn WD, Vasey FB, Mahowald ML, Cush JJ, Schumacher HR Jr, Silverman SL, Alepa FP, Luggen ME, Cohen MR, Makkena R, Haakenson CM, Ward RH, Manaster BJ, Anderson RJ, Ward JR, Henderson WG

Publication

Arthritis Rheum. December 1996;39(12):2013–2020

Follow up

36 weeks

Psoriatic Arthritis: Sulfasalazine

Note

Physician global assessment improvement 41.3% (SSZ), 38.4% (placebo) Physician global assessment worsening 6.4% (SSZ), 10.7% (placebo) Patient global assessment improvement 45.9% (SSZ), 41.1% (placebo) Patient global assessment worsening 7.3% (SSZ), 9.8% (placebo) Joint tenderness score improvement 58.7% (SSZ), 47.3% (placebo) Joint tenderness score worsening 11.9% (SSZ), 13.4% (placebo) Joint swelling score improvement 59.6% (SSZ), 51.8% (placebo) Joint swelling score worsening 9.2% (SSZ), 13.4% (placebo) Change of: Duration of morning stiffness (hours) –0.8 (SSZ), –0.3 (placebo) Spondylitis Functional Index (number) –1.2 (SSZ), –0.5 (placebo) Joint tenderness score (number) –10.3 (SSZ), –7.8 (placebo) Joint swelling score (number) –7.8 (SSZ), –8.0 (placebo) Enthesopathy Index (number) –1.5 (SSZ), –0.9 (placebo) Spondylitis Articular Index (number) –0.9 (SSZ), –0.6 (placebo) Chest expansion (cm) +0.1 (SSZ), +0.1 (placebo) Modified Schober’s test (cm) +0.1 (SSZ), 0 (placebo) Occiput-to-wall (cm) +0.3 (SSZ), +0.2 (placebo) Fingers-to-floor (cm) –0.5 (SSZ), 0 (placebo) % body surface area affected –1.0 (SSZ), +1.1 (placebo) ESR (mm/h), –6.4 (SSZ) +1.1 (placebo) C-reactive protein (mg/ml) –0.43 (SSZ), –1 (placebo)

Adverse events

Withdrew from study n = 35 (SSZ), n = 25 (placebo) Withdrawal of consent n =5 (SSZ), n = 5 (placebo) Lost to follow up n = 10 (SSZ), n = 4 (placebo) Lack of improvement or worsened disease n = 5 (SSZ), n = 7 (placebo) Intercurrent illness n = 1 (SSZ), n = 2 (placebo) Adverse drug reaction n = 14 (SSZ), n = 6 (placebo) Gastrointestinal symptoms n = 3 (SSZ), n = 0 (placebo) Dermatologic symptoms n = 2 (SSZ), n = 3 (placebo) Central nervous system symptoms n = 2 (SSZ), n = 1 (placebo) Fever, chills n = 1 (SSZ), n = 0 (placebo) Increased liver enzyme n = 1 (SSZ), n = 0 (placebo)

377

378

Psoriatic Arthritis: Adalimumab

ADEPT-Trial

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial ADEPT: adalimumab Effectiveness in Psoriatic Arthritis Trial

Substance

40 mg adalimumab/2 weeks (n = 147) Placebo (n = 138) Concomitant medication: Prednisone £ 10 mg/day or equivalent Methotrexate (MTX) continued at a stable dose < 30 mg/week Previous medication: No DMARDs other than MTX £4 weeks No oral retinoids £4 weeks No topical treatments for psoriasis £2 weeks No prior anti-TNF treatment NSAIDs

Result

Adalimumab treatment of patients with moderately to severely active psoriatic arthritis significantly improved joint and skin manifestations. It inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life

Patients

PsoA patients with active disease Inadequate response to NSAIDs ³3 swollen joints ³3 tender joints Active or history of active psoriatic skin

Authors

Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, Sharp JT, Ory PA, Perdok RJ, Weinberg MA; adalimumab Effectiveness in Psoriatic Arthritis Trial Study Group

Publication

Arthritis Rheum. October 2005;52(10):3279–3289

Follow up

24 weeks

ACR 20

Week 12: 58% (Ada), 14% (placebo) Week 24: 57% (Ada), 15% (placebo)

ACR 50

Week 12: 36% (Ada), 4% (placebo) Week 24: 39% (Ada), 6% (placebo)

ACR 70

Week 12: 20% (Ada), 1% (placebo) Week 24: 23% (Ada), 1% (placebo)

Psoriatic Arthritis: Adalimumab

Note

Week 12: PASI 50 72% (Ada), 15% (placebo) PASI 75 49% (Ada), 4% (placebo) PASI 90 30% (Ada), 1% (placebo) Week 24: PASI 50 75% (Ada), 12% (placebo) PASI 75 59% (Ada), 1% (placebo) PASI 90 42% (Ada), 0% (placebo) Change of: Sharp score –0.2 (Ada), +1.0 (placebo) HAQ –0.4 (Ada), –0.1 (placebo) SF36 physical component summary +9.3 (Ada), +1.4 (placebo) SF36 mental component summary +1.8 (Ada), +0.6 (placebo)

Adverse events

Upper respiratory tract infections 14.8% (placebo), 12.6% (Ada) Nasopharyngitis 9.3% (placebo), 9.9% (Ada) Injection-site reaction 3.1% (placebo), 6.6% (Ada) Headache 8.6% (placebo), 6.0% (Ada) Hypertension 3.1% (placebo), 5.3% (Ada) Psoriatic arthropathy aggravated 6.8% (placebo), 3.3% (Ada) Arthralgia 5.6% (placebo), 2.0% (Ada) Psoriasis aggravated 6.2% (placebo), 2.0% (Ada) Diarrhea 5.6% (placebo), 2.0% (Ada)

379

380

Psoriatic Arthritis: Adalimumab

ADEPT-Trial (Follow up)

Adalimumab for long-term treatment of psoriatic arthritis: 48 week data from the adalimumab effectiveness in psoriatic arthritis trial ADEPT: adalimumab Effectiveness in Psoriatic Arthritis Trial

Substance

Open label 40 mg adalimumab every 2 weeks after 40 mg adalimumab every 2 weeks (n = 162, second year 147) Placebo (n = 151, second year 139) Concomitant medication: DMARDs were continued NSAIDs were continued Corticosteroids were continued Previous medication: No DMARDs other than methotrexate (MTX) £4 weeks No oral retinoids £4 weeks No topical treatments for psoriasis £2 weeks No prior anti-TNF treatment NSAIDs

Result

Adalimumab was safe and improved joint and skin manifestations in patients with PsoA over 48 weeks. It reduced disability, and inhibited radiographic progression. Addition of methotrexate was not required for clinical or radiographic efficacy

Patients

PsoA patients with active disease ³3 swollen joints ³3 tender joints Active or history of active psoriatic skin Inadequate response NSAIDs or DMARDs

Authors

Gladman DD, Mease PJ, Ritchlin CT, Choy EH, Sharp JT, Ory PA, Perdok RJ, Sasso EH

Publication

Arthritis Rheum. February 2007;56(2):476–488

Follow up

48 weeks

ACR 20

50% (Ada Mono), 63% (Ada + MTX) 48% (Placebo/Ada), 56% (Ada/Ada)

ACR 50

38% (Ada Mono), 49% (Ada + MTX) 34% (Placebo/Ada), 44% (Ada/Ada)

ACR 70

29% (Ada Mono), 31% (Ada + MTX) 20% (Placebo/Ada), 30% (Ada/Ada)

Note

Week 48: PASI 50 67% (Placebo/Ada), 61% (Ada/Ada) PASI 75 58% (Placebo/Ada), 53% (Ada/Ada) PASI 90 46% (Placebo/Ada), 41% (Ada/Ada) PASI 100 33% (Placebo/Ada), 31% (Ada/Ada) Change of comparing weeks 48 and 24: According to Sharp units Mean change –0.1 (Placebo/Ada), –0.2 (Ada/Ada) Increase (>0.5) 28.9% (Placebo/Ada), 9% (Ada/Ada) No change (–0.5 to 0.5) 65.8% (Placebo/Ada), 72.2% (Ada/Ada) Decrease (>–0.5) 5.3% (Placebo/Ada), 18.8% (Ada/Ada) According to Sharp van der Heijde Score Increase (>1.88) 15.1% (Placebo/Ada), 4.2% (Ada/Ada) No change (–1.88–1.88) 82.9% (Placebo/Ada), 89.6% (Ada/Ada) Decrease (<–1.88) 2% (Placebo/Ada), 6.2% (Ada/Ada)

Psoriatic Arthritis: Adalimumab

381

Trial

Safety and efficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic drug therapy

Substance

Adalimumab 40 mg/2 weeks (n = 51) Placebo (n = 51) Followed by a period of open-label treatment with adalimumab 40 mg/2 weeks (n = 97) Patients were randomized depending on whether they have prior been treated with DMARDs Concomitant medication: Prednisone £10 mg/day stable ³4 weeks DMARDs were continued NSAIDs were continued Previous medication: DMARDs No prior anti-TNF treatment No topical treatments for psoriasis £2 weeks No alefacept or siplizumab £12 weeks

Result

Adalimumab treatment of patients with psoriatic arthritis was well tolerated and significantly reduced the signs, symptoms of the disease, and disability

Patients

102 patients with active PsoA Despite DMARD therapy ³3 swollen joints ³3 tender or painful joints Active cutaneous lesion of chronic plaque psoriasis

Authors

Genovese MC, Mease PJ, Thomson GT, Kivitz AJ, Perdok RJ, Weinberg MA, Medich J, Sasso EH; M02-570 Study Group

Publication

J Rheumatol. May 2007;34(5):1040–1050. Epub April 15, 2007

Follow up

24 weeks

ACR 20

Week 12: 39% (Ada), 16% (placebo) Week 24: 65% (Ada), 57% (Ada after Placebo)

ACR 50

Week 12: 25% (Ada), 2% (placebo) Week 24: 43% (Ada), 37% (Ada after Placebo)

ACR 70

Week 12: 14% (Ada), 0% (placebo) Week 24: 27% (Ada), 22% (Ada after Placebo)

382

Psoriatic Arthritis: Adalimumab

Note

Change of: Swollen joint count –1.9 (Placebo, week 12), –5.7 (Ada, week 12), –9.4 (Placebo/Ada, week 24), –9.1 (Ada/Ada week 24) Tender joint count –6.2 (Placebo, week 12), –9.7 (Ada, week 12), –19.3 (Placebo/Ada, week 24), –15.7 (Ada/Ada week 24) Patient assessment of pain (0–100 mm VAS) +0.2 (Placebo, week 12), –15.4 (Ada, week 12), –24.8 (Placebo/Ada, week 24), –19.6 (Ada/Ada week 24) Patient global assessment of disease activity (0–100 mm VAS) –0.4 (placebo, week 12), –14.8 (Ada, week 12), –19.8 (placebo/Ada, week 24), –20.6 (Ada/Ada week 24) Physician global assessment of disease activity (0–100 mm VAS) –9.7 (placebo, week 12), –21.4 (Ada, week 12), –32.3 (Placebo/Ada, week 24), –33.5 (Ada/Ada week 24) HAQ-DI –0.1 (placebo, week 12), –0.3 (Ada, week 12), –0.4 (Placebo/Ada, week 24), –0.3 (Ada/Ada week 24) C-reactive protein (mg/dL) 0 (Placebo, week 12), –0.5 (Ada, week 12), –1.3 (Placebo/Ada, week 24), –0.5 (Ada/Ada week 24) Target lesion score (0–15) –0.3 (Placebo, week 12), –3.7 (Ada, week 12), –4.7 (Placebo/Ada, week 24), –4.5 (Ada/Ada week 24) Physician global assessment for psoriasis 6.7% (Placebo, week 12), 40.6% n (Ada, week 12), 50% (Placebo/Ada, week 24), 56.3% (Ada/Ada week 24) Dermatology Life Quality Index score (0–30) –1.7 (Placebo, week 12), –3.4 (Ada, week 12), –3.9 (Placebo/Ada, week 24), –3.5 (Ada/Ada week 24) SF-36 Physical Component Summary (0–100) 2.8 (Placebo, week 12), 5.7 (Ada, week 12), 11.7 (Placebo/Ada, week 24), 8.6 (Ada/Ada week 24) SF-36 Mental Component Summary (0–100) –0.6 (Placebo, week 12), +1.1 (Ada, week 12), +0.3 (Placebo/Ada, week 24), +1.9 (Ada/Ada week 24) FACIT-F score (0–52) 2.3 (Placebo, week 12), 2.6 (Ada, week 12), 5.6 (Placebo/Ada, week 24), 2.9 (Ada/Ada week 24)

Adverse events

Upper respiratory tract infection 8.2% (placebo), 13.7% (Ada), 6.2% (open label) Injection-site pain 12.2% (placebo), 11.8% (Ada), 0% (open label) Psoriasis aggravated 16.3% (placebo), 3.9% (Ada), 4.1% (open label) Diarrhea 6.1% (placebo), 2.0% (Ada), 2.1% (open label) Back pain 6.1% (placebo), 2.0% (Ada), 2.1% (open label) Psoriatic arthropathy aggravated 14.3% (placebo), 2.0% (Ada), 1.0% (open label) Headache 6.1% (placebo), 0% (Ada), 3.1% (open label)

Psoriatic Arthritis: Adalimumab

383

Adept-Trial

Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) ADEPT: adalimumab Effectiveness in Psoriatic Arthritis Trial

Substance

Open label 40 mg adalimumab every 2 weeks after 40 mg adalimumab every 2 weeks (n = 162, end second year 128) Placebo (n = 151, end second year 115) Concomitant medication: DMARDs were continued NSAIDs were continued Corticosteroids were continued Previous medication: No DMARDs other than methotrexate (MTX) £4 weeks No oral retinoids £4 weeks No topical treatments for psoriasis £2 weeks No prior anti-TNF treatment NSAIDs

Result

Adalimumab of patients with psoriatic arthritis was clinically and radiographically effective during short- and long-term treatment

Patients

PsoA patients with active disease ³3 swollen joints ³3 tender joints Active or history of active psoriatic skin Inadequate response NSAIDs or DMARDs

Authors

Mease PJ, Ory P, Sharp J T, Ritchlin CT, Van den Bosch F, Wellborne F, Birbara C, Thomson GTD, Perdok RJ, Medich J, Wong RL, Gladman DD

Publication

Ann Rheum Dis. 2009;68:702–709

Follow up

144 weeks

ACR 20

58.7% (48 weeks), 57.3% (104 weeks)

ACR 50

42.7% (48 weeks), 45.2% (104 weeks)

ACR 70

27.8 (48 weeks), 29.9% (104 weeks)

384

Note

Psoriatic Arthritis: Adalimumab

Change of (week 104): Modified total Sharp scores 0.5 (Ada/Ada), 0.9 (placebo/Ada) Decrease/no change of Sharp scores 68.8% (placebo/Ada), 79.1% (Ada/Ada) Increase Sharp scores 31.3% (placebo/Ada), 20.9% (Ada/Ada) Change of (baseline to week 104): HAQ-DI -0.3 SF-36 physical component summary +9.4 SF-36 mental component summary +2.3 FACIT-F +6.1 Dermatology life quality index –5.8 Patient’s pain assessment –23.4 Patient’s disease activity assessment –21.6 Improvement in PASI 68.5 (48 weeks) 63.9 (104 weeks)

Adverse events

Respiratory tract infection 21.5% Nasopharyngitis 17.4% Sinusitis in 10.7% Elevation of alanine aminotransferase ³3 times upper normal limit 4.7% ³1 serious adverse event (16.8%) (Cholelithiasis (1%), myocardial infarction, appendicitis, urinary tract infection, osteoarthritis, psoriatic arthropathy, convulsion, nephrolithiasis: 0.7% each) Infections 77/100 patient years Malignancies 0.6/100 patient years Demyelinating disease 0/100 patient years Injection-site reaction 32.7/100 patient years Opportunistic infections excluding tuberculosis 0.6/100 patient years Peritoneal tuberculosis 0.1/100 patient years Lupus and lupus like disease 0/100 patient years Congestive heart failure 0/100 patient years Death 0.4/100 patient years

Psoriatic Arthritis: Alefacept

Trial

Alefacept in combination with Methotrexate for the treatment of psoriatic arthritis: results of a randomized, double-blind, placebo-controlled study

Substance

15 mg alefacept/week i.m. (n = 123) administered for 12 weeks Placebo (n = 62) Concomitant medication: 10–25 mg methotrexate (MTX)/week Prednisone £ 10 mg/day or equivalent NSAIDs at stable doses Previous medication: 10–25 mg MTX/week No other DMARDs £4 weeks No infliximab, adalimumab, or systemic retinoids £3 months No etanercept or ciclosporine £2 months No phototherapy or other DMARDs £4 weeks No high-potency topical steroids £2 weeks

Result

Alefacept treatment of psoriatic arthritis in combination with methotrexate was effective and safe

Patients

185 PsoA patients ³3 swollen joints ³3 tender joints Despite treatment with MTX for ³3 months

Authors

Mease PJ, Gladman DD, Keystone EC; alefacept in Psoriatic Arthritis Study Group

Publication

Arthritis Rheum. May 2006;54(5):1638–1645

Follow up

24 weeks

ACR 20

54% (alefacept), 23% (placebo)

ACR 50

17% (alefacept), 10% (placebo)

ACR 70

7% (alefacept), 2% (placebo)

Note

Change of: Tender joint count –30.9 (alefacept), –17.5 (placebo) Swollen joint count –46.1 (alefacept), –35.1 (placebo) Physician’s global assessment of disease activity –36.5 (alefacept), –22.3 (placebo) Patient’s global assessment of disease activity –22.3 (alefacept), –13.1 (placebo) Patient’s assessment of pain –20.8 (alefacept), –1.7 (placebo) HAQ disability index –24.3 (alefacept), –7.7 (placebo) ESR (mm/h) –7.0 (alefacept), –2.4 (placebo) CRP level (mg/dL) –1.0 (alefacept), –2.7 (placebo) PASI50 response 45% (alefacept), 31% (placebo) PASI75 response 28% (alefacept), 24% (placebo) Physician’s global assessment (PGA) of the skin: “clear” or “almost clear” 31% (alefacept), 24% (placebo)

Adverse events

Increased ALT level 6% (alefacept), 2% (placebo) Back pain 6% (alefacept), 3% (placebo) Nasopharyngitis 5% (alefacept), 11% (placebo) Upper respiratory tract infection 4% (alefacept), 8% (placebo) Nausea 3% (alefacept), 6% (placebo)

385

386

Psoriatic Arthritis: Alefacept

Trial

Alefacept with Methotrexate for treatment of psoriatic arthritis: open-label extension of a randomized, double-blind, placebo-controlled study

Substance

Open label alefacept after 12 weeks of treatment and 12 weeks of observation: 15 mg alefacept/week i.m. (n = 123, entering open label 105) Placebo (n = 62, entering open label 55) Concomitant medication: 10–25 mg MTX/week Prednisone £ 10 mg/day or equivalent NSAIDs at stable doses Previous medication: 10–25 mg methotrexate (MTX)/week No other DMARDs £4 weeks No Infliximab, adalimumab, or systemic retinoids £3 months No etanercept or ciclosporine £2 months No phototherapy or other DMARDs £4 weeks No high-potency topical steroids £2 weeks

Result

Patients with psoriasis and psoriatic arthritis on stable doses of methotrexate derived benefit for both conditions from one or more courses of alefacept. Further benefit in psoriatic arthritis was apparent after a second course of treatment. No additional toxicity was observed

Patients

185 PsoA patients ³3 swollen joints ³3 tender joints Despite treatment with MTX for ³3 months

Authors

Mease PJ, Reich K; alefacept in Psoriatic Arthritis Study Group

Publication

J Am Acad Dermatol. March 2009;60(3):402–411. Epub November 25, 2008

Follow up

6 + 6 months open label extension

ACR 20

55% (alefacept/alefacept), 51% (Placebo/alefacept)

ACR 50

34% (alefacept/alefacept)

ACR 70

12% (alefacept/alefacept)

Note

50% Reduction of PASI score 53% (alefacept), 17% (placebo)

Psoriatic Arthritis: Alefacept Adverse events

Increase ALT level 2% (placebo), 6% (alefacept), 0% (placebo/alefacept), 2% (alefacept/alefacept) Back pain 3% (placebo), 6% (alefacept), 4% (placebo/alefacept), 2% (alefacept/alefacept) Nasopharyngitis 11% (placebo), 5% (alefacept), 2% (placebo/alefacept), 5% (alefacept/alefacept) Upper respiratory infection 8% (placebo), 5% (alefacept), 5% (placebo/alefacept), 3% (alefacept/alefacept) Headache 5% (placebo), 4% (alefacept), 4% (placebo/alefacept), 3% (alefacept/alefacept) Nausea 8% (placebo), 3% (alefacept), 2% (placebo/alefacept), 3% (alefacept/alefacept) Extremity pain 5% (placebo), 1% (alefacept), 0% (placebo/alefacept), 1% (alefacept/alefacept) Sinusitis 5% (placebo), 1% (alefacept), 4% (placebo/alefacept), 1% (alefacept/alefacept) Gastroenteritis 5% (placebo), 0% (alefacept), 0% (placebo/alefacept), 0% (alefacept/alefacept) Fall 0% (placebo), 0% (alefacept), 5% (placebo/alefacept), 0% (alefacept/alefacept)

387

388

Psoriatic Arthritis: Etanercept

Trial

Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial

Substance

Etanercept (2 × 25(MTX)/week, n = 30) Placebo (n = 30) Concomitant medication: £25 mg methotrexate (MTX)/week was continued Other DMARDs were discontinued £10 mg prednisone/day was continued Topical therapies and oral retinoids for psoriasis were discontinued Phototherapy was discontinued NSAIDs at stable doses Previous medication: NSAIDs MTX

Result

Etanercept was effective in treating signs and symptoms of psoriatic arthritis and psoriasis

Patients

Psoriatic arthritis and psoriasis with active disease: active arthritis ³3 swollen joints ³3 tender or painful joints Inadequate response to NSAIDs

Authors

Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ

Publication

Lancet. July 29, 2000;356(9227):385–390

Follow up

12 weeks

ACR 20

73% (ETN), 13% (placebo)

ACR 50

50% (ETN), 3% (placebo)

ACR 70

13% (ETN), 0% (placebo)

Note

PsARC 87% (ETN), 23% (placebo) PASI 75% improvement 26% (ETN), 0% (placebo) Median PASI improvement 46% (ETN), 9% (placebo) Change of: Tender joint count –16.5 (ETN), +3.5 (placebo) Swollen joint count –11 (ETN), –3.7 (placebo) HAQ –1.2 (ETN), –0.1 (placebo) ESR (mm/h) –17 (ETN), +2 (placebo) CRP (mg/L) –10 (ETN), +2 (placebo)

Adverse events

Respiratory tract infection 13% (placebo), 27% (ETN) Pharyngitis 10% (placebo), 17% (ETN) Rhinitis 13% (placebo), 17% (ETN) Sinusitis 7% (placebo), 10% (ETN) Influenza syndrome 20% (placebo), 0% (ETN) Injection-site bruise 17% (placebo), 20% (ETN) Injection-site reaction 3% (placebo), 20% (ETN) Headache 10% (placebo), 13% (ETN) Fatigue 0% (placebo), 13% (ETN)

Psoriatic Arthritis: Etanercept

Trial

Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with Etanercept

Substance

Etanercept 25 mg twice weekly (n = 141) Originally randomized to ETN (n = 70) to placebo (n = 71) Concomitant medication: £10 mg prednisone/day, dose modifications were permitted +NSAIDs not exceeding maximum. dose, dose modifications were permitted +MTX £ 25 mg/week, dose modifications were permitted Topical vitamin A or D analog preparations and anthralin were permitted only for treatment of the scalp, axillae, and groin Previous medication: NSAIDs No DMARDs £4 weeks No Phototherapy No oral retinoids

Result

Etanercept treatment led to a significant inhibition of radiographic progression in patients with psoriatic arthritis

Patients

141 psoriatic arthritis patients ³3 swollen and 3 tender/painful joints Inadequate response to NSAID therapy ³1 of the following DIP joint involvement Polyarticular arthritis; Arthritis mutilans Asymmetric peripheral arthritis Ankylosing spondylitis-like arthritis Stable psoriasis Target lesion with a diameter of at least 2 cm at any location other than the scalp, axillae, or groin

Authors

Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, Salonen D, Rubenstein J, Sharp JT, Dunn M, Tsuji W

Publication

J Rheumatol. April 2006;33(4):712–721. Epub February 1, 2006

Follow up

2 years

ACR 20

ACR20 63% (Placebo-ETN), 64% (ETN-ETN)

ACR 50

ACR20 49% (Placebo-ETN), 44% (ETN-ETN)

ACR 70

ACR20 13% (Placebo-ETN), 23% (ETN-ETN)

Note

Progression of total Sharp score 63% (Placebo-ETN), 86% (ETN-ETN) Progression of erosions 74% (Placebo-ETN), 87% (ETN-ETN) Progression of joint space narrowing 80% (Placebo-ETN), 87% (ETN-ETN) PsARC 80% (Placebo-ETN), 84% (ETN-ETN) PASI 50 73% (Placebo-ETN), 62% (ETN-ETN) Achieving clear or almost clear target lesions 49% (Placebo-ETN), 62% (ETN-ETN)

Adverse events

Injection-site reactions 27% (Placebo-ETN), 10% (ETN-ETN) Severe transient elevated alanine n = 1 Moderate left shoulder fracture/dislocation n = 1 Mild numbness in fingers n = 1 Infections n = 3

389

390

Psoriatic Arthritis: Etanercept

EDUCATE-Trial

Use of Etanercept for psoriatic arthritis in the dermatology clinic: the Experience Diagnosing, Understanding Care, and Treatment with Etanercept (EDUCATE), study EDUCATE: Experience Diagnosing, Understanding Care, and Treatment with Etanercept

Substance

Etanercept therapy 50 mg s.c. one time per week Concomitant medication: Prednisone £ 10 mg/day Acetaminophen and NSAIDs were allowed Methotrexate (MTX) £ 20 mg/week was continued at stable dosage Previous medication: No prior TNF antagonists No psoralen-ultraviolet A therapy No oral retinoids No topical corticosteroids No Vit. A or D analogues NSAIDs No DMARDs £4 weeks

Result

Etanercept was an effective treatment of patients with psoriatic arthritis. Etanercept was well tolerated

Patients

1,122 patients who had active psoriatic arthritis Plaque psoriasis involving ³10% body surface area and joint disease ³2 swollen and ³2 tender/painful joints for ³3 months ³1 joint with sacroiliitis or spondylitis

Authors

Gottlieb AB, Kircik L, Eisen D, Jackson JM, Boh EE, Strober BE, Frankel E, Xia HA, Stevens SR

Publication

J Dermatol Treat. 2006;17(6):343–352

Follow up

24 weeks

Note

Responders 77.1% Decrease of psoriasis –16.9% of the body surface Improvement of patient’s global assessment –2.3 Pain Score –2.3 Morning stiffness –75 min Tender joint count –7

Adverse events

Total 3.1% Chest pain 0.3% Diverticulitis 0.3% Condition aggravated 0.2% Headache 0.2%

Psoriatic Arthritis: Golimumab

391

GO-REVEAL Trial

Golimumab, a new human tumor necrosis factor alpha antibody, administered every 4 weeks as a subcutaneous injection in psoriatic arthritis: 24-week efficacy and safety results of a randomized, placebo-controlled study

Substance

Subcutaneous injections of placebo (n = 113) Golimumab 50 mg (n = 146) Golimumab 100 mg (n = 146) every 4 weeks through week 20 Concomitant medication: Stable doses of methotrexate (MTX) Stable doses of NSAIDs Prednisone £10 mg/day Previous medication: No previous anti-TNF agents No previous rituximab No previous natalizumab No previous cytotoxic agents NSAIDs MTX

Result

Treatment of psoriatic arthritis with golimumab (50 and 100 mg) significantly improved skin and joint symptoms of the disease

Patients

405 active psoriasis arthritis patients ³3 tender and swollen joints Negative rheumatoid factor Minimum one plaque psoriasis >2 cm Despite NSAID therapy Despite DMARD therapy

Authors

Kavanaugh A, McInnes I, Mease P, Krueger GG, Gladman D, Gomez-Reino J, Papp K, Zrubek J, Mudivarthy S, Mack M, Visvanathan S, Beutler A

Publication

Arthritis Rheum. April 2009;60(4):976–986

Follow up

24 weeks

ACR20

Week 14: 48% (all Golimumab), 51% (Golimumab 50 mg), and 45% (Golimumab 100 mg), 9% (placebo)

392

Note

Psoriatic Arthritis: Golimumab

Achieving Psoriatic Arthritis Response Criteria 29% (placebo), 70% (50 mg Gol), 85% (100 mg Gol) EULAR response 24% (placebo), 64% (50 mg Gol), 78% (100 mg Gol) Patients with dactylitis 22% (placebo), 16% (50 mg Gol), 14% (100 mg Gol) Patients with enthesitis 69% (placebo), 49% (50 mg Gol), 50% (100 mg Gol) PASI50 8% (placebo), 76% (50 mg Gol), 82% (100 mg Gol) PASI75 1% (placebo), 56% (50 mg Gol), 66% (100 mg Gol) PASI90 0% (placebo), 32% (50 mg Gol), 32% (100 mg Gol) Improvement of target lesion score 1.0% (placebo), 60% (50 mg Gol), 83% (100 mg Gol) Change of: DAS28-CRP –0.12 (placebo), –1.43 (50 mg Gol), –1.56 (100 mg Gol) Dactylitis score –42% (placebo), –100% (50 mg Gol), –100% (100 mg Gol) MASES –12% (placebo), –60% (50 mg Gol), –67% (100 mg Gol) Morning stiffness –20.4 (placebo), –67.2 (50 mg Gol), –90.1 (100 mg Gol) NAPSI –0% (placebo), –33% (50 mg Gol), –54% (100 mg Gol)

Adverse events

Upper respiratory tract infection 6% (placebo), 12% (50 mg Gol), 9% (100 mg Gol) Nasopharyngitis 4% (placebo), 7% (50 mg Gol), 13% (100 mg Gol) Headache 7% (placebo), 5% (50 mg Gol), 6% (100 mg Gol) Back pain 4% (placebo), 4% (50 mg Gol), 5% (100 mg Gol) Diarrhea 4% (placebo), 3% (50 mg Gol), 5% (100 mg Gol) Hypertension 4% (placebo), 7% (50 mg Gol), 1% (100 mg Gol) Cough 4% (placebo), 5% (50 mg Gol), 3% (100 mg Gol) Injection-site erythema 2% (placebo), 3% (50 mg Gol), 4% (100 mg Gol) Nausea 4% (placebo), 3% (50 mg Gol), 4% (100 mg Gol) Elevated ALT level 4% (placebo), 3% (50 mg Gol), 3% (100 mg Gol)

Psoriatic Arthritis: Infliximab

Impact-Trial

Sustained benefits of Infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the Infliximab multinational psoriatic arthritis controlled trial (IMPACT) IMPACT: Infliximab Multinational Psoriatic Arthritis Controlled Trial

Substance

Infliximab (n = 52, 5 mg/kg) Placebo (n = 52) at weeks 0, 2, 6, and 14 Cross over for placebo treated patients after week 16

393

Concomitant medication: Maximum 1 DMARD: £15 mg/week methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine, intramuscular gold, D-penicillamine, or azathioprine at stable doses £10 mg prednisone or equivalent Stable doses of NSAIDs Standard topical treatments for psoriatic lesions (e.g., topical steroids) were permitted Psoralen ultraviolet A was not permitted Previous medication: No previous anti-TNF agents No previous rituximab No previous natalizumab No previous cytotoxic agents NSAIDs MTX Result

5 mg/kg infliximab significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active psoriatic arthritis that had been resistant to DMARD therapy. The benefits were sustained through 50 weeks

Patients

104 patients who had previous failed of treatment with ³1 DMARD ³5 swollen and tender joints ESR ³28 mm/h CRP ³15 mg/L Morning stiffness ³45 min Negative for rheumatoid factor and tuberculin skin test

Authors

Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen J

Publication

Arthritis Rheum. April 2005;52(4):1227–1236

Follow up

50 weeks

394

Psoriatic Arthritis: Infliximab

ACR 20

Week 16: 9.6% (placebo), 65.4% (IFX) Week 50: 68% (Placebo/IFX), 69.4% (IFX/IFX)

ACR 50

Week 16: 0% (placebo), 46.2% (IFX) Week 50: 42.0% (Placebo/IFX), 53.1% (IFX/IFX)

ACR 70

Week 16: 0% (placebo), 28.8% (IFX) Week 50: 34.0% (Placebo/IFX), 38.8% (IFX/IFX)

Note

Change of (week 16): Tender joint count +23.6% (placebo), –55.2% (IFX) Swollen joint count +1.8% (placebo), –59.9% (IFX) Patient’s pain assessment +8.7% (placebo), –53.7%(IFX) Patient’s global disease assessment +13.9% (placebo), –47.5% (IFX) Physician’s global disease assessment +4.7% (placebo), –58.4% (IFX) CRP (mg/dL) –3.6 (placebo), –57.1 (IFX) HAQ score +1.6% (placebo), –49.8% (IFX) DAS28 improvement –2.8% (placebo), –45.5% (IFX) Enthesitis –31.4% (placebo), –13.5% (IFX) Dactylitis score –29.2% (placebo), –84.5% (IFX) Change of (week 50): Tender joint count –62.3% (Placebo/IFX), –66.9% (IFX/IFX) Swollen joint count –76.8% (Placebo/IFX), –72.5% (IFX/IFX) Patient’s pain assessment –54.1% (Placebo/IFX), –54.1% (IFX/IFX) Patient’s global disease assessment –49.5% (Placebo/IFX), –50.0% (IFX/IFX) Physician’s global disease assessment –67.4% (Placebo/IFX), –70.3% (IFX/IFX) CRP (mg/dL) –48.2 (Placebo/IFX), –25.7 (IFX/IFX) HAQ score –49.2% (Placebo/IFX), –42.5% (IFX/IFX) DAS28 improvement –47.8% (Placebo/IFX), –48.2% (IFX/IFX) Enthesitis –6.1% (Placebo/IFX), –8.2% (IFX/IFX) Dactylitis score –81.5% (placebo/IFX), –91.0% (IFX/IFX)

Adverse events

Headache n = 3 (placebo), n = 4 (IFX) Bronchitis n = 3 (placebo), n = 4 (IFX) Upper respiratory tract infection n = 5 (placebo), n = 1 (IFX) Influenza-like symptoms n = 4 (placebo), n = 1 (IFX) Rhinitis n = 2 (placebo), n = 3 (IFX) Rash n = 2 (placebo), n = 3 (IFX) Rectal bleeding due to diverticulitis n = 1 (placebo), n = 0 (IFX) Infusion reactions n = 5 (placebo), n = 4 (IFX), n = 3 (Placebo/IFX), n = 4 (IFX/IFX) Open label phase: Respiratory tract infection n = 23 Headache n = 7 Dizziness n = 6 Influenza-like symptoms n = 5 patients Nonproductive cough n = 5 patients Rhinitis n = 4 patients Hypertension n = 4 Sinusitis n = 4

Psoriatic Arthritis: Infliximab

395

Impact-2-Trial

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial; Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) IMPACT: Infliximab Multinational Psoriatic Arthritis Controlled Trial

Substance

Infliximab (n = 100, 5 mg/kg) at weeks 0, 2, 6, and 14 Placebo (n = 100) Concomitant medication: £10 mg prednisone or equivalent Methotrexate £25 mg/week Previous medication: No intra-articular corticosteroids was prohibited £4 weeks prior screening No DMARDs £4 weeks prior screening No topical or systemic drugs/treatments for psoriasis NSAIDs

Result

Infliximab (5 mg/kg) treatment through 24 weeks significantly improved signs and symptoms of active psoriatic arthritis, including dactylitis and enthesopathy, and associated psoriasis

Patients

200 PsoA patients with active disease: ³5 tender and swollen joints CRP ³ 15 mg/L Morning stiffness ³45 min ³1 active plaque psoriasis target lesion ³2 cm in diameter Despite DMARD or NSAID treatment Negative rheumatoid factor

Authors

Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, Guzzo C, Zhou B, Dooley LT, Kavanaugh A; IMPACT 2 Trial Investigators

Publication

Ann Rheum Dis. August 2005;64(8):1150–1157. Epub January 27, 2005

Follow up

24 weeks

ACR 20

16% (placebo), 54% (IFX)

ACR 50

4% (placebo), 41% (IFX)

ACR 70

2% (placebo), 27% (IFX)

396

Note

Psoriatic Arthritis: Infliximab

Achieving PsARC 32% (placebo), 70% (IFX) Patients with >1 dactylitis digits (at the ends), 34% (placebo), –12% (IFX) Patients with enthesopathy (at the end), 37% (placebo), 20% (IFX) PASI response >50% 8% (placebo), 75% (IFX) PASI response >50% 1% (placebo), 60% (IFX) PASI response >50% 0% (placebo), 39% (IFX) PASI response of patients with >3% body surface area affected with psoriasis (baseline), 87% (placebo), 83% (IFX) Change of: Number of swollen joints –23.5 (placebo), –58.0 (IFX) Number of tender joints –14.9 (placebo), –54.1 (IFX) CRP (mg/L) +7.0 (placebo), –34.7 (IFX) Physician’s global assessment of disease activity (VAS) –18.0 (placebo), –57.3 (IFX) Patient’s global assessment of disease activity (VAS) –7.2 (placebo), –35.1 (IFX) Patient’s assessment of pain (VAS) +10 (placebo), –37.4 (IFX) HAQ disability index +19.4 (placebo), –46.0 (IFX) Duration of morning stiffness +152.0 min (placebo), –43.1 min (IFX) Improvement in target lesion score –1.0 (placebo), 64.2 (IFX) SF-36 physical component –8.2 (placebo), –9.8 (IFX) SF-36 mental component –11.6 (placebo), –11.9 (IFX)

Adverse events

Upper respiratory tract infections 14% (placebo), 10% (IFX) Headache 5% (placebo), 6% (IFX) Increased ALT 1% (placebo), 6% (IFX) Pharyngitis 4% (placebo), 5% (IFX) Sinusitis 4% (placebo), 5% (IFX) Dizziness 5% (placebo), 4% (IFX) Infusion reactions 6% (placebo), 7% (IFX)

Psoriatic Arthritis: Infliximab

397

IMPACT-Trial

The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year IMPACT: Infliximab Multinational Psoriatic Arthritis Controlled Trial

Substance

Infliximab (n = 52, 5 mg/kg) Placebo (n = 52), at weeks 0, 2, 6, and 14 Cross over for placebo treated patients after week 16 Concomitant medication: Maximum 1 DMARD: £15 mg/week methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine, intramuscular gold, penicillamine, or azathioprine at stable doses £10 mg prednisone or equivalent Stable doses of NSAIDs Standard topical treatments for psoriatic lesions (e.g., topical steroids) were permitted Psoralen ultraviolet A was not permitted Previous medication: No previous anti-TNF agents No previous rituximab No previous natalizumab No previous cytotoxic agents NSAIDs MTX

Result

Radiographic progression in patients with psoriatic arthritis was inhibited by infliximab treatment

Patients

104 patients who had previous failed of treatment with ³1 DMARDs ³5 swollen and tender joints ESR ³28 mm/h CRP ³15 mg/L Morning stiffness ³45 min Negative for rheumatoid factor and tuberculin skin test

Authors

Kavanaugh A, Antoni CE, Gladman D, Wassenberg S, Zhou B, Beutler A, Keenan G, Burmester G, Furst DE, Weisman MH, Kalden JR, Smolen J, van der Heijde D

Publication

Ann Rheum Dis. August 2006;65(8):1038–1043. Epub January 26, 2006

398

Psoriatic Arthritis: Infliximab

Follow up

50 weeks

ACR 20

Week 16: 10% (placebo), 65% (IIFX) Week 50: 68% (Placebo/IFX), 69% (IFX/IFX)

Note

Change of: Sharp van der Heijde Score Overall: –1.95 (Placebo/IFX), –1.52 (IFX/IFX) Hands: –1.37 (Placebo/IFX), –0.87 (IFX/IFX) Feet: –0.53 (Placebo/IFX), –0.65 (IFX/IFX) Erosion score Overall –1.48 (Placebo/IFX), –0.98 (IFX/IFX) Hands: –0.94 (Placebo/IFX), –0.68 (IFX/IFX) Feet: –0.56 (Placebo/IFX), –0.30 (IFX/IFX) Joint space narrowing Overall: –0.47 (Placebo/IFX), –0.54 (IFX/IFX) Hands: –0.43 (Placebo/IFX), –0.19 (IFX/IFX) Feet: –0.03 (Placebo/IFX), –0.35 (IFX/IFX)

Psoriatic Arthritis: Infliximab

IMPACT-2 Trial

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial IMPACT: Infliximab Multinational Psoriatic Arthritis Controlled Trial

Substance

Infliximab (n = 100, 5 mg/kg) at weeks 0, 2, 6, and 14 Placebo (n = 100) Patients were crossed over to IFX after 24 weeks

399

Concomitant medication: £10 mg prednisone or equivalent Methotrexate £25 mg/week Previous medication: No intra-articular corticosteroids was prohibited £4 weeks prior screening No DMARDs £4 weeks prior screening No topical or systemic drugs/treatments for psoriasis NSAIDs Result

Infliximab was clinically highly effective and well tolerated in patients with psoriatic arthritis through 1 year of treatment

Patients

200 PsoA patients with active disease Despite DMARD or NSAID treatment ³5 tender and swollen joints CRP ³15 mg/L Morning stiffness ³45 min ³1 active plaque psoriasis target lesion ³2 cm in diameter Negative rheumatoid factor

Authors

Kavanaugh A, Krueger GG, Beutler A, Guzzo C, Zhou B, Dooley LT, Mease PJ, Gladman DD, de Vlam K, Geusens PP, Birbara C, Halter DG, Antoni C; IMPACT 2 Study Group

Publication

Ann Rheum Dis. April 2007;66(4):498–505. Epub November 17, 2006

Follow up

54 weeks

ACR 20

Week 24: 16.0% (placebo), 54.0% (IFX) Week 54: 61.4% (Placebo/IFX), 58.9% (IFX/IFX)

ACR 50

Week 24: 4.0% (placebo), 41.0% (IFX) Week 54: 43.4% (Placebo/IFX), 36.7% (IFX/IFX)

ACR 70

Week 24: 2.0% (placebo), 27.0% (IFX) Week 54: 25.3% (Placebo/IFX), 22.2% (IFX/IFX)

400

Note

Psoriatic Arthritis: Infliximab

After 24 weeks: Patients with at least one dactylitis digits 34.0% (placebo), 11.8% (IFX) Patients with enthesopathy 37.2% (placebo), 20.4% (IFX) PASI ³50% improvement PASI 8.0% (placebo), 74.7% (IFX) PASI ³75% improvement 1.1% (placebo), 60.2% (IFX) PASI ³90% improvement 0% (placebo), 38.6% (IFX) After 54 weeks: Patients with at least one dactylitis digits –14.8% (Placebo/IFX), –12.2% (IFX/IFX) Patients with enthesopathy –19.8% (Placebo/IFX), –18.9% (IFX/IFX) PASI ³50% improvement 79.5% (Placebo/IFX), 69.4% (IFX/IFX) PASI ³75% improvement 60.3% (Placebo/IFX), 50.0% (IFX/IFX) PASI ³90% improvement 42.2% (Placebo/IFX), 41.7% (IFX/IFX) Change of (week 24): Number of swollen joints –23.5% (placebo), –58.0% (IFX) Number of tender joints –14.9% (placebo), –54.1% (IFX) CRP +7% (placebo), –34.7% (IFX) Physician’s global assessment –18.0% (placebo), –57.3% (IFX) Patient’s global assessment –7.2% (placebo), –35.1% (IFX) Patient’s assessment of pain (VAS) +10.0% (placebo), –37.4% (IFX) HAQ disability index –1.1% (placebo), –0.7% (IFX) Morning stiffness (duration) +152.0% (placebo), –43.1% (IFX) SF 36 physical component –1.3 (placebo), –7.7 (IFX) SF 36 mental component –0.4 (placebo), –3.9 (IFX) Change of (week 54): Number of swollen joints –57.5% (Placebo/IFX), –59.6% (IFX/IFX) Number of tender joints –54.8% (Placebo/IFX), –52.0% (IFX/IFX) CRP –16.6% (Placebo/IFX) –8.3% (IFX/IFX) Physician’s global assessment –66.5% (Placebo/IFX), –62.6% (IFX/IFX) Patient’s global assessment –45.9% (Placebo/IFX), –31.3% (IFX/IFX) Patient’s assessment of pain (VAS) –48.9% (Placebo/IFX), –38.9% (IFX/IFX) HAQ disability index –35.5% (Placebo/IFX), –41.2% (IFX/IFX) Morning stiffness (duration) –29.0% (Placebo/IFX), –12.4% (IFX/IFX) SF 36 physical component 10.7 (Placebo/IFX), –8.8 (IFX/IFX) SF 36 mental component –2.8 (Placebo/IFX), –3.7 (IFX/IFX)

Adverse events

Total 85% (week 54 both groups), 67% (week 24/IFX) Infusion reactions 2.1% (IFX), 1.6% (placebo) Abnormal ALT and AST values 4.2% (IFX), 2.1% (placebo) Serious infections n = 3 (IFX), n = 2 (placebo) Malignancies n = 1 (basal cell skin cancer, placebo), n = 1 (stage I Hodgkin’s lymphoma, IFX)

Psoriatic Arthritis: Infliximab

IMPACT-2 Trial

Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through 1 year of treatment: Results from the induction and Maintenance psoriatic arthritis clinical trial 2 (IMPACT) IMPACT: Infliximab Multinational Psoriatic Arthritis Controlled Trial

Substance

Infliximab (n = 100, 5 mg/kg) at weeks 0, 2, 6, and 14 Placebo (n = 100) Patients were crossed over to IFX after 24 weeks

401

Concomitant medication: £10 mg prednisone or equivalent Methotrexate £25 mg/week Previous medication: No intra-articular corticosteroids was prohibited £4 weeks prior screening No DMARDs £4 weeks prior screening No topical or systemic drugs/treatments for psoriasis NSAIDs Result

Infliximab significantly inhibited radiographic progression in patients with psoriatic arthritis

Patients

200 PsoA patients with active disease Despite DMARD or NSAID treatment ³5 tender and swollen joints CRP ³15 mg/L Morning stiffness ³45 ³1 active plaque psoriasis target lesion ³2 cm in diameter Negative rheumatoid factor

Authors

van der Heijde D, Kavanaugh A, Gladman DD, Antoni C, Krueger GG, Guzzo C, Zhou B, Dooley LT, de Vlam K, Geusens P, Birbara C, Halter D, Beutler A

Publication

Arthritis Rheum. August 2007;56(8):2698–2707

Follow up

54 weeks

Note

Radiological Progression (% of patients, week 24): Total Sharp van der Heijde score 12% (placebo), 3% (IFX) Erosion score 12% (placebo), 2% (IFX) Joint space narrowing 11% (placebo), 1% (IFX) Radiological progression (% of patients, week 54): Total Sharp van der Heijde score 8% (placebo), 1% (IFX) Erosion score 9% (placebo), 1% (IFX) Joint space narrowing 6% (placebo), 0% (IFX) Change of Sharp van der Heijde score (week 24): Total score +0.82 (placebo), –0.70 (IFX) Erosion score +0.51 (placebo), –0.56 (IFX) Joint space narrowing +0.31 (placebo), –0.14 (IFX) Hands +0.74 (placebo), –0.31 (IFX) Feet +0.08 (placebo), –0.39 (IFX) Change of sharp van der Heijde score (week 54): Heijde score +0.53 (Placebo/IFX), –0.94 (IFX/IFX) Erosion score +0.42 (Placebo/IFX), –0.61 (IFX/IFX) Joint space narrowing +0.11 (Placebo/IFX), –0.33 (IFX/IFX) Hands +0.54 (placebo), –0.45 (IFX) Feet +0.01 (placebo), –0.48 (IFX)

402

Psoriatic Arthritis: Infliximab

Impact-Trial

2-year efficacy and safety of Infliximab treatment in patients with active psoriatic arthritis: findings of the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) IMPACT: Infliximab Multinational Psoriatic Arthritis Controlled Trial

Substance

Open label infliximab (n = 104, 5 mg/kg) After: 5 mg/kg infliximab (n = 52) Placebo (n = 52) at weeks 0, 2, 6, and 14 Cross over for placebo treated patients after week 16 Concomitant medication: Maximum 1 DMARD: £15 mg/week methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine, intramuscular gold, penicillamine, or azathioprine at stable doses £10 mg prednisone or equivalent Stable doses of NSAIDs Standard topical treatments for psoriatic lesions (e.g., topical steroids) were permitted Psoralen ultraviolet A was not permitted Previous medication: No previous anti-TNF agents No previous rituximab No previous natalizumab No previous cytotoxic agents NSAIDs MT

Result

Infliximab treatment led to a sustained improvement in joint and skin symptoms, inhibited radiographic progression in patients with treatmentrefractory psoriatic arthritis

Patients

104 patients who had previous failed of treatment with ³1 DMARDs ³5 swollen and tender joints ESR ³28 mm/h CRP ³15 mg/L Morning stiffness ³45 min Negative for rheumatoid factor and tuberculin skin test

Authors

Antoni CE, Kavanaugh A, van der Heijde D, Beutler A, Keenan G, Zhou B, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman DD, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen JS

Publication

J Rheumatol. May 2008;35(5):869–876. Epub March 15, 2008

Follow up

98 weeks

Psoriatic Arthritis: Infliximab

ACR 20

61.5% (IFX)

ACR 50

44.9% (IFX)

ACR 70

34.6% (IFX)

Note

Sharp van der Heijde score 5.98 (first year), 5.74 (second year) Change of: Tender joint count –50.8% Swollen joint count –58.9% Patient pain assessment –46.4% Patient global disease assessment –40.3% Physician global disease assessment –54.8% CRP –16.1% HAQ –37.7% DAS28 –42.4% Patients with enthesitis –12.8% No. of digits with dactyliti (mean) –0.19 PsARC –66.7% PASI –4.2

Adverse events

All events 94.9% Treatment-related events 66.7% Infusion-associated adverse events 5.1% Surgical procedures n = 4 Events of atrial fibrillation (in the same patient) n = 2 Infections (knee wound and bowel) n = 2 Neoplasms (benign abdominal mutinous cystoma and non-resectable pancreatic ductal adenocarcinoma) n = 2 Urinary incontinence n = 1 Abdominal pain n = 1 Exacerbation of psoriasis n = 1 Mild hemangioma and another had leukocythemia n = 1

403

404

Psoriatic Arthritis: Ustekinumab

Trial

Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomized, double-blind, placebo-controlled, crossover trial

Substance

Ustekinumab 90 mg/week for 4 weeks Followed by placebo at weeks 12 and 16 (n = 76; Group 1) Placebo (weeks 0–3) for 4 weeks Followed by ustekinumab (90 mg/week) at weeks 12 and 16 (n = 70; Group 2) Concomitant medication: Methotrexate £15 mg/week £10 mg prednisone or equivalent NSAIDs were permitted Previous medication: DMARDs Anti-TNF NSAIDs

Result

Ustekinumab was well tolerated and reduced clinical manifestations of psoriatic arthritis and diminished skin lesions compared with placebo

Patients

146 active psoriasis arthritis patients CRP ³15 mg/L Morning stiffness ³45 min ³3 tender and swollen joints

Authors

Gottlieb A, Menter A, Mendelsohn A, Shen YK, Li S, Guzzo C, Fretzin S, Kunynetz R, Kavanaugh A

Publication

Lancet. February 21, 2009;373(9664):633–640. Epub February 11, 2009

Follow up

12 weeks and 24 weeks open label extension

ACR 20

Week 12: 42% (Group 1), 14% (Group 2) Week 24: 45% (Group 1), 51% (Group 2)

ACR 50

Week 12: 25% (Group 1), 7% (Group 2)

ACR 70

Week 12: 11% (Group 1), 0% (Group 2)

Psoriatic Arthritis: Ustekinumab

Note

Week 12: Psoriasis affecting 3% or more body surface area n = 64 (Group 1), n = 60 (Group 2) PASI 75 52% (Group 1), 5% (Group 2) 75% improvement in psoriasis area and severity index 52% (Group 1), 5% (Group 2) Good-to-moderate DAS28 rate 58% (Group 1), 30% (Group 2) Patients with enthesopathy 23% (Group 1), 42% (Group 2) Change of (week 12): HAQ –42% (Group 1), –14% (Group 2)

Adverse Events

Nasopharyngitis 12% (Group 1), 7% (Group 2) Diarrhea 9% (Group 1), 4% (Group 2) CRP increase 7% (Group 1), 4% (Group 2) Headache 7% (Group 1), 4% (Group 2) Sinusitis 5% (Group 1), 5% (Group 2) Back pain 7% (Group 1), 2% (Group 2) Influenza 5% (Group 1), 4% (Group 2) Nausea 4% (Group 1), 5% (Group 2) ALT increase 5% (Group 1), 2% (Group 2) Arthralgia 5% (Group 1), 2% (Group 2) Bronchitis 3% (Group 1), 5% (Group 2)

405

Systemic Lupus Erythematosus

Corticosteroids

Trial

A double-blind controlled trial of methylprednisolone infusions in systemic lupus erythematosus using individualized outcome assessment

Substance

Three daily infusions of methylprednisolone 100 mg (n = 10) Methylprednisolone 1 g (n = 11) Alternative dose: Nine patients who not responded satisfactorily to the first set of infusions were treated with a second set of infusions at the alternative dose Concomitant medication: No limitations about any other drug Oral corticosteroids were withdrawn on the day of infusion

Result

Half of patients with severe episodes of systemic lupus erythematosus treated with infusions of methylprednisolone displayed improvement at 3 months, three doses of 1 g did not appear to have any advantage over three of 100 mg

Patients

21 SLE patients with active disease Failed to chloroquine (no precise number of patients) Failed to oral prednisolone (£15 mg/day, n = 21) Various features: Febrile without evidence of infection Cerebral or renal problems Rash or arthralgia Hematological or serositis

Authors

Edwards JC, Snaith ML, Isenberg DA

Publication

Ann Rheum Dis. October 1987;46(10):773–776

Follow up

3 months

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_4, © Springer-Verlag London Limited 2011

407

408

Systemic Lupus Erythematosus: Corticosteroids

Note

Outcome: Ideal n = 2 (1 g), n = 1 (100 mg) Useful n = 3 (1 g), n = 5 (100 mg) n = 2 (1 g alternative dose), n = 2 (100 mg, alternative dose) Static n = 4 (1 g), n = 2 (100 mg) n = 3 (1 g alternative dose), n = 2 (100 mg, alternative dose) Worse n = 2 (1 g), n = 2 (100 mg)

Adverse events

No gastrointestinal bleeding No osteonecrosis occurred Blood pressure rose temporarily in some patients Headache, mood swings, and other non-specific symptoms Plasma urea levels rose in many cases Raised serum glucose levels were transient (No percentages are listed)

Systemic Lupus Erythematosus: Corticosteroids

409

FLOAT-trial

Flares in lupus: Outcome Assessment Trial (FLOAT), a comparison between oral methylprednisolone and intramuscular Triamcinolone FLOAT: Flares in lupus: Outcome Assessment Trial

Substance

100 mg Triamcinolone injection (n = 26) Oral prednisone or methylprednisolone (n = 24) Concomitant medication: Prednisone was permitted to treat flares Cytotoxic agents were permitted to treat flares DMARDs were permitted to treat flares NSAID permitted to treat flares

Result

Triamcinolone and oral methylprednisolone treatment of SLE patients suffering from a mild or moderate flare equally reduced clinical signs and symptoms of the disease. Triamcinolone lead to a more rapid response than oral methylprednisolone

Patients

50 patients with SLE presenting Mild or moderate flare: SELENA-SLEDAI score of >3 points, total score <12 New or worsening discoid, photosensitive, or other Lupus rash, nasopharyngeal ulcers, pleuritis, pericarditis, arthritis, or fever not attributable to infection Increase in prednisone, but not to >0.5 mg/kg/day Initiation of either hydroxychloroquine or non-steroidal anti-inflammatory agents Change in the physician’s global assessment by ³1.0 but remaining £2.5

Authors

Danowski A, Magder L, Petri M

Publication

J Rheumatol. January 2006;33(1):57–60

Follow up

4 weeks

Note

Lupus flare gone 25% (methylprednisolone), 38% (triamcinolone) Lupus flare much better 29.1% (methylprednisolone), 23.8% (triamcinolone) Lupus flare a little better 20.8% (methylprednisolone), 23.5% (triamcinolone) No change 16.6% (methylprednisolone), 9.5% (triamcinolone) Lupus flare even worse 8.3% (methylprednisolone), 0% (triamcinolone) SF 36 improved 66.6% (methylprednisolone), 73.9% (triamcinolone) Rapid response 41.6% (methylprednisolone), 69.5% (triamcinolone)

Adverse events

No side effects were seen with either treatment

410

Systemic Lupus Erythematosus: Corticosteroids

Trial

The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial

Substance

Prednisone 30 mg/day for 2 weeks Prednisone 20 mg/day for 1 week Prednisone 10 mg/day for 1 week (n = 21) Placebo (n = 20) Concomitant medication: Prednisone £15 mg/day at study entry DMARDs were continued at stable doses (³2 months prior randomization) Cyclophosphamide was permitted

Result

Short-term, moderate-dose corticosteroid treatment seemed to prevent severe flares of SLE in patients with serologically active but clinically stable disease

Patients

154 SLE patients with inactive disease History of anti DNS antibodies SLEDAI score £4 Serologic flare (n = 41): Elevations of C3a levels >50% Elevations of anti-dsDNA levels >25% Clinically stable => Randomization

Authors

Tseng CE, Buyon JP, Kim M, Belmont HM, Mackay M, Diamond B, Marder G, Rosenthal P, Haines K, Ilie V, Abramson SB

Publication

Arthritis Rheum. November 2006;54(11):3623–3632

Follow up

12–18 months

Note

Mean prednisone dose 350 mg (placebo), 135 mg (prednisone) Severe flares n = 6 (placebo), n = 0 (prednisone)

Adverse events

No hypertension No glucose intolerance Dyspepsia n = 1 (prednisone) Total n = 12 (prednisone), 11 (placebo)

Systemic Lupus Erythematosus: Azathioprine

Trial

Long-term survival of lupus nephritis patients treated with Azathioprine and prednisone

Substance

Azathioprine Loading dose 10, 8, 6 mg/kg/day for 2 days Maintenance dose 1–4 mg/kg/day +30–60 mg prednisone/day, tapered to an alternate day regimen Worsening of renal parameters: => 60 mg prednisone/day Concomitant medication: No information provided Previous treatment: DMARDs were permitted Azathioprine was permitted

Result

Treatment of severe renal disease with initial high dose corticosteroids followed by combination of azathioprine with corticosteroids and a rapid reduction in corticosteroid dosage led to improved survival

Patients

47 SLE patients with severe renal disease Renal biopsy: Diffuse proliferative or membranous glomerulonephritis Nephrotic syndrome

Authors

Barnett EV, Dornfeld L, Lee DB, Liebling MR

Publication

J Rheumatol. Fall 1978;5(3):275–287

Follow up

12 years

Note

Survivorship 82% (5 years), 74% (10 years) Death n = 8 Haemodialysis n = 2 Improvement in creatinine n = 21 Decreased proteinuria n = 35

Adverse events

Hypertension n = 13 Herpes zoster n = 3 Sepsis n = 10

411

412

Systemic Lupus Erythematosus: Azathioprine

Trial

Treatment of pure membranous lupus nephropathy with prednisone and azathioprine: an open-label trial

Substance

0.8–1 mg/kg prednisone/day Tapered by 5 mg every week To Maintenance dose 5–10 mg/day +1 mg/kg azathioprine/day Increased to 2 mg/kg/day Concomitant medication: Hypertension: beta-blockers or calcium channel blockers Persisting proteinuria after 12 months: ACE inhibitors Hyperlipidemia: HMG CoA reductase inhibitors Previous medication: Prednisone 66% Aza 18% HCQ 21% Cyc 5%

Result

A combination of prednisone and azathioprine had some effect in the initial treatment of pure membranous lupus nephritis. Severe adverse effects were uncommon

Patients

38 consecutive SLE patients Biopsy proven pure membranous glomerulonephritis

Authors

Mok CC, Ying KY, Lau CS, Yim CW, Ng WL, Wong WS, Au TC

Publication

Am J Kidney Dis. February 2004;43(2):269–276

Follow up

12 months

Note

Complete/partial remission n = 32 No remission n = 4 Withdrawal n = 2 Change of: Proteinuria –2.72 g/day Urinary casts –14% Serum creatinine 0 mg/dL Creatinine clearance +11.9 mL/min Serum albumine +10.2 g/dL Nephrotic syndrome –50% Hypertension +3% Anti dsDNA –25% Depressed serum C3 –31% Depressed serum C4 –16% SLEDAI score –8.5

Adverse events

Cerebrovascular accident 5% Cardiovascular disorder 3% Amaurosis fugax 3% Pulmonary embolism 3% Avascular necrosis of the hips 8% Agranulozytosis 3% Leucopenia 5% Hepatitis 0% Azathioprine hypersensitivity 3% Herpes zoster 3% Severe infections 0% Malignancy 0%

Systemic Lupus Erythematosus: Azathioprine vs. Ciclosporin

Trial

A randomized pilot trial comparing Ciclosporin and Azathioprine for Maintenance therapy in diffuse lupus nephritis over 4 years

Substance

Induction/Flare Treatment: Oral Cyclophosphamide 1–2 mg/kg/day for 3 months Intravenous Methylprednisolone pulse for 3 days (0.5 g £50 kg body weight; 1 g >50 kg body weight) Followed by oral prednisone 1 mg/kg/day for 10–15 days Tapered to 0.7 mg/kg/day for the next 10–15 days Then tapered to 0.5 mg/kg/day up to the end of 2 months

413

Subsequently, patients were randomly assigned either to: Ciclosporin arm: 4 mg/kg ciclosporin/day (n = 36, 4 mg/kg/day, blood level £200 ng/mL) Dose reduction 2.5 –3 mg/kg/day If proteinuria persists >1 g/day: Dose was reduced slower Azathioprine arm: Azathioprine (n = 33, 2 mg/kg/day) Optional reduction to 1.5 mg/kg/day after 1 month Neither ciclosporine nor azathioprine was increased if renal or Extra-renal signs of lupus activity occurred Concomitant medication: 0.2–0.5 mg/kg prednisone/day Prednisone was increased at clinical discretion of the clinician (maximum 25 mg/day) Result

Maintenance therapy with azathioprine or ciclosporin combined with corticosteroids after initial high dose corticosteroid and cyclophosphamide treatment demonstrated equal efficacy in the prevention of flares in patients with diffuse proliferative lupus nephritis

Patients

75 patients with diffuse proliferative lupus biopsy-proven WHO class IV, Vc, or Vd nephritis Chronicity index of £4 Active urine sediment (³5 erythrocytes/high-power field) Proteinuria >1 g/day in the case of newly diagnosed nephritis or >2 g/day in the case of a new renal flare Serum creatinine levels of £4 mg/dL

Authors

Moroni G, Doria A, Mosca M, Alberighi OD, Ferraccioli G, Todesco S, Manno C, Altieri P, Ferrara R, Greco S, Ponticelli C

Publication

Clin J Am Soc Nephrol. September 2006;1(5):925–932. Epub June 28, 2006

414

Systemic Lupus Erythematosus: Azathioprine vs. Ciclosporin

Follow up

2 years (core study) Treatment continued for up to 4 years (follow-up study)

Note

After 24 months: Mean prednisolone dose 7.5 mg/day (Cyc), 7.2 mg/day (Aza) Cumulative Prednisone dose 7667 mg (Cyc), 7377 mg (Aza) Change of Prednisone dose –16.7 mg/day (Cyc), –15.7 mg/day (Aza) Mean systolic blood pressure 120/78 mmHg (Cyc), 124/79 mmHg (Aza) Flares n = 7 (Cyc), n = 8 (Aza) Proteinuria decreased from 2.8 to 0.38 g/day (Cyc), 2.2–0.53 g/day (Aza) After 4 years, mean proteinuria was 0.2 g/day (Cyc), 0.3 g/day (Aza)

Adverse events

Leucopenia 11.1% (Cyc), 30.3% (Aza) Anemia 13.9% (Cyc), 15.2% (Aza) Hypertension 19.4% (Cyc), 15.2% (Aza) Hypercholesterolemia 5.6% (Cyc), 12.1% (Aza) Gum hyperplasia 5.6% (Cyc), 0% (Aza) Hypertrichosis 5.6% (Cyc), 0% (Aza) Diabetes 0% (Cyc), 3.0% (Aza) Hyperkalemia 2.8% (Cyc), 0% (Aza) Hypertensive crisis 2.8% (Cyc), 0% (Aza) Infections 19.4% (Cyc), 42.4 (Aza) Arthralgias 38.9% (Cyc), 9.1% (Aza) Gastrointestinal disorders 30.6% (Cyc), 9.1% (Aza)

Systemic Lupus Erythematosus: Chloroquine and Hydroxychloroquine

415

Trial

A randomized study of the effect of withdrawing Hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group

Substance

100–400 mg hydroxychloroquine sulfate (n = 25) Placebo (n = 22), dusted with 1 mg of hydroxychloroquine to give the same unfavorable taste Concomitant medication: Prednisone was continued Previous medication: No patients treated with HCQ >6.5 mg/kg

Result

Hydroxychloroquine treatment in patients with quiescent systemic lupus erythematosus decreased the occurrence of flares

Patients

47 patients with clinically stable SLE In remission or minimal disease activity Treated with 100–400 mg hydroxychloroquine for minimum 6 months, discontinued at trial entry

Authors

The Canadian Hydroxychloroquine Study Group

Publication

N Engl J Med. January 17, 1991;324(3):150–154

Follow up

24 weeks

Note

New flare 73% (placebo), 36% (HCQ) New objective manifestations n = 16 (placebo), n = 9 (HCQ) Severe exacerbations of the disease n = 5 (placebo), n = 1 (HCQ) Increasing prednisone dose n = 22 (+2.7 mg/day, Placebo), n = 0.4 (+2.7 mg/day, HCQ) Withdrawal because of flairs n = 5 (placebo), n = 1 (HCQ)

Adverse events

Lightheadedness and loss of apetite n = 1 (placebo) Bruising n = 1 (HCQ) Nausea n = 1 (HCQ) Diaphoresis n = 1 (HCQ)

416

Systemic Lupus Erythematosus: Chloroquine and Hydroxychloroquine

Trial

Comparison of Hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus

Substance

2× 200 mg Hydroxychloroquine/day (n = 40) Placebo (n = 31) Concomitant medication: Prednisone £ 10 mg/day at stable doses NSAIDs were continued Previous medication: NSAIDs were permitted No antimalarials <6 weeks prior randomization

Result

Treatment of the articular manifestations of SLE with hydroxychloroquine lead to some improvement of joint pain but of no other joint variables

Patients

71 patients with mild SLE Requiring £10 mg of Prednisone With arthritis or arthralgia ³4 joints Treated unsuccessfully with NSAIDs No cerebral, nephritic or other manifestations requiring corticosteroids No information on other DMARDs

Authors

Williams HJ, Egger MJ, Singer JZ, Willkens RF, Kalunian KC, Clegg DO, Skosey JL, Brooks RH, Alarcón GS, Steen VD, Polisson RP, Ward JR

Publication

J Rheumatol. August 1994;21(8):1457–1462

Follow up

48 weeks

Note

Change of (week 48): Painful swollen joint count –5.7 (HCQ), –1.1 (placebo) Painful swollen joint score –7.1 (HCQ), –3.1 (placebo) Swollen joint count –0.5 (HCQ), –2.2 (placebo) Swollen joint score –1.1 (HCQ), –2.2 (placebo) Grip strength right (mmHg) –2 (HCQ), –25 (placebo) Grip strength left +1 (HCQ), –15 (placebo) General assessment (VAS 1–5) –0.1 (HCQ), +0.1 (placebo) General pain assessment (VAS 1–5) –0.2 (HCQ), +0.1 (placebo) Severity of pain (VAS 1–5) –0.5 (HCQ), 0 (placebo) ESR (mm/h) –9 (HCQ), +3 (placebo) ANA titer +40 (HCQ), +40 (placebo) Komplement C3 (mg/dL) –31 (HCQ), +12 (placebo)

Adverse events

Rash n = 1 (HCQ), n = 0 (placebo) Dizziness n = 1 (HCQ), n = 0 (placebo) Lack of articular response n = 4 (HCQ), n = 4 (placebo) Lack of non articular response n = 1 (HCQ), n = 3 (placebo)

Systemic Lupus Erythematosus: Chloroquine and Hydroxychloroquine

Trial

Controlled trial with Chloroquine diphosphate in systemic lupus erythematosus

Substance

250 mg chloroquine diphosphate/day (CDP, n = 11) Placebo (n = 12) Concomitant medication: Prednisone £0.5 mg/kg/day Previous medication: No immunosuppressive therapy

Result

Chloroquine treatment of patients with non life-threatening systemic lupus erythematosus prevented disease exacerbation and reduced the required prednisone dose

Patients

24 SLE patients with no life-threatening manifestation Fever n = 1 (CDP), n = 3 (placebo) General symptoms n = 0 (CDP), n = 1 (placebo) Articular complaints n = 0 (CDP), n = 8 (placebo) Skin lesions n = 1 (CDP), n = 5 (placebo) Serositis n = 0 (CDP), n = 2 (placebo) Alopecia n = 1 (CDP), n = 1 (placebo) Renal involvement n = 1 (CDP), n = 0 (placebo) Central nervous system involvement n = 0 (CDP), n = 2 (placebo) Hematological involvement n = 0 (CDP), n = 2 (placebo) Hypocomplementenia n = 1 (CDP), n = 3 (placebo) Anti DNA antibodies n = 2 (CDP), n = 1 (placebo)

Authors

Meinão IM, Sato EI, Andrade LE, Ferraz MB, Atra E

Publication

Lupus. June 1996;5(3):237–241

Follow up

12 months

Note

Exacerbation of disease n = 2 (CDP), n = 10 (placebo) Decrease of Prednisone dose n = 9 (CDP), n = 3 (placebo) SLEDAI (12 months) ca. 0 (CDP), ca. 3 (placebo)

Adverse events

Dyspepsia n = 0 (CDP), n = 1 (placebo)

417

418

Systemic Lupus Erythematosus: Chloroquine and Hydroxychloroquine

HELP-trial

Hydroxychloroquine Effects on Lipoprotein Profiles (the HELP trial): A Double-Blind, Randomized, Placebo-Controlled, Pilot Study In Patients With Systemic Lupus Erythematosus HELP: Hydroxychloroquine Effects on Lipoprotein Profiles

Substance

Placebo (n = 5) 400 mg hydroxychloroquine/day (n = 6) 800 mg hydroxychloroquine/day (n = 6) Concomitant medication: Prednisone £20 mg/day No information on other DMARDs Previous medication: NSAIDs ³1 month Corticosteroids ³1 month

Result

Hydroxychloroquine achieved a significant decrease in total cholesterol in both dosage groups and also of triglycerides, VLDL and the LDL/HDL ratio in the higher dosage group in SLE known for a high prevalence of atherosclerotic cardiovascular disease

Patients

19 SLE patients with a disease flare Stable Doses of NSAIDs Corticosteroids ³1 month

Authors

Kavanaugh A, Adams-Huet B, Jain R, Denke M, McFarlin J

Publication

J Clin Rheumatol. February 1997;3(1):3–8

Follow up

3 months

Note

Change of: TC –6.1 (placebo), –11.6 (400 mg HCQ), –13.4 (800 mg HCQ) Triglycerides +13.6 (placebo), –9.6 (400 mg HCQ), –18.9 (800 mg HCQ) VLDL cholesterol +1.7 (placebo), –2.0 (400 mg HCQ), –4.5 (800 mg HCQ) LDL cholesterol –5.1 (placebo), –8.9 (400 mg HCQ), –11.7 (800 mg HCQ) HDL cholesterol –2.6 (placebo), +0.7 (400 mg HCQ), +2.7 (800 mg HCQ) Non–HDL cholesterol –3.4 (placebo), –10.9 (400 mg HCQ), +16.2 (800 mg HCQ) TC/HDL ratio –0.1 (placebo), –0.3 (400 mg HCQ), –0.8 (800 mg HCQ) LDL/HDL ratio –0.1 (placebo), –0.2 (400 mg HCQ), –0.6 (800 mg HCQ) No differences in SLAM scores, C3 and C4 concentrations, anti double strand DNA titers, ESR and CRP, physician’s or patients visual analogue scale

Systemic Lupus Erythematosus: Chloroquine and Hydroxychloroquine

Adverse events

No adverse events n = 3 (placebo), n = 0 (400 mg HCQ), n = 1 (800 mg HCQ) Headache n = 1 (placebo), n = 0 (400 mg HCQ), n = 0 (800 mg HCQ) Pleuritic chest pain n = 1 (placebo), n = 0 (400 mg HCQ), n = 0 (800 mg HCQ) Gastrointestinal symptoms (nausea, abdominal cramping, diarrhea, anorexia) n = 1 (placebo), n = 3 (400 mg HCQ), n = 3 (800 mg HCQ) Visual disturbance n = 0 (placebo), n = 0 (400 mg HCQ), n = 2 (800 mg HCQ) Pruritus n = 0 (placebo), n = 0 (400 mg HCQ), n = 1 (800 mg HCQ) Bluring of vision n = 0 (placebo), n = 0 (400 mg HCQ), n = 1 (800 mg HCQ) Electrooculography “borderline normal” n = 0 (placebo), n = 0 (400 mg HCQ), n = 1 (800 mg HCQ)

419

420

Systemic Lupus Erythematosus: Chloroquine and Hydroxychloroquine

Trial

A long-term study of Hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group

Substance

100–400 mg hydroxychloroquine sulfate (n = 25) Placebo (n = 22), dusted with 1 mg of hydroxychloroquine to give the same unfavorable taste Concomitant medication: Prednisone £ 10 mg/day

Result

Hydroxychloroquine seemed to reduce the major flare rate

Patients

47 patients with clinically stable SLE In remission or minimal disease activity Treated with 100–400 mg hydroxychloroquine for minimum 6 months, discontinued at trial entry

Authors

Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senécal JL, Cividino A, Danoff D, Osterland CK, Yeadon C, Smith CD

Publication

Lupus. 1998;7(2):80–85

Follow up

42 months

Note

Major flare 28% (HCQ), 50% (placebo) Secondary flare subtype Nephritis 4% (HCQ), 14% (placebo) Vasculitis 8% (HCQ), 14% (placebo) Other 16% (HCQ), 23% (placebo) Hospitalization 12% (HCQ), 18% (placebo) Proportion without flare 16% (HCQ), 9% (placebo) Patients without flae n = 16 (HCQ), n = 9 (placebo)

Systemic Lupus Erythematosus: Chloroquine and Hydroxychloroquine

Trial

Hydroxychloroquine (HCQ), in lupus pregnancy: double-blind and placebo-controlled study

Substance

HCQ (n = 10) Placebo (n = 10) Concomitant medication: ASA 100 mg/day was permitted Prednisone was permitted

Result

Hydroxychloroquine was beneficial during lupus pregnancy. SLEPDAI scores and prednisone dosages decreased

Patients

20 consecutive pregnant patients Diagnosed SLE or Biopsy-proven discoid Lupus erythematosus for more than 1 year No CNS involvement

Authors

Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, Albuquerque EM, Jesús NR

Publication

Lupus. 2001;10(6):401–404

Note

Flair n = 3 (Placebo, skin rashes, arthritis and uveitis), n = 1 (HCQ, hemolytic anemia, polyserositis and anti-dsDNA antibody) Fetal death n = 1 (placebo), n = 0 (HCQ) Toxemia during pregnancy n = 3 (placebo), n = 0 (HCQ) Early delivery n = 1 (placebo), n = 0 (HCQ)

421

SLEPDAI scores (0–3): Study entry n = 5 (HCQ), n = 8 (placebo) Delivery n = 10 (placebo), n = 5 (placebo) SLEPDAI scores (4–11): Study entry n = 5 (HCQ), n = 2 (HCQ) Delivery n = 0 (HCQ), n = 3 (placebo) SLEPDAI scores (>12): Study entry n = 0 (HCQ), n = 0 (HCQ) Delivery n = 0 (placebo), n = 2 (placebo) Prednisolone doses HCQ treated patients lower than placebo treated patients Delivery age and Apgar scores were higher in the HCQ group Neonatal examination did not reveal congenital abnormalities Examination of children (1.5, 3 years) revealed no differences (height, weight, auditory capacities, cognitive development, ophthalmoscopic examination) Adverse events

No retinal effects

422

Systemic Lupus Erythematosus: Hydroxychloroquine + Mycophenolate Mofetil

Trial

Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with Mycophenolate mofetil therapy for membranous lupus nephritis

Substance

400 mg hydroxychloroquine/day (n = 11) No hydroxychloroquine (n = 18) Concomitant medication: 2 g mycophenolate mofetil/day (increased to 3 g/day if well tolerated) Prednisone was adjusted to control extrarenal manifestations ACE and angiotensin inhibitors were permitted Previous medication: Mycophenolate mofetil ³ 3 months

Result

Hydroxychloroquine had a benefit for renal remission when mycophenolate mofetil was used as the initial therapy for membranous lupus nephritis

Patients

29 SLE patients With membranous lupus nephritis Or Proliferative lupus nephritis

Authors

Kasitanon N, Fine DM, Haas M, Magder LS, Petri M

Publication

Lupus. 2006;15(6):366–370

Follow up

12 months

Note

MMF was discontinued n = 6 (treatment failure) After 12 months: Renal remission 38% (all patients), 64% (HCQ), 22% (No HCQ) Partial remission 7% (all patients) Protein excretion 1.52 g (HCQ), 2.27 g (No HCQ)

Adverse events

Death n = 1

Systemic Lupus Erythematosus: Cyclophosphamide vs. Azathioprine

423

Trial

A double-blind controlled trial comparing Cyclophosphamide, Azathioprine and placebo in the treatment of lupus glomerulonephritis

Substance

Azathioprine 3 mg/kg/day (increased to 4 mg/kg after 4 weeks, n = 13) Cyclophosphamide 3 mg/kg/day (increased to 4 mg/kg after 4 weeks, n = 10) Placebo (n = 15) Concomitant medication: Prednisolone <0.5 mg/kg/day (maximum 30 mg/day)

Result

Cyclophosphamide was better than azathioprine and placebo, leading to an improvement of proteinuria, hematuria, and serum C3 in patients with systemic lupus associated glomerulonephritis

Patients

38 patients with glomerulonephritis Steroid dose £0.5 mg/kg/day prednisolone 1. Hematuria ³20/mL 2. ³20 white blood cells/mL or Proteinuria ³1 g/24 h or high dsDNA antibodies + Low complement factors 3. Renal biopsy proven diffuse glomerulonephritis

Authors

Steinberg AD, Decker JL

Publication

Arthritis Rheum. November–December 1974; 17(6):923–937

Follow up

6 months

Note

Creatinine Clearence +5.9 (Cyc), –1.15 (Aza), –1.27 (placebo) Proteinuria –0.79 (Cyc), –0.47 (Aza), +0.54 (placebo) Red cells (urine sediment, No./hpf) –9.3 (Cyc), –1.0 (Aza), +2.3 (placebo) Granular and cellular casts (urine sediment, grade) –1.02 (Cyc), –0.22 (Aza), –0.09 (placebo)

424

Systemic Lupus Erythematosus: Cyclophosphamide vs. Azathioprine

Trial

Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial

Substance

Initial therapy: Methylprednisolone arm: 1 g/m2 methylprednisolone for 3 days Followed by 12 monthly 1 g/m2 Methylprednisolone for ³12 months (n = 27) Cyclophosphamide arm: 6 × 1 g/m2 cyclophosphamide Followed by 1 g/m2 cyclophosphamide every 3 months for ³2 years (n = 27) Combination arm: Methylprednisolone + cyclophosphamide (n = 28) After 1 year: If inadequate improvement restart of therapy Concomitant medication: £0.5 mg/kg prednisone/day Tapered by 5 mg every other day each week to minimum 0.25 mg/kg every other day Previous medication: No cytotoxic drug treatment £6 weeks before study entry No cyclophosphamide for more than 10 weeks No pulse or oral corticosteroids >0.5 mg/kg/day

Result

Monthly bolus therapy with cyclophosphamide was more effective than methylprednisolone bolus therapy. There was a trend toward greater efficacy with combination therapy

Patients

82 patients with proliferative lupus nephritis Glomerulonephritis ³10 or more erythrocytes per high-power field Erythrocyte or leukocyte casts Histologic evidence of active proliferative lupus glomerulonephritis No cytotoxic drugs £6 weeks for longer than 2 weeks No pulse therapy with corticosteroids during the 6 weeks before study entry; No oral corticosteroids (or equivalkent) ³0.5 mg/kg/day

Authors

Gourley MF, Austin HA 3rd, Scott D, Yarboro CH, Vaughan EM, Muir J, Boumpas DT, Klippel JH, Balow JE, Steinberg AD

Publication

Ann Intern Med. October 1, 1996;125(7):549–557

Follow up

72 months

Systemic Lupus Erythematosus: Cyclophosphamide vs. Azathioprine

Note

Renal remission n = 17 (combination) n = 13 (Cyc), n = 7 (methylprednisolone) Serum creatinine doubled n = 0 (combination) n = 1 (Cyc), n = 4 (methylprednisolone) Developed end stage renal disease n = 0 (combination) n = 1 (Cyc), n = 3 (methylprednisolone)

Adverse events

Amenorrhea 52% (Cyc), 57% (combination), 10% (methylprednisolone) Cervical dysplasia 11% (Cyc), 7.1% (combination), 0% (methylpred.) Avascular necrosis 11% (Cyc), 18% (combination), 22% (methylpred.) Herpes zoster 15% (Cyc), 21% (combination), 3.7% (methylprednisolone) Infection 26% (Cyc), 32% (combination), 7.4% (methylprednisolone) Newly diagnosed avascular necrosis 11% (Cyc), 18% (combination), 22% (methylprednisolone) Pulmonary infection 11% (Cyc), 7.1% (combination), 3.7% (methylprednisolone) Gastrointestinal infection 3.7% (Cyc), 3.6% (combination), 0% (methylprednisolone) Cardiovascular infection 0% (Cyc), 3.6% (combination), 0% (methylprednisolone) Neutropenic fever 3.7% (Cyc), 3.6% (combination), 0% (methylprednisolone) Death 7.4% (Cyc), 3.6% (combination), 0% (methylprednisolone)

425

426

Systemic Lupus Erythematosus: Cyclophosphamide Followed by Azathioprine

Trial

Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression

Substance

0.8 mg/kg prednisolone/day 2–2.5 mg/kg cyclophosphamide/day for 6 months Prednisolone dosage was gradually tapered to 10 mg/day at 6 months Concomitant medication: No information provided Previous medication: No information provided

Result

Sequential immunosuppression with prednisolone and cyclophosphamide was effective in 90% of SLE patients with pure membranous lupus nephropathy

Patients

20 SLE patients Pure membranous lupus nephropathy WHO Class Va and Vb

Authors

Chan TM, Li FK, Hao WK, Chan KW, Lui SL, Tang S, Lai KN

Publication

Lupus. 1999;8(7):545–551

Follow up

73.5 ± 48.9 months

Note

Within 12 months: Complete remission 55% Partial remission 35% Proteinuria 6.2 => 2 g/24 h Two patients failed to respond Renal function remained stable during follow-up Relapse n = 8

Adverse events

Herpes zoster 40% Hair loss 30% Minor respiratory or urinary tract infections 25% Mild leukopenia 15% Transient amenorrhea 14.3% Pulmonary tuberculosis n = 4 Hyperlipidemia n = 8

Systemic Lupus Erythematosus: Cyclophosphamide

Trial

Combination therapy with pulse Cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis

Substance

Study protocol: 12 boluses of methylprednisolone (1 g/m2, n = 27) continued up to 36 months 6 × cyclophosphamide (1 g/m2, n = 27), followed by 1×/3 months for 24 months Methylprednisolone + cyclophosphamide (n = 28)

427

Concomitant medication: 0.5 mg/kg prednisone/day Tapered by 5 mg every other day each week to minimum 0.25 mg/kg every other day Extrarenal flares: 1 mg/kg prednisone/day for 2 weeks After study protocol: Therapy was dictated by the clinical needs Result

Treatment of lupus nephritis with pulse cyclophosphamide was more effective than pulse methylprednisolone alone in this long term study. The combination of pulse cyclophosphamide and methylprednisolone appeared to provide additional benefit over pulse cyclophosphamide alone

Patients

82 patients with proliferative lupus nephritis Glomerulonephritis ³10 or more erythrocytes per high-power field Erythrocyte or leukocyte casts Histologic evidence of active proliferative lupus glomerulonephritis No cytotoxic drugs £6 weeks for longer than 2 weeks No pulse therapy with corticosteroids during the 6 weeks before study entry; No oral corticosteroids (or equivalkent) ³0.5 mg/kg/day

Authors

Illei GG, Austin HA, Crane M, Collins L, Gourley MF, Yarboro CH, Vaughan EM, Kuroiwa T, Danning CL, Steinberg AD, Klippel JH, Balow JE, Boumpas DT

Publication

Ann Intern Med. August 21, 2001;135(4):248–257

Follow up

120 months

428

Note

Systemic Lupus Erythematosus: Cyclophosphamide

End of study: 50% increase of creatinine concentration n = 2 (Cyc), n = 2 (Cyc + methylprednisolone), n = 5 (methylprednisolone) Doubling of creatinine concentration n = 1 (Cyc), n = 0 (Cyc + methylprednisolone), n = 4 (methylprednisolone) End stage renal disease n = 1 (Cyc), n = 0 (Cyc + methylprednisolone), n = 3 (methylprednisolone) End of follow up: 50% increase of creatinine concentration n = 8 (Cyc), n = 1 (Cyc + methylprednisolone), n = 9 (methylprednisolone) Doubling of creatinine concentration n = 5 (Cyc), n = 0 (Cyc + methylprednisolone), n = 6 (methylprednisolone) End stage renal disease n = 2 (Cyc), n = 0 (Cyc + methylprednisolone), n = 4 (methylprednisolone) Patient without treatment failure n = 7 (Cyc), n = 12 (Cyc + methylprednisolone), n = 6 (methylprednisolone)

Adverse events

Hypertension n = 10 (Cyc), n = 10 (Cyc + methylprednisolone) Ischemic heart disease n = 1 (Cyc), n = 4 (Cyc + methylprednisolone) Hyperlipoproteinemia n = 7 (Cyc), n = 8 (Cyc + methylprednisolone) Valvular heart disease n = 9 (Cyc), n = 7 (Cyc + methylprednisolone) Premature menopauses n = 9 (Cyc), n = 10 (Cyc + methylprednisolone) Herpes zoster infections n = 7 (Cyc), n = 9 (Cyc + methylprednisolone), n = 2 (methylprednisolone) Death n = 5 (Cyc), n = 5 (Cyc + Methylprednisolone), n = 1 (methylprednisolone) Avascular necrosis n = 7 (Cyc), n = 8 (Cyc + methylprednisolone), n = 6 (methylprednisolone) Osteoporosis n = 5 (Cyc), n = 5 (Cyc + methylprednisolone), n = 3 (methylprednisolone) Premature menorrhea n = 12 (Cyc), n = 12 (Cyc + methylprednisolone), n = 7 (methylprednisolone) Age of premature menorrhea 33 a (Cyc), 37 a (Cyc + methylprednisolone), 35 a (methylprednisolone) Infections (during protocol) n = 7 (Cyc), n = 9 (Cyc + methylprednisolone), n = 2 (methylprednisolone) Infections (during follow up) n = 0 (Cyc), n = 0 (Cyc + methylprednisolone), n = 5 (methylprednisolone)

Systemic Lupus Erythematosus: Cyclophosphamide Followed by Azathioprine

429

Euro-Lupus Nephritis trial

Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous Cyclophosphamide

Substance

0.5 gm/m2 cyclophosphamide pulses (n = 45) 6 monthly pulses and 2 quarterly pulses Doses increased according to the white blood cell count nadir Low-dose i.v. cyclophosphamide (500 mg every 2 weeks, 6 ×, n = 44) Concomitant therapy: Three daily pulses of 750 mg of i.v. methylprednisolone Followed by oral 0.5 mg/kg prednisolone/day for 4 weeks Prednisolone was tapered by 2.5 mg every 2 weeks Maintenance therapy: Azathioprine (2 mg/kg/day) started 2 weeks after the last CYC application Continued at least until month 30 after study inclusion Benign renal flares: £15 mg of prednisolone/day for a 2-week + hydroxychloroquine (6 mg/kg/day) ± NSAIDs Severe renal flairs: Renal impairment: >serum creatinine increase >33% Increase in proteinuria: albuminemia ³3.5 gm/dL and proteinuria ³3 g Severe systemic disease: central nervous system disease, thrombocytopenia (<100,000 platelets/µL), hemolytic anemia, lupus pneumonitis, lupus myocarditis, extensive skin vasculitis, or serositis not responding to low-dose glucocorticoid and/or NSAID treatment => 0.5–1 mg prednisolone/kg/day of for 1 month Promptly tapered to the patient’s preflare dosage 2 × i.v. pulses 750 mg methylprednisolone within a 1-week period

Result

Low-dose and high-dose i.v. cyclophosphamide regimen, followed by azathioprine in SLE patients with proliferative lupus nephritis achieved comparable clinical results

Patients

90 SLE patients with biopsy proven proliferative lupus glomerulonephritis (WHO class III, IV, Vc, or Vd) Proteinuria ³ 500 mg/24 h Not pre-treated with Cyc or Aza No Prednisolon ³15 mg/day

Authors

Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gül A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R

Publication

Arthritis Rheum. August 2002;46(8):2121–2131

430

Systemic Lupus Erythematosus: Cyclophosphamide Followed by Azathioprine

Follow up

60 months

Note

Renal flare 27% (high dose), 29% (low dose) Treatment failure 20% (high dose), 16% (low dose) Renal remission 54% (high dose), 71% (low dose)

Adverse events

Death n = 0 (high dose), n = 2 (low dose) End stage renal disease n = 2 (high dose), n = 1 (low dose) Doubling of creatinine level n = 1 (high dose), n = 3 (low dose) Severe infections n = 10 (high dose), n = 5 (low dose) Pneumonia n = 4 (high dose), n = 3 (low dose) Other bacterial infections n = 5 (high dose), n = 1 (low dose) CMV n = 3 (high dose), n = 1 (low dose) VZV n = 5 (high dose), n = 2 (low dose) Mucocutaneous infections n = 5 (high dose), n = 4 (low dose) Lower urinary tract n = 2 (high dose), n = 5 (low dose) Upper resp. tract n = 2 (high dose), n = 1 (low dose) Ear nose throat n = 1 (high dose), n = 0 (low dose) Leucopenia n = 5 (high dose), n = 5 (low dose) Toxic Anemia n = 0 (high dose), n = 1 (low dose) Bone marrow aplasia n = 0 (high dose), n = 1 (low dose) Menopause n = 2 (high dose), n = 2 (low dose) Transient amenorrhea n = 1 (high dose), n = 1 (low dose) Azathioprine induced hepatitis n = 0 (high dose), n = 3 (low dose) Ischemic heart disease n = 1 (high dose), n = 2 (low dose) Deep venous thrombosis n = 2 (high dose), n = 0 (low dose) Diabetes n = 1 (high dose), n = 1 (low dose) Avascular osteonecrosis n = 1 (high dose), n = 0 (low dose) Tendon rupture n = 0 (high dose), n = 1 (low dose)

Systemic Lupus Erythematosus: Cyclophosphamide

Trial

Therapy with intermittent pulse Cyclophosphamide for pulmonary hypertension associated with systemic lupus erythematosus

Substance

6 monthly i.v. cyclophosphamide (IVCYC, 0.5 g/m2/month, n = 16) Oral enalapril (10 mg/day, n = 18) Concomitant medication: Prednisone in stable doses <15 mg/day Antimalarials Anti-inflammatory drugs Antibiotics in the case of infections Ondansetron was used for treatment of nausea and vomiting No prednisone doses >15 mg/day, beta-blockers, or calcium channel blockers trial

Result

I.v. cyclophosphamide was more effective than enalapril in mild and moderate pulmonary hypertension associated with SLE

Patients

SLE patients Prednisone doses of <15 mg/day Doppler echocardiography SPAP >30 mmHg with exercise or SPAP >25 mmHg at rest

Authors

Gonzalez-Lopez L, Cardona-Muñoz EG, Celis A, García-de la Torre I, Orozco-Barocio G, Salazar-Paramo M, Garcia-Gonzalez C, GarciaGonzalez A, Sanchez-Ortiz A, Trujillo-Hernandez B, Gamez-Nava JI

Publication

Lupus. 2004;13(2):105–112

Follow up

34 patients with SLE who had systolic pulmonary artery pressure (SPAP), > 30 mmHg by Doppler echocardiography

Note

Response in patients who finished the trial: SPAP >30 mmHg at baseline 12/15 (Cyc), 12/18 (enalapril) SPAP ³35 mmHg at baseline 11/11 (Cyc), 3/9 (Eenalapril) Intention-to-treat SPAP >30 mmHg at baseline 12/16 (Cyc), 12/18 (enalapril) SPAP ³35 mmHg at baseline 11/12 (Cyc), 3/9 (enalapril) Change of: SPAP (mmHg) –15 (Cyc), –7 (Enalapril) SPAP (Patients with initial SPAP ³35 mmHg) –15 (Cyc), –10 (enalapril)

Adverse events

Withdrawals 6% (Cyc), 0% (enalapril) Side effects (total) 94% (Cyc), 67% (enalapril) Infections total by group 87% (Cyc), 55% (enalapril) Mild infections 81% (Cyc), 55% (enalapril) Severe infections 6% (Cyc), 0% (enalapril) Nausea or vomiting 81% (Cyc), 6% (enalapril) Arterial hypotension 0% (Cyc), 44% (enalapril) Leucopoenia 6% (Cyc), 0% (enalapril)

431

432

Systemic Lupus Erythematosus: Cyclophosphamide

Trial

EULAR randomized controlled trial of pulse Cyclophosphamide and methylprednisolone versus continuous Cyclophosphamide and prednisolone followed by Azathioprine and prednisolone in lupus nephritis

Substance

Intermittent pulse therapy protocol: 4 × 10 mg/kg cyclophosphamide pulse (3 weekly, maximum 1 g, n = 16) 2 × 5 mg/kg Cyc for 2 days in 4 weekly intervals for 9 months After week 58 6 weekly intervals for 12 months Dose modification for neutrophil nadir, cytopenia, renal impairment Pulse i.v. 6.6 mg methylprednisolone/kg (maximum 1 g) Then orally at the same dose split together with oral Cyc Low dose orally 3 mg/kg prednisolone/day Reducing by 0.1 mg/kg/day with each pulse Maintenance dose of 0.05 mg/kg/day, or 0.1 mg/kg/day Metoclopramide or ondansetron were recommended as antiemetics 3 × oral mesna at 25% of the Cyc dose in mg at 0, 4, and 18 h after Cyc Continuous therapy protocol: Cyclophosphamide continuous (2 mg/kg day, n = 13) After 3 months change to azathioprine (1.5 mg/kg/day), for 2 years Dose modification for neutrophil nadir, cytopenia, renal impairment Oral starting at 0.85 mg/kg prednisolone/day (maximum 60 mg) Tapering: and reducing according to protocol (see paper)

Result

There was no statistically significant difference in efficacy and side effects between the two regimens. Infectious complications were common

Patients

32 SLE patients Biopsy proven proliferative glomerulonephritis caused by SLE No Cyc or Aza treatment within the preceding 3 weeks No pure membranous or pure mesangial proliferative glomerulonephritis No previous treatment with cyclophosphamide for more than 3 months

Authors

Yee CS, Gordon C, Dostal C, Petera P, Dadoniene J, Griffiths B, Rozman B, Isenberg DA, Sturfelt G, Nived O, Turney JH, Venalis A, Adu D, Smolen JS, Emery P

Publication

Ann Rheum Dis. May 2004;63(5):525–529

Follow up

104 weeks

Note

Doubled serum creatinine 6.3% (continuous), 0% (pulse) Dialysis 12.5% (continuous), 0% (pulse)

Adverse events

Neutropenia 18.8% (continuous), 7.7% (pulse) Infections 25% (continuous), 38.5% (pulse) Nausea/vomiting 6.3% (continuous), 23.1% (pulse) Haemorrhagic cystitis 6.3% (continuous), 0% (pulse) Malignancy 0% (continuous), 7.7% (pulse) Permanent amenorrhea 6.3% (continuous), 7.7% (pulse) Withdrawn from therapy 43.8% (continuous), 53.8% (pulse) Death 6.3% (continuous), 15.4% (pulse)

Systemic Lupus Erythematosus: Cyclophosphamide

433

Trial

Controlled clinical trial of i.v. Cyclophosphamide versus i.v. Methylprednisolone in severe neurological manifestations in systemic lupus erythematosus

Substance

Induction treatment: 1 g of i.v. methylprednisolone/day for 3 days Followed by: Monthly 0.75 g/m2 cyclophosphamide for 1 year (n = 19) Then every 3 months Monthly 1 g i.v. methylprednisolone for 3 months (n = 13) Then bimonthly for 6 months Then every 3 months for 1 year Concomitant therapy: Oral 1 mg/kg prednisone/day started on the fourth day (maximum 3 months) Tapered according to disease activity/remission

Result

Cyclophosphamide was more effective than methylprednisolone in the treatment of acute, severe neurological manifestations of systemic lupus erythematosus

Patients

32 SLE patients With severe neuro-psychiatric manifestations such as seizures, optic neuritis, peripheral or cranial neuropathy, coma, brainstem disease, or transverse myelitis No antiphospholipid antibody associated manifestations No pure psychiatric manifestations

Authors

Barile-Fabris L, Ariza-Andraca R, Olguín-Ortega L, Jara LJ, Fraga-Mouret A, Miranda-Limón JM, Fuentes de la Mata J, Clark P, Vargas F, Alocer-Varela J

Publication

Ann Rheum Dis. April 2005;64(4):620–625

Follow up

18 months

Note

Change of (after 12 months): Response rate n = 18/19 (Cyc) n = 7/13 (methylprednisolone) Leucocytes (cells × 106/L) +0.1 (Cyc), –4.5 (methylprednisolone) Lymphocytes (cells × 106/L) +10.8 (Cyc), +10.9 (methylprednisolone) SLEDAI –9 (Cyc) –10 (methylprednisolone) SLICC –0.16 (Cyc), –0.02 (methylprednisolone) Prednisone (mg/day) –48.8 (Cyc), –29.4 (methylprednisolone) Disappearance of epileptogen foci of sessures n = 5/5 (Cyc), n = 2/5 (methylprednisolone) Improved visual function after optic neuritis, n = 4/4 (Cyc), n = 0/2 (methylprednisolone) Improvement of peripheral neuropathy n = 3/4 (Cyc), n = 1/3 (methylprednisolone) Improvement of Coma n = 1/1 (Cyc), n = 1/1 (methylprednisolone) Improvement of brainstem disease n = 1/1 (Cyc), n = 0/0 (methylprednisolone)

Adverse events

Urinary tract infections n = 8 (methylprednisolone), n = 10 (Cyc) Respiratory n = 4 (methylprednisolone), n = 6 (Cyc) Oropharyngeal candidiasis n = 0 (methylprednisolone), n = 2 (Cyc) Herpes zoster n = 0 (methylprednisolone), n = 2 (Cyc) Systemic hypertension n = 1 (methylprednisolone), n = 0 (Cyc) Hyperglycaemia n = 1 (methylprednisolone), n = 0 (Cyc) Pancreatitis n = 1 (methylprednisolone), n = 0 (Cyc) Death n = 1 (methylprednisolone), n = 3 (Cyc)

434

Systemic Lupus Erythematosus: Cyclophosphamide vs. Azathioprine

The Dutch Lupus Azathioprine/methylprednisolone versus Cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial Nephritis group-trial Substance

Cyclophosphamide pulses (750 mg/m2, six pulses every 4 weeks): Followed by seven pulses every 12 weeks + oral 1 mg/kg prednisone/day (n = 50) Tapered to 10 mg/day after 6 months Azathioprine (2 mg/kg/day in 2 years): + Intravenous pulses of methylprednisolone (3× 3 pulses of 1,000 mg) + Oral 20 mg prednisone/day for 5 months (n = 37) Tapered to 10 mg/day after 6 months

Result

Cyclophosphamide was superior to azathioprine with regard to renal relapses and less herpes zoster virus infections. There were no differences in serum creatinine or proteinuria between the two groups.

Patients

87 proliferative lupus nephritis patients Creatinine clearance (Cockcroft–Gault) >25 mL/min) Biopsy-proven proliferative lupus nephritis WHO-class IV or Vd lupus nephritis No membranous lupus nephritis WHO-class Va or Vb 56 renal impairment (56%, clearance <70 mL/min)

Authors

Grootscholten C, Ligtenberg G, Hagen EC, van den Wall Bake AW, de Glas-Vos JW, Bijl M, Assmann KJ, Bruijn JA, Weening JJ, van Houwelingen HC, Derksen RH, Berden JH; Dutch Working Party on Systemic Lupus Erythematosus

Publication

Kidney Int. August 2006;70(4):732–742. Epub July 6, 2006

Follow up

Median 5.7 a (Cyc), 5.5a (Aza)

Note

Primary treatment failure n = 0 (Cyc, n = 1 (Aza) Renal relapse n = 2 (Cyc), n = 10 (Aza) Renal relapse rate (relapse/100 patient years) 1.1 (Cyc), 7.1 (Aza) Reaching study end point (doubling of serum creatinine) n = 2 (Cyc), n = 6 (Aza) Therapy switch n = 1 (Cyc), n = 3 (Aza) End-stage renal disease n = 0 (Cyc), n = 1 (Aza) Death n = 2 (Cyc), n = 3 (Aza) Became pregnant during follow-up n = 9 (Cyc), n = 5 (Aza) Pregnancies during follow-up n = 10 (Cyc), n = 10 (Aza) Unwillingly childless n = 3 (Cyc), n = 1 (Aza) Became postmenopausal during follow-up n = 6 (Cyc), n = 3 (Aza) Premature ovarian failure n = 2 (Cyc), n = 2 (Aza) Creatinine 80 µmol/L (Cyc), 86 μmol/L (Aza) Proteinuria 0.2 g/24 h (Cyc), 0.4 g/24 h (Aza) Cumulative steroid dose 11 g (Cyc), 20 g (Aza)

Adverse events

Infection Rate 37/100 patient years (Aza), 18/100 patient years (Cyc)

Systemic Lupus Erythematosus: Leflunomide

Trial

Benefits of Leflunomide in systemic lupus erythematosus: a pilot observational study

Substance

100 mg leflunomide/day loading dose for 3 days Followed by 20 mg leflunomide/day (n = 18) Concomitant medication: No information on concomitant DMARDs and corticosteroids

Result

Leflunomide was efficacious and safe in this cohort of SLE patients after 2–3 months of therapy

Patients

18 SLE patients With non organ threatening signs and symptoms

Authors

Remer CF, Weisman MH, Wallace DJ

Publication

Lupus. 2001;10(7):480–483

Follow up

6 months

Note

SLEDAI decreased –2.1 ESR –9 mm/h Anti-ds DNA decreased –13.7 IU/mL C3 decreased –2.1 mg/dL

Adverse events

Diarrhea n = 7, n = 2 discontinued Rash n = 1 after discontinuation of leflunomide

435

436

Systemic Lupus Erythematosus: Leflunomide

Trial

Double-blind, randomized, placebo-controlled pilot study of Leflunomide in systemic lupus erythematosus

Substance

Oral 20 mg leflunomide after a loading dose of 100 mg for 3 days (n = 6) Placebo (n = 6) Concomitant medication: 20 mg prednisolone/day Tapered by 5 mg every 4 weeks until 10 mg/day Tapered by 2.5 mg every 4 weeks until 5 mg/day Hydroxychloroquine and NSAIDs were allowed to continue Safe contraceptive methods

Result

Leflunomide was more effective than placebo in treating SLE patients with mild to moderate disease activity. It was safe and well tolerated

Patients

12 systemic lupus erythematosus patients with mild to moderate disease activity (SLEDAI of ³6) <0.5 mg/kg prednisolone/day No life-threatening disease requiring addition of immunosuppressants such ascyclophosphamide or azathioprine

Authors

Tam LS, Li EK, Wong CK, Lam CW, Szeto CC

Publication

Lupus. 2004;13(8):601–604

Follow up

24 weeks

Note

SLEDAI decreased –11.0 (Lef), –4.5 (placebo) The changes in proteinuria, complement C3 levels, anti ds-DNA binding and prednisolone dosage were similar between the two groups

Adverse events

Transient elevation in ALT >5× n = 1 (Lef), n = 0 (placebo) Hypertension n = 2 (Lef), n = 0 (placebo) Diarrhea n = 0 (Lef), n = 0 (placebo)

Systemic Lupus Erythematosus: Methotrexate

Trial

Methotrexate in patients with moderate systemic lupus erythematosus (exclusion of renal and central nervous system disease)

Substance

MTX orally at a dose of 15 mg/week over 6 months Concomitant medication: Prednisolone was continued Antimalarial drugs were discontinued 100 mg indomethacin/day was permitted No other anti-inflammatory drugs

Result

Methotrexate treatment of SLE patients reduced disease activity and the dose of corticosteroids needed

Patients

22 SLE patients Refractory Cutaneous rashes Active vasculitis of the skin Active pleurisy Active arthritis Patients with evidence for active lupus nephritis or central nervous system involvement were excluded Prednisolone >7.5 mg/day ³6 months without achieving remission

Authors

Gansauge S, Breitbart A, Rinaldi N, Schwarz-Eywill M

Publication

Ann Rheum Dis. June 1997;56(6):382–385

Follow up

6 months

Note

SLEDAI 12.2 (start), 4 (end) Prednisolone dose 17.4 mg (start), 8.8 mg (end) ESR 46 mm/h (start), 32 mm/h (end) Disappearance of symptoms: Arthritis n = 10 of 12 Dermatitis n = 8 of 10 Pleuritis n = 3 of 4 Vasculitis of the skin n = 6 of 9 Disease activity completely suppressed n = 16 (SLEDAI score = 2) Disease activity considerable reduced n = 4 (SLEDAI score 3–6)

Adverse events

General malaise n = 4 Increased in liver enzymes n = 2 In no case did MTX have to be stopped

437

438

Systemic Lupus Erythematosus: Methotrexate

SMILE-trial

Double-blind, randomized, placebo controlled clinical trial of Methotrexate in systemic lupus erythematosus SMILE: Study of methotrexate in lupus erythematosus

Substance

MTX 15 mg/week (<50 kg body weight) MTX 20 mg/week (>50 kg body weight, n = 20) Placebo (n = 21) Concomitant medication: Prednosone <0.5 mg/kg/day Safe contraception Previous medication: No antimalarials or immunosuppressives £4 months

Result

Methotrexate treatment led to a control of cutaneous and articular activity of SLE. Prednisone dose could be reduced

Patients

SLE patients Arthralgia ³3 joints ³1 week Active discoid lesions, molar rash, pleuritis, pericarditis, vasculitis, proteinuria, or urinary casts

Authors

Carneiro JR, Sato EI

Publication

J Rheumatol. June 1999;26(6):1275–1279

Follow up

6 months

Note

End of the follow up: Articular complaints n = 16 (placebo), n = 1 (MTX) VAS scores for pain were higher in the placebo group than in the MTX group Cutaneous lesions n = 16 (placebo), n = 3 (MTX) SLEDAI scores were higher in placebo treated patients Prednisone dose decreased by 50% n = 13 (MTX), n = 1 (placebo)

Adverse events

70% of the MTX patients developed adverse events Nausea n = 6 (MTX) Weakness n = 5 (MTX) Diarrhea n = 5 (MTX) Oral ulcers n = 6 (MTX) Dyspepsia n = 9 (MTX) Increased AST n = 10 (MTX) Increased ALT n = 8 (MTX) Increased gGT n = 6 (MTX) Increased AP n = 3 (MTX) Increased Bilirubin n = 4 (MTX) Urticaria n = 1 (MTX) Infection n = 4 (MTX) Tuberculosis n = 1 (MTX) Thrombopenia, Proteinuria, increase of serum creatinine n = 1 (placebo), n = 0 (MTX)

Systemic Lupus Erythematosus: Methotrexate

Trial

Steroid-sparing effects of Methotrexate in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial

Substance

7.5 mg methotrexate/week increased monthly by 2.5 mg, maximum 20 mg/week (n = 41) Placebo (n = 45) Concomitant therapy: 2.5 mg folic acid/week £ 4 weeks Stable dose of NSAIDs £4 weeks Stable dose of Prednisone £4 weeks Stable dose of antimalarial drugs £4 weeks ³30 mg prednisone/day was tapered by 5 mg/day every 2 weeks <30 mg prednisone/day was tapered by 2.5 mg/day every 2 weeks

Result

Methotrexate treatment of patients with a moderately active lupus lowered the daily prednisone dose and slightly decreased lupus disease activity

Patients

86 SLE patients Systemic Lupus Activity Measure (SLAM-R) score of ³8 SLICC-DI/ACR score £15 Patients treated with azathioprine or cyclophosphamide were excluded

Authors

Fortin PR, Abrahamowicz M, Ferland D, Lacaille D, Smith CD, Zummer M; Canadian Network for Improved Outcomes in Systemic Lupus

Publication

Arthritis Rheum. December 15, 2008;59(12):1796–1804

Follow up

12 months

Note

No prednisone at baseline or 12 months 44% (MTX), 37% (placebo) Prednisone at baseline but not at 12 months 5% (MTX), 2% (placebo) No Prednisone at baseline but taken at 12 months 2% (MTX), 13% (placebo) Prednisone dose decreased from baseline to 12 months 24% (MTX), 13% (placebo) Same Prednisone dose 12% (MTX), 16% (placebo) Prednisone dose increased 12% (MTX), 18% (placebo)

Adverse events

Cardiovascular 0% (MTX), 0% (placebo) Central/peripheral nervous system 7.3% (MTX), 4.4% (placebo) Ear, eye, nose, throat, larynx 2.4% (MTX), 0% (placebo) Endocrine/metabolic 2.4% (MTX), 0% (placebo) Gastrointestinal 56.1% (MTX), 33.3% (placebo) Genitourinary 2.4% (MTX), 0% (placebo) Hematologic 26.8% (MTX), 22.2% (placebo) Infection 4.9% (MTX), 2.2% (placebo) Mucocutaneous 31.7% (MTX), 46.7% (placebo) Musculoskeletal 2.4% (MTX), 2.2% (placebo) Psychological 9.8% (MTX), 0% (placebo) Renal 0% (MTX), 0% (placebo) Respiratory 0% (MTX), 0% (placebo)

439

440

Systemic Lupus Erythematosus: Mycophenolate Mofetil vs. Cyclophosphamide, Azathioprine

Trial

Long-term study of Mycophenolate mofetil as continuous induction and Maintenance treatment for diffuse proliferative lupus nephritis

Substance

MMF protocol (n = 32): 2 × 1,000 mg mycophenolate mofetil/day for 6 months Thereafter 2 × 500 mg mycophenolate mofetil/day for 6 months Thereafter drug was discontinued Followed by 1–1.5 mg/kg azathioprine/day Cyc–Aza protocol (n = 31): 2.5 mg/kg cyclophosphamide/day p.o. (Cyc-Aza) for 6 months Followed by 1.5–2 mg/kg azathioprine/day for 6 months Followed by 1–1.5 mg/kg azathioprine/day for 6 months Concomitant medication: +0.8 mg/kg prednisolone Tapered to 10 mg/day at approximately 6 months Tapered to 7.5 mg/day 9 months Tapered to 7.5 mg/day 12 months Cellular or fibrocellular crescents affecting >50% of the glomeruli: 500 mg methylprednisolone/day i.v. for 3 days at the initiation of treatment Intravenous Ig or plasmapheresis was not used

Result

Mycophenolate mofetil and prednisolone was an effective continuous induction and maintenance treatment for diffuse proliferative lupus nephritis in Chinese patients

Patients

62 patients with diffuse proliferative lupus nephritis (WHO class IV) Urinary protein excretion of ³1 g/24 h Serum albumin concentration <35 g/L

Authors

Chan TM, Tse KC, Tang CS, Mok MY, Li FK; Hong Kong Nephrology Study Group

Publication

J Am Soc Nephrol. April 2005;16(4):1076–1084. Epub February 23, 2005

Follow up

24 months

Systemic Lupus Erythematosus: Mycophenolate Mofetil vs. Cyclophosphamide, Azathioprine

Note

Doubling of baseline creatinine during follow up 6.3% (MMF), 10% (Cyc-Aza) Complete remission 72.7% (MMF), 74.2% (Cyc-Aza) Partial remission was 24.2% (MMF), and 22.6% (Cyc-Aza) Time to reach complete remission 15.3 weeks (MMF), 19.7 weeks (Cyc-Aza) Doubling of baseline creatinine n = 2 (MMF), n = 3 (Cyc-Aza) End stage renal failure not depicted (MMF), n = 2 (Cyc-Aza) Renal impairment n = 4 (MMF), n = 3 (Cyc-Aza) Disease relapse n = 11 (MMF), n = 9 (Cyc-Aza) Time of relapse 20.2 weeks (MMF), 32.7 weeks (Cyc-Aza)

Adverse events

Leucopenia 0% (MMF), 25.8% (Cyc-Aza) Gastrointestinal 9.1% (MMF), 3.2% (Cyc-Aza) Severe hair loss 0% (MMF), 29% (Cyc-Aza) Amenorrhea n = 1 of 28 (MMF), n = 9 of 25 (Cyc-Aza) Withdrawal as a result of side effects 3% (MMF), 9.7% (Cyc-Aza) Death 0% (MMF), 6.5% (Cyc-Aza) Infections 12.5% (MMF), 40% (Aza) Infection requiring hospitalization 6.3% (MMF), 30% (Cyc-Aza) VZV 6.3% (MMF), 16.7% (Cyc-Aza) Progressive renal impairment 12.5% (MMF), 10% (Cyc-Aza)

441

442

Systemic Lupus Erythematosus: Mycophenolate Mofetil

ALMS-trial

Mycophenolate mofetil as induction and Maintenance therapy for lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study (ALMS) ALMS: Aspreva Lupus Management Study

Substance

MMF-arm (n = 179): Week 1: 2 × 500 mg Mycophenolate mofetil/day Week 2: 2 × 1,000 mg Mycophenolate mofetil/day Week 3–24: 2 × 1,500 mg Mycophenolate mofetil/day Intravenous CYC–arm (n = 179): Week 1–4: 0.75 g Cyclophosphamide/m2 Week 4–24: 0.5–1 g Cyclophosphamide/m2 Week 24 re–randomization of responders (n = 278): MMF-arm (n = 139): 2 × 1,000 mg mycophenolate mofetil/day If prior Cyc arm 1 week 2 × 500 mg MMF/day Aza–arm: Start azathioprine (2 g/kg/day, n = 139) Concomitant therapy: Corticosteroids £60 mg/day Tapering of prednisolone by 10 mg/day every 2 weeks until 40 mg/day. Then tapered by 5 mg/day every 3 weeks until 10 mg/day Reductions below 10 mg/day are allowed after 4 weeks of stable response No MMF, Cyc, nitrogen mustard, chlorambucil, vincristine, procarbazine, etoposide, Aza, CsA, MTX £12 months No i.v. corticosteroids, plasmapheresis, i.v. immunoglobulin £2 weeks No infliximab, adalimumab, etanercept, efalizumab, alefacept £6 months No rituximab within 12 months No enteric-coated corticosteroids during the study No allopurinol within 4 weeks No cholestyramine or other agents No NSAIDs or cyclo-oxygenase-2 inhibitors No phenobarbital at high dose

Result

Mycophenolate mofetil as an induction therapy was comparably effective in controlling lupus nephritis as i.v. cyclophosphamide. For maintenance therapy mycophenolate mofetil was comparably effective in controlling lupus nephritis as azathioprine

Systemic Lupus Erythematosus: Mycophenolate Mofetil

Patients

443

358 SLE patients (n = 278 after second randomization) Biopsy-demonstrated LN (Class III-V) Active nephritis: Proteinuria ³1,000 mg/24 h Serum creatinine >1.3 mg/dL Active urinary sediment in patients with class IV-S or IV-G disease + Significant proteinuria (³2,000 mg/24 h) Elevated serum creatinine levels (>1.3 mg/dL) in patients with Class III or V disease

Authors

Sinclair A, Appel G, Dooley MA, Ginzler E, Isenberg D, Jayne D, Wofsy D, Solomons N

Publication

Lupus. 2007;16(12):972–980

Follow up

24 months

Note

Response rate first phase 70% (intravenous CYC), 85% (MMF) Flares after randomization 59.5% (Aza), 40.7% (MMF)

444

Systemic Lupus Erythematosus: Mycophenolate or Azathioprine after Cyclophosphamide

Trial

Sequential therapies for proliferative lupus nephritis

Substance

Introduction therapy (n = 59): 0.5–1 g/m2 cyclophosphamide i.v. boli followed by corticosteroids Maintenance therapy: 500–3,000 mg mycophenolate mofetil/day (n = 20) 1–3 mg/kg azathioprine/day (n =19) 0.5–1 mg cyclophosphamide/sqm (n = 20) every 3 months – Combined with mesna (hemorrhagic cystitis) and granisetron hydrochloride (nausea/vomiting) Concomitant medication: 0.5 mg prednisone/kg (or equivalent) for 1–3 years Maintenance immunosuppressive therapy was stopped Prior randomization: £7 intravenous cyclophosphamide prior randomization £8 weeks azathioprine prior randomization

Result

Induction therapy with i.v. cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine was more efficacious and safer than long-term therapy with i.v. cyclophosphamide in lupus nephritis

Patients

59 SLE patients Biopsy: type III/IV/Vb lupus nephritis No creatinine clearance £20 mL/min

Authors

Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O’Nan P, Roth D

Publication

N Engl J Med. March 4, 2004;350(10):971–980

Follow up

72 months

Note

Death during follow up n = 0 (Aza), n = 1 (MMF), n = 4 (Cyc) Chronic renal failure n = 1 (Aza), n = 1 (MMF, after 2 weeks of therapy), n = 3 (Cyc) Cumulative rate of renal survival 80% (Aza), 95% (MMF), 74% (Cyc) Relapse rate n = 6 (Aza), n = 3 (MMF), n = 8 (Cyc) Relapse with increase in the serum creatinine n = 2 (Aza), n = 1 (MMF), n = 3 (Cyc)

Adverse events

Amenorrhea 8% (Aza), 6% (MMF), 32% (Cyc) Pneumonia 2% (Aza), 2% (MMF), 15% (Cyc) Total infections 29% (Aza), 32% (MMF), 77% (Cyc) Major infections 2% (Aza), 2% (MMF), 15% (Cyc) Sepsis 0% (Aza), 0% (MMF), 15% (Cyc) Sepsis with bacteremia 0% (Aza), 0% (MMF), 8% (Cyc) Meningitis 0% (Aza), 0% (MMF), 3% (Cyc) Upper respiratory tract infections 22% (Aza), 14% (MMF), 32% (Cyc) Urinary tract infections 2% (Aza), 10% (MMF), 3% (Cyc) Herpes zoster infection 4% (Aza), 6% (MMF), 17% (Cyc) Leucopoenia 6% (Aza), 2% (MMF), 10% (Cyc) Nausea 7% (Aza), 14% (MMF), 65% (Cyc) Vomiting 4% (Aza), 10% (MMF), 55% (Cyc) Diarrhea 9% (Aza), 12% (MMF), 12% (Cyc)

Systemic Lupus Erythematosus: Tacrolimus

445

Trial

Tacrolimus for induction therapy of diffuse proliferative lupus nephritis: an open-labelled pilot study

Substance

Oral 0.1 mg/kg tacrolimus/day for 2 months – Followed by 0.06 mg/kg/day Concomitant medication: Oral 0.6 mg/kg prednisolone/day for 6 weeks Tapered by 5 mg/week until a dose of £10 mg/day Maintained throughout the study period Antimalarials at the discretion of attending physicians No angiotensin-converting enzyme (ACE) inhibitors Other antihypertensive agents could be used No NSAIDs No prior treatment with CsA or tacrolimus

Result

Tacrolimus was safe and effective as an induction treatment of SLE-diffuse proliferative glomerulonephritis

Patients

Nine consecutive SLE patients Biopsy-proven diffuse proliferative glomerulonephritis (WHO class IV) Serum creatinine <200 µmol/L

Authors

Mok CC, Tong KH, To CH, Siu YP, Au TC

Publication

Kidney Int. August 2005;68(2):813–817

Follow up

6 months

Note

Daily proteinuria –3.28 g Nephrotic syndrome –67% Serum albumin +8.8 g/L Serum C3 +0.28 mg/dL Serum creatinine –8.6 µmol/L Creatinine clearance +0.5 mL/min Hemoglobin +1.9 g/dL SLEDAI scores –9.1 Complete response 67% Partial response 22% Seroconversion of dsDNA antibodies 33%

Adverse events

Herpes zoster 0% Major infection (hospitalization) 0% Amenorrhea >2 months 0% Alopecia 22% Transient hyperglycaemia 22% Nausea, vomiting 0% Diarrhea 0% Hemorrhagic cystitis 0% Cervical dysplasia 0% New onset hypertension 0% Neurotoxicity (e.g., tremor) 11% Hypertrichosis 0% Gingivitis/gum hypertrophy 0% Increase in serum creatinine by 30% 11%

446

Systemic Lupus Erythematosus: Tacrolimus

Trial

Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis

Substance

0.1–0.2 mg/kg tacrolimus/day for 6 months (n = 18) Control group (n = 19): 1.5 mg/kg/azathioprine/day (n = 26) Or oral cyclophosphamide (n = 25) Concomitant therapy: Prednisolone 30 mg/day Tapered by 5 mg every 2 weeks until 20 mg/day Tapered by 5 mg every 4 weeks until 10 mg/day Tapered by 2.5 mg every 4 weeks until 5 mg/day Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Additional anti-hypertensive therapy if needed Maintenance therapy: After 6 months tacrolimus was stopped 1.5 mg/kg AZA/day

Result

Tacrolimus, as compared to standard immunosuppressive treatment, was a safe and effective treatment of pure class V lupus nephritis

Patients

69 SLE patients Biopsy: Pure class V (membranous) nephritis secondary to SLE Nephrotic syndrome with: Proteinuria (>3 g/day) Serum albumin <30 g/dL ± Active urinary sediments

Authors

Szeto CC, Kwan BC, Lai FM, Tam LS, Li EK, Chow KM, Gang W, Li PK

Publication

Rheumatology (Oxford). November 2008;47(11):1678–1681. Epub August 27, 2008

Follow up

12 months

Note

After 12 weeks: Complete remission: 27.8% (tacrolimus) 15.8% (control) Partial remission 50% (tacrolimus), 47.4% (control) New lupus flares n = 4 (tacrolimus) n = 11 (control) SLEDAI no differences After 24 weeks: Complete remission: 38.9% (tacrolimus) 36.8% (control) Partial remission 44.4% (tacrolimus), 57.9% (control) Change of (week 12): Proteinuria –76.2% (tacrolimus), –47.1% (control)

Adverse events

Infection n = 3 (tacrolimus: gastroenteritis, oral herpes, urinary tract infection), n = 2 (control: gastroenteritis, herpes zoster) Elevated liver enzymes n = 1 (tacrolimus), n = 1 (control) Dyspepsia n = 8 (tacrolimus), n = 0 (control) Tremor n = 2 (tacrolimus), n = 0 (control) Angio-edema n = 1 (tacrolimus), n = 0 (control)

Systemic Lupus Erythematosus: Infliximab

Trial

Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study

Substance

300 mg infliximab (»5 mg/kg), at weeks 0, 2, 6, and 10 + azathioprine or methotrexate Concomitant medication: Azathioprine, methotrexate, chloroquine were continued at stable doses Prednisone was continued at stable doses

Result

Infliximab had a therapeutic effect in patients with SLE with respect to kidney and joint disease and. did not lead to adverse events related to an increase in SLE activity

Patients

Six patients with SLE Low-to-moderate disease activity, for at least 3 months prior to inclusion In case of renal disease: patients unresponsive to cytotoxic therapy

Authors

Aringer M, Graninger WB, Steiner G, Smolen JS

Publication

Arthritis Rheum. October 2004;50(10):3161–3169

Follow up

52 weeks

Note

No significant serum titer changes of dsDNA antibodies None of the patients experienced an increased disease activity SIS 10 (baseline), 6 (end of follow up) SLEDAI 9 (baseline), 5 (end of follow up) Joint swelling stopped in all three patients with active arthritis In all 4 patients with nephritis proteinuria decreased – Creatinine clearance rate 79 mL/min (baseline), 100 mL/min (end of follow up)

Adverse events

Febrile episode n = 1 Urinary tract infection n = 3 Increase of anti dsDNA level n = 4 Increase of anti cardiolipin antibodies n = 4

447

448

Systemic Lupus Erythematosus: Infliximab

Trial

Efficacy and safety of Infliximab in active SLE: a pilot study

Substance

3 mg/kg infliximab at 0, 2, 6 weeks and then every 8 weeks (n = 18) INH Prophylaxis in case of pos. TBC testing Concomitant medication: Corticosteroids were continued DMARds were continued

Result

Several clinical and serological parameters improved, the safety profile was good

Patients

27 active SLE patients 19 healthy control volunteers

Authors

Uppal SS, Hayat SJ, Raghupathy R

Publication

Lupus. July 2009;18(8):690–697

Follow up

24 weeks

Note

After 6 months: SLEDAI –27.75 (IFX), –13.33 (control) SLICC 0.0 (IFX), +0.1(control) VAS Fatigue –35.0 (IFX), –15.0 (control) Glucosteroid dose –38.75 mg (IFX), +4 mg (control) SF36-Physical +10.9 (IFX), +3.36 (control) SF36-Role physical +16.92 (IFX), +5.63 (control) SF36-Bodily pain +17.56 (IFX), +15.15 (control) SF36-General +8.74 (IFX), +0.93 (control) SF36-Vitality +6.6 (IFX), +2.13 (control) SF36-Social +16.26 (IFX), +10.31 (control) SF36-Role emotional +14.76 (IFX), +8.42 (control) SF36-Mental +14.08 (IFX), +4.1 (control) SF36-Physical component +13.22 (IFX), +6.13 (control) SF36-Mental component +12.26 (IFX), +5.79 (control) SF36-Total +25.48 (IFX), +11.92 (control) Requirement of Glucosteroid pulses 0.4 (IFX), 0.4 (control) 24 h urine protein –1.23 g (IFX), –2.22 (control) Total ds DNA (IU/mL) –5.4 (IFX), –25.81 (control) Complement C3 (g/L) +0.41 (IFX), +0.39 (control) Complement C4 (g/L) +0.11 (IFX), +0.07 (control)

Adverse events

Infections/patient n = 0.4 (IFX), n = 0.5 (control) Admissions/patient n = 0.6 (IFX), n = 1.2 (control) Fever and chills n = 1 (IFX) Chest pain and dyspnea n = 1 (IFX) Hypostension, headache and vomiting n = 1 (IFX) Intense Pruritus/urticarial rash n = 1 (IFX)

Systemic Lupus Erythematosus: Rituximab

Trial

A multicenter phase I/II trial of Rituximab for refractory systemic lupus erythematosus

Substance

Four infusions of 500 mg/body every week (n = 5) Two infusions of 1,000 mg/body every other week (n = 10)

449

Concomitant medication: No corticosteroid boli No DMARDs Result

Rituximab therapy was safe for the treatment of active SLE patients

Patients

15 patients with active and refractory SLE Flares according to BILAG score: 1× BILAG A or 2 × BILAG B Moderate to severe flare, although they were treated with ³30.4 mg/kg/day prednisolone

Authors

Tanaka Y, Yamamoto K, Takeuchi T, Nishimoto N, Miyasaka N, Sumida T, Shima Y, Takada K, Matsumoto I, Saito K, Koike T

Publication

Mod Rheumatol. 2007;17(3):191–197. Epub June 20, 2007

Follow up

28 weeks

Note

Change from BILAG B: General baseline n = 4, improvement n = 3, no change n = 1 Mucocutaneous baseline n = 9, improvement n = 3, no change n = 6 Nervous system baseline n = 2, improvement n = 2, no change n = 0 Musculoskeletal baseline n = 2, improvement n = 1, no change n = 1, worsend n = 1 Cardiovascular/respiratory n = 0, improvement n = 0, no change n = 0 Vasculitis n = 2, improvement n = 0, no change n = 2 Renal n = 4, improvement n = 1, no change n = 3 Hematological baseline n = 2, improvement n = 1, no change n = 1, worsend n = 3 Change from BILAG A: General baseline n = 1, improvement n = 0, no change n = 1 Mucocutaneous baseline n = 0, improvement n = 0, no change n = 0 Nervous system baseline n = 3, improvement n = 3, no change n = 0 Musculoskeletal baseline n = 0, improvement n = 0, no change n = 0 Cardiovascular/respiratory n = 1, improvement n = 0, no change n = 1 Vasculitis n = 0, improvement n = 0, no change n = 0 Renal n = 2, improvement n = 2, no change n = 0 Hematological baseline n = 1, improvement n = 1, no change n = 0

Adverse events

Grade 1 (n = 16): Infection (n = 5), redness of foot pad (n = 1), flush (n = 1), muscle weakness of hands (n = 1), tremor (n = 1), tachycardia (n = 1), edema of feet (n = 1), subcutaneous nodule (n = 1), hypertension (n = 1), headache (n = 1), sore throat (n = 1), paresthesia (n = 1) Grade 2 (n = 27): Infections (21), diarrhea (n = 1), skin eruption (n = 1), muscular pain of lower limbs (n = 1), abdominal pain (n = 1), keratosis of foot pad (n = ), sleeping disturbance (n = 1) Grade 3 (n = 3): Infections (n = 3)

450

Systemic Lupus Erythematosus: Rituximab

Trial

Efficacy of Rituximab (anti-CD20), for refractory systemic lupus erythematosus involving the central nervous system

Substance

Patient 1–5 and 10: 375 mg/m2 rituximab 1×/week for 2 weeks Patient 9: 375 mg/m2 rituximab 1× Patients 6, 7: 500 mg rituximab once a week for 4 weeks Patient 8: 1,000 mg once biweekly for 4 weeks Concomitant therapy: Moderate doses of corticosteroids (15–40 mg/day) No precise information on concomitant DMARD usage

Result

Rituximab rapidly improved refractory neuropsychiatric SLE, as evident by resolution of various clinical signs and symptoms and improvement of radiographic findings

Patients

10 patients with refractory neuropsychiatric SLE Despite intensive treatment 1. The presence of a highly active disease 2. CNS lesions resistant to conventional treatment (intravenous cyclophosphamide pulse, ciclosporin)

Authors

Tokunaga M, Saito K, Kawabata D, Imura Y, Fujii T, Nakayamada S, Tsujimura S, Nawata M, Iwata S, Azuma T, Mimori T, Tanaka Y

Publication

Ann Rheum Dis. April 2007;66(4):470–475. Epub November 15, 2006

Follow up

3 months

Note

SLEDAI scores reduced at day 28 n = 10 These effects lasted for 1 year in five patients Complete recovery n = 4 Improvement of psychosis n = 1 Improvement of depression n = 2 Improvement of consciousness n = 1 Resolution of headache n = 1 Resolution of paresthesia n = 1 Reduction of paresis n = 1

Adverse events

Pneumonia n = 2 Herpes zoster n = 1 Chickenpox n = 1 Intractable infection of decubitus ulceration n = 1 All infections were successfully controlled with antibiotics

Systemic Lupus Erythematosus: Rituximab

451

Trial

Treatment of refractory SLE with Rituximab plus Cyclophosphamide: clinical effects, serological changes, and predictors of response

Substance

375 mg/m2 rituximab (RTX) once weekly for 4 weeks 0.5 g/m2 cyclophosphamide together with first and last RTX application 250 mg methylprednisolone together with Cyc Followed by oral glucocorticoids (0.5 mg/kg/day) for 4 weeks Glucocorticoids were tapered down to the lowest possible dose Previous medication: All patients were prior treated with DMARDs

Result

The majority of patients improved following rituximab plus cyclophosphamide

Patients

16 SLE patients 1 × BILAG A or 2 × BILAG B in any organ system Not responding to conventional immunosuppressive treatment including cyclophosphamide

Authors

Jónsdóttir T, Gunnarsson I, Risselada A, Henriksson EW, Klareskog L, van Vollenhoven RF

Publication

Ann Rheum Dis. March 2008;67(3):330–334. Epub September 7, 2007

Follow up

6 months

Note

50% reduction in SLEDAI n = 13 Response according to BILAG n = 15 Remission defined as SLEDAI <3 n = 9 Relapse n = 7 (median 18 months, range 10–40)

452

Systemic Lupus Erythematosus: Rituximab

EXPLORERtrial

Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase ii/iii systemic lupus erythematosus evaluation of rituximab tria Explorer: The Exploratory Phase II/III SLE Evaluation of Rituximab

Substance

1,000 mg rituximab (RTX) on days 1, 15, 168, and 182 (n = 169) Placebo (n = 88) Concomitant medication: Acetaminophen together with RTX Diphenhydramine together with RTX 100 mg methylprednisolone together with RTX Azathioprine 100–250 mg/day, mycophenolate mofetil 1–4 g/day, methotrexate 7.5–27.5 mg/week were continued at stable doses Oral prednisone 0.5 mg/kg, 0.75 mg/kg, or 1 mg/kg based on the BILAG score at entry and the amount of steroids already Steroids were tapered after day 16 (aim £10 mg/day over 10 weeks, £5 mg/day by week 52)

Result

Placebo and rituximab treatment of moderately to severely active SLE and used aggressive background treatment a did not differ in clinical response

Patients

257 SLE patients entered ³1 BILAG A score or ³2 BILAG B scores No central nervous system manifestations No organ threatening disease or active condition requiring cyclophosphamide or a calcineurin inhibitor Despite background immunosuppressant therapy

Authors

Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG

Publication

Arthritis Rheum. January 2010;62(1):222–233

Follow up

52 weeks

Note

No clinical response 71.6% (placebo), 70.4% (RTX) Partial clinical response 12.5% (placebo), 17.2% (RTX) Major clinical response 15.9% (placebo), 12.4% (RTX) Anti-dsDNA antibody (median decrease 76% (RTX), 55% (placebo) Median increase of C3 129% (RTX), 114% (placebo) Median increase of C4 173% (RTX), 115% (placebo) Area under the curve minus baseline of the BILAG score –5.9 (placebo), –5.8 (RTX) Subgroup analysis amon Hispanic patients: Partial clinical response 9.4% (placebo), 13.8% (RTX) Major clinical response 6.3% (placebo), 20% (RTX)

Systemic Lupus Erythematosus: Rituximab

Adverse events

Cardiac disorder 5.7% (placebo), 3% (RTX) Infections and infestations 17% (placebo), 9.5% (RTX) Gastrointestinal disorders 8% (placebo), 4.7% (RTX) General disorder 5.7% (placebo), 4.1% (RTX) Musculoskeletal and connect tissue disorders 5.7% (placebo), 5.3% (RTX) Neutropenia 0% (placebo), 3.6% (RTX) Any study drug-related treatment emergent SAE 9.1% (placebo), 7.7% (RTX) Any infusion-related AE 38.6% (placebo), 43.8% (RTX) First infusion 29.5% (placebo), 27.2% (RTX) Second infusion 16.5% (placebo), 17.6% (RTX) Third infusion 10% (placebo), 16.3% (RTX) Fourth infusion 5.9% (placebo), 18.5% (RTX) Any infusion-related SAE 17% (placebo), 9.5% (RTX) Any treatment-emergent infection related SAE 17% (placebo), 9.5% (RTX) Lower respiratory tract and lungs 4.5% (placebo), 3% (RTX) Bacterial 4.5% (placebo), 2.4% (TRX) Abdominal and gastrointestinal 4.5% (placebo), 1.2% (RTX) Sepsis, bacteremia, viremia, and fungemia infections 3.4% (placebo), 1.2% (RTX) Death 1.1% (placebo), 2.4% (RTX)

453

Antiphospholipid Syndrome

Aspirin

Trial

Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial

Substance

75 mg aspirin/day (n = 20) Placebo (n = 20) Concomitant medication: No NSAIDs No corticosteroids No heparin

Result

Low-dose aspirin treatment of women with antiphospholipid syndrome and recurrent miscarriages had no additional benefit

Patients

50 women ³3 miscarriages Antiphospholipid antibodies: (³5 u IgG, ³5 u IgM anti-phospholipid antibodies, or pos. lupus anticoagulant) No SLE

Authors

Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J

Publication

Am J Obstet Gynecol. 2000;183(4):1008–1012

Note

Pregnancy complications: Bleeding (any in pregnancy) 35% (placebo), 45% (ASS) Hypertension or preeclampsia 18% (placebo), 19% (ASS) Preterm birth (24–37 weeks) 0% (placebo), 13% (ASS) Cesarean delivery 29% (placebo), 31% (ASS) Outcome: Live birth 85% (placebo), 80% (ASS) Neonatal outcome: Birth weight 3,367 g (placebo), 3,038 g (ASS) Small for gestational age 24% (placebo), 6% (ASS) Neonatal admission 12% (placebo), 13% (ASS) Congenital anomalies 6% (placebo), 6% (ASS)

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_5, © Springer-Verlag London Limited 2011

455

456

Antiphospholipid Syndrome: Aspirin

APLASA-Trial

Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals APLASA: Antiphospholipid Antibody Acetylsalicylic Acid

Substance

81 mg aspirin/day (n = 48) Placebo (n = 50) Concomitant medication: No warfarin No prior aspirine

Result

Asymptomatic, persistently anti-phospholipid-antibody-positive individuals did not benefit from low-dose aspirin for primary thrombosis prophylaxis

Patients

98 patients Positive Lupus anticoagulant test On ³2 occasions, at least 6 weeks apart Positive cardiolipin IgG/IgM/IgA ³20 units on ³2 occasions ³6 weeks apart No thrombosis orpulmonary embolism or transient ischemic attack No history of bleeding £5 years No thrombocytopenia (<30 × 109 cells/L)

Authors

Erkan D, Harrison MJ, Levy R, Peterson M, Petri M, Sammaritano L, Unalp-Arida A, Vilela V, Yazici Y, Lockshin MD

Publication

Arthritis Rheum. 2007;56(7):2382–2391

Follow up

3 years

Note

Incidence rate of acute thrombosis (No./100 patient-years) 2.75 (aspirin), 0 (placebo) Incidence rate of chronic vascular events (No./100 patient-years) 1.83 (aspirin), 0.86 (placebo)

Adverse events

Mild gastrointestinal disturbances n = 5 (aspirin), n = 1 (placebo) Minor bleeding events n = 3 (aspirin), n = 1 (placebo) Easy bruising n = 2 (aspirin), n = 1 (placebo) Malignancies n = 1 (aspirin), n = 1 (placebo) Death n = 1 (aspirin), n = 1 (placebo)

Antiphospholipid Syndrome: Aspirin vs. Heparin

457

Trial

Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies)

Substance

75 mg Aspirin/day after pos. pregnancy test (n = 45) After detection of fetal heart activity => ramdomization: + 2 × 5,000 U unfractionated heparin/day subcutaneously (ASS-Hep, n = 45) No additional heparin (ASS, n = 45)

Result

Treatment with aspirin and heparin of women with a history of recurrent miscarriage associated with phospholipid antibodies led to a significantly higher rate of live births than that achieved with aspirin alone

Patients

90 women with antiphospholipid syndrome History of recurrent miscarriage (minimum 3, median 4, range 3–15) Positive results for phospholipid antibodies on minimum 2 occasions No SLE patients No uterine abnormality No hypersecretion of luteinising hormone No multiple pregnancy No women with partner who had an abnormal karyotype

Authors

Rai R, Cohen H, Dave M, Regan L

Publication

BMJ. 1997;314(7076):253–257

Note

Gestation age (weeks) at randomization 6.6 (ASS), 6.7 (ASS-Hep) Live births n = 19 (ASS), n = 32 (ASS-Hep) Miscarriages n = 26 (ASS), n = 13 (ASS-Hep) Live births: Gestation age at randomization (weeks) 6.7 (ASS), 6.8 (ASS-Hep) Gestation age at delivery (weeks) 39.6 (ASS), 38.0 (ASS-Hep) Deliveries before 37 weeks’ gestation n = 4 (ASS), n = 8 (ASS-Hep) Median birth weight (g) 3,080 (ASS), 3,330 (ASS-Hep) No congenital abnormalities were detected Caesarean section n = 1 (ASS, growth retardation) Baby with parietal lobe infarction n = 1 (ASS) Unsuccessful pregnancies: Gestation ageat randomization (weeks) 6.5 (ASS), 6.4 (ASS-Hep) Gestation age at miscarriage (weeks) 8.3 (ASS), 9.4 (ASS-Hep) No with loss of pregnancy: Under 14 weeks n = 24 (ASS), n = 11 (ASS-Hep) Between 14 and 28 weeks n = 2 (ASS), n = 2 (ASS-Hep)

458

Antiphospholipid Syndrome: Aspirin vs. Heparin

Trial

A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies

Substance

Subcutaneous 2 × 5,000 IU unfractionated heparin/day + 100 mg aspirin/day (158 transfers of 296 embryos) Placebo (neither heparin nor ASS, 142 transfers of 259 embryos)

Result

Heparin and aspirin did not improve pregnancy or implantation rates for antiphospholipid or antinuclear antibodies-positive patients with in vitro fertilization implantation failure

Patients

143 women seropositive without achieving pregnancy Pos. for antiphospholipid, antinuclear, or beta 2 glycoprotein I autoantibodies ³10 embryos transferred

Authors

Stern C, Chamley L, Norris H, Hale L, Baker HW

Publication

Fertil Steril. 2003;80(2):376–383

Note

Total embryo transfers n = 296 (Hep + ASS), n = 259 (placebo) Fetal hearts detected n = 20 (Hep + ASS), n = 22 (placebo) Number of babies born n = 18 (Hep + ASS), n = 17 (placebo) Live birth rate 6% (Hep + ASS), 7% (placebo) Pos. Pregnancy test 14.6% (Hep + ASS), 17.6% (placebo)

Adverse events

Bruising at the Injection-site 64% (Hep + ASS), 6% (placebo)

Antiphospholipid Syndrome: Aspirin vs. Heparin

459

HepASA-Trial

Low Molecular Weight Heparin and Aspirin for Recurrent Pregnancy Loss: Results from the Randomized, Controlled HepASA Trial HepASA: Heparin and ASA

Substance

5,000 IU/day low molecular weight heparin/day (n = 45) until 35th week of gestation or delivery +81 mg ASA (Heparin + ASA) 81 mg acetylsalicylic acid (ASA, n = 43)

Result

Low molecular weight heparin and acetylsalicylic acid had no additional effect as compared to acetylsalicylic acid alone with respect to pregnancy outcome, regardless of the presence of absence of antiphospholipid antibodies

Patients

88 women with confirmed pregnancies Age 18–44 years ³2 unexplained consecutive pregnancy losses prior to 32 weeks gestation ³1 of the following: ANA, aPL, or an inherited thrombophilia on two occasions No SLE No peptic ulcer disease No hyopersensitivity to ASA or heparin obtained No bone mineral density z score < –2.5 No previous thromboembolic event requiring ongoing anticoagulant therapy No genetic, anatomic, or hormonal etiology for pregnancy loss No hysterosalpingogram/sonohystogram

Authors

Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, Kingdom JC, Barrett J, Gent M

Publication

J Rheumatol. 2009;36(2):279–287

Note

All patients: Pregnancy loss £14 weeks gestation 15.6% (Heparin + ASA), 18.6% (ASA) Pregnancy loss 14–20 weeks gestation 0% (Heparin + ASA), 0% (ASA) Ectopic pregnancy 4.4% (Heparin + ASA), 0% (ASA) Still birth (20–32 weeks) 2.2% (Heparin + ASA), 2.3% (ASA) Live birth 77.8% (Heparin + ASA), 79.1% (ASA) Induced delivery 20.0% (Heparin + ASA), 18.2% (ASA) Caesarian section 24.4% (Heparin + ASA), 31.8% (ASA) Neonatal death n = 0 (Heparin + ASA), n = 1 (ASA) Pregnancy outcome dependent on the presence or absence of antiphospholipid antibodies: Spontaneous abortion n = 3 (aPL pos. Heparin + ASA), n = 4 (aPL neg. Heparin + ASA), n = 5 (aPL pos. ASA), n = 3 (aPL neg. ASA) Still birth n = 1 (aPL pos. Heparin + ASA), n = 0 (aPL neg. Heparin + ASA), n = 0 (aPL pos. ASA), n = 1 (aPL neg. ASA) Ectopic pregnancy n = 1 (aPL pos. Heparin + ASA), n = 1 (aPL neg. Heparin + ASA), n = 0 (aPL pos. ASA), n = 0 (aPL neg. ASA) Neonatal death n = 0 (aPL pos. Heparin + ASA), n = 0 (aPL neg. Heparin + ASA), n = 0 (aPL pos. ASA), n = 1 (aPL neg. ASA) Live birth n = 17 (aPL pos. Heparin + ASA only), n = 18 (aPL neg. Heparin + ASA only), n = 15 (aPL pos. ASA), n = 19 (aPL neg. ASA) Birthweight < 10th percentile n = 1 (aPL pos. Heparin + ASA), n = 2 (aPL neg. Heparin + ASA), n = 0 (aPL pos. ASA), n = 6 (aPL neg. ASA)

Adverse events

BMD at the spine –0.05 g/cm2 (Heparin + ASA), –0.01 (ASA)

460

Antiphospholipid Syndrome: Aspirin + Heparin

Trial

Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment

Substance

75 mg Aspirin/day (ASS, n = 47) 75 mg Aspirin/day + 5,000 IU heparin/day ( ASS-heparin, n = 51) Concomitant medication: No use of steroids during pregnancy No systemic lupus erythematosus requiring medication

Result

Low-dose aspirin was effective in pregnant women with antiphospholipid syndrome. The addition of low molecular weight heparin did not significantly improve pregnancy outcome

Patients

98 consecutive women Pregnant before 12th weeks of gestation ³3 consecutive pregnancy losses or ³2 consecutive pregnancy losses with proven fetal death after tenth week of gestation ³9 U/mL IgG anti-cardiolipin and/or ³5 U/mL IgM anti-cardiolipin No parental chromosomal abnormality No uterine anomaly No previous arterial or venous thrombosis No complicated by nephritis No other thrombophilia

Authors

Farquharson RG, Quenby S, Greaves M

Publication

Obstet Gynecol. 2002;100(3):408–413

Note

Live Birth 72% (ASS), 78% (ASS-heparin) Mean birth weight 3,221 g (ASS), 3,127 g (ASS-heparin) Embryo loss n = 9 (ASS), n = 3 (ASS-heparin) Fetal loss n = 4 (ASS), n = 8 (ASS-heparin) Gestation at delivery: <30 week n = 1 (ASS), n = 1 (ASS-heparin) 30–36 week n = 3 (ASS), n = 1 (ASS-heparin) >36 weeks n = 30 (ASS), n = 38 (ASS-heparin)

Antiphospholipid Syndrome: Aspirin + Heparin

Trial

Treatment of antiphospholipid antibody syndrome (APS), in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated Heparin

Substance

Dalteparin group (n = 14): 81 mg acetylsalicylic acid/day Started preconceptionally + Dalteparin 2,500 IE/day Increased to 5,000 IE/day in the second trimester Increased to 7,500 IE/day in the third trimester Unfractionated Heparin group (n = 14): Unfractionated heparin 2 × 5,000 IE/day Increased to 2 × 10,000 IE/day in the second trimester Concomitant medication: No prior heparin treatment

Result

Dalteparin was an effective alternative to unfractionated heparin for treatment of antiphospholipid antibody syndrome in pregnancy

Patients

28 women ³3 consecutive, unexplained miscarriages Lupus anticoagulant pos Anticardiolipin pos (IGM or IgG) No thrombophilia

Authors

Stephenson MD, Ballem PJ, Tsang P, Purkiss S, Ensworth S, Houlihan E, Ensom MH

Publication

J Obstet Gynaecol Can. 2004;26(8):729–734

Note

Live birth n = 9 (dalteparin), n = 4 (unfractionated heparin) Weight 3,304 g (dalteparin), 3,536 g (unfractionated heparin) Embryonic demise n = 0 (dalteparin), n = 2 (unfractionated heparin) Anembryonic demise n = 4 (dalteparin), n = 7 (unfractionated heparin)

461

462

Antiphospholipid Syndrome: Aspirin + Heparin

Trial

Treatment of recurrent miscarriage and antiphospholipid syndrome with low-dose enoxaparin and aspirin

Substance

20 mg Enoxaparin/day + 75 mg Aspirin/day Treatment started shortly after positive pregnancy test Until the women went into labour or the day before elective delivery

Result

In this open study of 20 mg Enoxaparin in combination with 75 mg aspirin treatment of women with recurrent miscarriages and antiphospholipid syndrome a rate of live birth of 80% was observed

Patients

35 women with antiphospholipid syndrome Confirmed pregnancy Positive lupus anticoagulant on two occasions Antiphospholipid antibodies IgG (³8 U/L) IgM (³5 U/L) ³3 consecutive miscarriages before tenth week’ gestation or ³1 consecutive miscarriages beyond tenth week’ gestation ³1 premature birth of morphological normal neonate before 34th week’ gestation because of pre-eclamisia or eclamsia or placental insufficiency

Authors

Mo D, Saravelos S, Metwally M, Makris M, Li TC

Publication

Reprod Biomed Online. 2009;19(2):216–220

Note

Outcome of 35 pregnancies: Biochemical pregnancy 3% First trimester loss: Ultrasound gestation sac only 3% Ultrasound showed gestation sac and fetal pole 9% Ultrasound demonstrated fetal heart beats 3% Second trimester loss: 0% Third trimester loss: 0% Live birth 80%

Antiphospholipid Syndrome: Aspirine + Prednisone

463

Trial

Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss

Substance

0.8 mg/kg prednisone/day for 4 weeks (maximum 60 mg/day) 0.5 mg/kg prednisone/day after week 4 until delivery (maximum 40 mg/day) + 100 mg aspirin/day until 36th weeks of gestation (n = 101) Placebo (n = 101)

Result

Treatment of women with different autoantibodis -including antiphospholipid-antibodies-autoantibodies and recurrent fetal loss with prednisone and aspirin was not effective in promoting live birth, and it increased the risk of prematurity

Patients

385 women participated, 202 were enrolled ³2 consecutive fetal losses before 32 weeks of gestation ³1 autoantibody: Antinuclear antibodies n = 83 Anti-DNA antibodies (single- or double-stranded) n = 37 Antilymphocyte IgM n = 64 Anticardiolipin IgG n = 20 Lupus anticoagulant n = 74 No chromosomal or anatomical abnormality No luteal-phase defect No peptic ulcer disease £3 years No systemic lupus erythematosus No diabetes mellitus

Authors

Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JW, Farewell V, Farine D, Spitzer K, Fielding L, Soloninka CA, Yeung M

Publication

N Engl J Med. 1997;337(3):148–153

Note

Live birth 65% (treatment), 56% (placebo) At term 38% (treatment), 88% (placebo) Before term 62% (treatment), 12% (placebo) Fetal loss 35% (treatment), 44% (placebo) Birth weight <2,500 g 28% (treatment), 18% (placebo) Male sex 62% (treatment), 46% (placebo) Admission to neonatal intensive care unit 35% (treatment), 4% (placebo) Days in neonatal intensive care unit 4.4 (treatment), 6.0 (placebo) Sepsis 2% (treatment), 0% (placebo) Congenital anomaly 0% (treatment), 4% (placebo)

Adverse events

Hypertension 13% (treatment), 5% (placebo) Gestational diabetes mellitus 15% (treatment), 5% (placebo) Cataract n = 2 (treatment), n = 0 (placebo)

464

Antiphospholipid Syndrome: Aspirine vs. Prednisone

Trial

Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients

Substance

Prednisone (20 mg/day and increased or decreased on the basis of observed changes in serial antibody levels, range 10–40 mg/day) + low-dose 81 mg aspirin (n = 17) 81 mg aspirin alone (n = 22)

Result

The use of prednisone therapy in conjunction with low-dose aspirin did not improve and may have contributed to worse pregnancy outcome in antiphospholipid antibody-positive patients, in comparison with aspirin alone

Patients

39 pregnant patients Pos. for anti-cardiolipin antibodies (IgG >8 units/ml, IgM >5 units/ml) or lupus anticoagulant ³1 fetal abortus before 12th week of gestation or ³2 unexplained first trimester miscarriages No anatomical abnormalities No hormonal abnormalities

Authors

Silver RK, MacGregor SN, Sholl JS, Hobart JM, Neerhof MG, Ragin A

Publication

Am J Obstet Gynecol. 1993;169(6):1411–1417

Note

Gestation age at onset treatment (week) 6.7 (prednisone + ASS), 8.4 (ASS) No perinatal losses were observed in the study cohort Preterm delivery n = 8/12 (prednisone + ASS), n = 3/22 (ASS)

Adverse events

Diabetes n = 2 (prednisone + ASS), n = 0 (ASS) Endometritis n = 3 (prednisone + ASS), n = 0 (ASS) Wound dehiscence n = 1 (prednisone + ASS), n = 0 (ASS) Bilateral lower extremity thrombosis n = 1 (prednisone + ASS), n = 0 (ASS) Autoimmune pneumonitis n = 0 (prednisone + ASS), n = 1 (ASS)

Antiphospholipid Syndrome: Heparin

Trial

Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin

Substance

Low-molecular-weight heparin (40 mg enoxaparin/day, n = 25) Until 5 days before scheduled caesarean section 2 × 5,000 IE unfractionated heparin (n = 25) Both heparin dosages were continued post partum for 2 weeks Concomitant medication: Low dose 81 mg aspirin/day until 37. gestational week Oral 2 × 600 mg calcium

Result

Combination therapy of low dose aspirin and unfractionated heparin or low-molecular-weight heparin during pregnancy for the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome was equally safe and effective

Patients

50 women ³3 pregnancy losses before 20th weeks’ gestation Positive antiphospholipid antibodies (cardiolipin IgG >80 units/ml, or phosphatidylserine IgM >70 units/ml) No other reasons for pregnancy loss (chromosomal, TSH, anatomical, hormonal, infections)

Authors

Noble LS, Kutteh WH, Lashey N, Franklin RD, Herrada J

Publication

Fertil Steril. 2005;83(3):684–690

Note

Life birth 84% (enoxoparin), 80% (unfract. heparin) Estimated getation age (weeks) 37.2 (enoxoparin), 38.1 (unfract. heparin) Birth weight 3,047 g (enoxoparin), 2,973 g (unfract. heparin) Vaginal delivery 66.7% (enoxoparin), 75.0% (unfract. heparin) Miscarriges 16% (enoxoparin), 20% (unfract. heparin) Estimated gestation age at miscarriage (weeks) 8.7 (enoxoparin), 7.2 (unfract. heparin)

Adverse events

No major bleeding episodes (both groups) No cases of deep venous thrombosis, thrombocytopenia, pre-eclampsia, gestational diabetes, or bone fractures (both groups) Hematuria n = 1 (enoxoparin – ASS), n = 0 (unfract. heparin – ASS) Bleeding at Injection-site n = 2 (enoxoparin – ASS), n = 0 (unfract. heparin – ASS) Minor bleeding n = 3 (enoxoparin – ASS), n = 2 (unfract. heparin – ASS) Intrauterine growth retardation n = 1 (enoxoparin), n = 1 (unfract. heparin)

465

466

Antiphospholipid Syndrome: Heparin vs. Prednisone

Trial

Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment

Substance

20 mg prednisone every 12 h (prednisone, n = 8) 10,000 IU heparin every 12 h (heparin, n = 12) Dose was reduced by 2,000 IU until PTT was within normal range Concomitant medication: 80 mg Aspirin/day (all patients) Start treatment after exclusion ectopic pregnancy 600–800 U vitamin D 4 g calcium carbonate No prednisone treatment

Result

Serious maternal morbidity and the frequency of preterm delivery were higher in high-risk pregnant women with antiphospholipid antibodies treated with prednisone rather than heparin

Patients

20 patients with antiphospholipid syndrome Confirmed Pregnancy Pos. lupus anticoagulant or anticardiolipin antibodies (2 × pos.) ³2 unexpected unexplained fetal losses on two occasions No other causes of recurrent miscarriages or fetal death No diabetes mellitus No lupus like disorders

Authors

Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L

Publication

Am J Obstet Gynecol. 1992;166(5):1318–1323

Note

Live birth 68% (prednisone), 73% (heparin) Preterm delivery n = 6 (prednisone), n = 2 (heparin) Prenature rupture of membrane n = 3 (prednisone), n = 0 (heparin) Mean week of delivery 32nd week (prednisone), 37th week (heparin) Minor thrush n = 2 (prednisone), n = 0 (heparin) Minor bleeding n = 0 (prednisone), n = 2 (heparin) Superficial thrombosis n = 0 (prednisone), n = 1 (heparin) Managable diabetes n = 3 (prednisone), n = 1 (heparin) Serious preeclamsia n = 3 (prednisone), n = 0 (heparin) Cataract n = 1 (prednisone), n = 0 (heparin) Life birth n = 6 (prednisone), n = 9 (heparin) Fetal death after 12. week of gestation n = 2 (prednisone), n = 1 (heparin)

Antiphospholipid Syndrome: Heparin vs. intravenous Immunoglobulin

467

Trial

A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group

Substance

I.v. immune globulin (IVIG, 1 g/kg, n = 7) Placebo (n = 9) For 2 consecutive days/month until 36 weeks of gestation Concomitant medication: 7,500 units of unfractionated sodium heparin by s.c./12 h Increased to 10,000 U in the second trimenon + 81 mg aspirin

Result

Intravenous immune globulin did not improve obstetric or neonatal outcomes beyond those achieved with a heparin and low-dose aspirin regimen

Patients

16 women With a single live conceptus £12 weeks gestation ³20 U IgG phospholipid-binding anticardiolipin antibodies or Lupus anticoagulant or ³40 units/ml History of fetal death (unexplained intrauterine death of a fetus) or History of unexplained venous or arterial thromboembolism No thrombocytopenia No history of a bleeding disorder No osteoporosis, or a known allergy to immune globulin, heparin, or aspirin No renal disease No active systemic lupus erythematosus No insulin-dependent diabetes mellitus or hypertension

Authors

Branch DW, Peaceman AM, Druzin M, Silver RK, El-Sayed Y, Silver RM, Esplin MS, Spinnato J, Harger J

Publication

Am J Obstet Gynecol. 2000;182(1 Pt 1):122–127

Note

Eclamsia n = 0 (IVIG), n = 0 (placebo) Pre-eclamsia n = 3 (IVIG), n = 1 (placebo) Comparison of neonatal outcomes: Neonatal intensive care unit admissions n = 1 (IVIG), n = 4 (placebo) Length of intensive care unit stay (days) 21 (IVIG, one single patient), 20.8 (placebo) Length of ventilator requirement (days) n = 1 (IVIG, one single patient), 3.0 (placebo) Infant respiratory distress syndrome n = 0 (IVIG), n = 1 (placebo) Pregnancy outcome: Gestational age at delivery (week) 34.8 (IVIG), 36.7 (placebo) Birth weight (g) 2,432.9 (IVIG), 2,604.4 (placebo) Preterm delivery (gestational age <37 week) n = 7 (IVIG), n = 3 (placebo) Oligohydramnios n = 2 (IVIG), n = 2 (placebo) Intrauterine growth restriction (birth weight £10th percentile), n = 1 (IVIG), n = 3 (placebo) Fetal distress n = 0 (IVIG), n = 3 (placebo) Preeclampsia n = 3 (IVIG), n = 1 (placebo)

Adverse events

No cases heparin-induced thrombocytopenia No bleeding No osteopenic fracture

468

Antiphospholipid Syndrome: Heparin vs. intravenous Immunoglobulin

Trial

Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies

Substance

Intravenous immunoglobulin group (IVIG, n = 21): 400 mg/kg/day intravenous immunoglobulin for 2 days Followed by a single dose every month Stoped after 31st week’s gestation: Low molecular weight heparin group (LMW, n = 19): Low molecular weight heparin 5,700 IU/day low-dose aspirin 75 mg/day Concomitant medication: No antihypertensive drugs No previous prednisone therapy

Result

Treatment with low molecular weight heparin plus low-dose aspirin of pregnant patients with antiphospholipid antibodies was superior to intravenous immunoglobulin treatment

Patients

40 women ³3 consecutive abortion before tenth week of gestation ³2 positive test results for anticardiolipin or lupus anticoagulant (>40 IU) No chromosomal or anatomic abnormality No luteal phase defect No confirmed peptic ulcer No diabetes mellitus No SLE No previous thromboembolism No hypertension

Authors

Triolo G, Ferrante A, Ciccia F, Accardo-Palumbo A, Perino A, Castelli A, Giarratano A, Licata G

Publication

Arthritis Rheum. 2003;48(3):728–731

Note

Number of pregnancies n = 21 (IVIG), n = 19 (LMW) Live births 57% (IVIG), 84% (LMW) Duration of pregnancy 38.3 weeks (IVIG), 38.7 weeks (LMW) Birth weight 3,246 g (IVIG), n = 3,298 g (LMW) Preterm deliveries n = 1 (IVIG), n = 0 (LMW) Infants admitted to neonatal intensive care unit n = 1 (IVIG), n = 0 (LMW) Congenital anomalies n = 0 (IVIG), n = 0 (LMW) Cesarean deliveries n = 1 (IVIG), n = 0 (LMW) First-trimester fetal loss 29% (IVIG), 11% (LMW) Fetal loss after 13 weeks n = 2 (IVIG), n = 0 (LMW) Intrauterine death n = 1 (IVIG), n = 1 (LMW)

Antiphospholipid Syndrome: Heparin vs. intravenous Immunoglobulin

Trial

Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome

Substance

Heparin–Aspirin arm: 4,500 IU low-molecular-weight heparin Heparin was discontinued after the 38th weeks of gestation +75 mg aspirin (n = 40) Aspirin was discontinued after the 32nd weeks of gestation Treatment was initiated after pos. pregnancy test

469

Intravenous immunoglobulin arm: 400 mg/kg i.v. immunoglobulins (n = 38) every 28 days Treatment was initiated after pos. pregnancy test Concomitant medication: 500 mg calcium/day (heparin arm) Result

Low-molecular-weight heparin plus low-dose aspirin resulted in a higher live birth rate than i.v. immunoglobulin in the treatment of antiphospholipid antibody syndrome in women with recurrent abortion

Patients

85 patients with antiphospholipid syndrome Age 18–39 years ³3 consecutive spontaneous abortions before 10 weeks of gestation APL antibody pos. ³2 occasions ³6 weeks apart Lupus anticoagulant pos. ³2 occasions ³6 weeks apart No systemic lupus erythematosus No aspirin allergy or sensitivity to aspirin

Authors

Dendrinos S, Sakkas E, Makrakis E

Publication

Int J Gynaecol Obstet. 2009;104(3):223–25, Epub December 29, 2008

Note

Pregnancies n = 40 (heparin-ASS), n = 38 (IVIG) Live birth n = 29 (heparin-ASS), n = 15 (IVIG) Preterm delivery n = 2 (heparin-ASS), n = 1 (IVIG) First trimester abortion n = 11 (heparin-ASS), n = 21 (IVIG) Intrauterine death n = 0 (heparin-ASS), n = 2 (IVIG) Birth weight (kg) n = 3.134 (heparin-ASS), n = 3.232 (IVIG) Vaginal delivery n = 24 (heparin-ASS), n = 11 (IVIG) Cesarean delivery n = 8 (heparin-ASS), n = 2 (IVIG)

Adverse events

Nausea, hypotension, and tachycardia n = 0 (heparin-ASS), n = 3 (IVIG) Thromboembolic complications n = 0 (heparin-ASS), n = 0 (IVIG) Decrease in lumbar spine bone density n = 0 (heparin-ASS), n = 0 (IVIG) Abnormal karyotype n = 1 (heparin-ASS), n = 3 (IVIG)

470

Antiphospholipid Syndrome: Intravenous Immunoglobulins

Trial

Recurrent first trimester spontaneous abortion associated with antiphospholipid antibodies: a pilot study of treatment with intravenous immunoglobulin

Substance

300 mg/kg i.v. immunoglobulin every 3 weeks After confirmation of pregnancy Until 16th to 17th week of pregnancy Concomitant medication: No apirin No other medication

Result

The authors interpreted the results of this open study with intravenous immunoglobulins as promising

Patients

38 women with antiphospholipid syndrome ³3 consecutive abortions within the first trimester Pos. antiphospholipid antibodies

Authors

Marzusch K, Dietl J, Klein R, Hornung D, Neuer A, Berg PA

Publication

Acta Obstet Gynecol Scand. 1996;75(10):922–926

Note

Spontaneous abortions n = 7 Live Birth n = 31 at 37 to 42 weeks of gestation 2,135–4,400 g

Antiphospholipid Syndrome: Warfarin

471

WAPS-Trial

A randomized clinical trial of high-intensity Warfarin versus conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS) WAPS: Warfarin in the antiphospholipid syndrome

Substance

High-intensity warfarin therapy (INR range 3.0–4.5, target 3.5, n = 54) 100 mg aspirin/day (ASS, n = 55)

Result

High-intensity warfarin was not superior to low-dose aspirin in preventing recurrent thrombosis in patients with antiphospholipid syndrome. It was associated with an increased rate of minor hemorrhagic complications

Patients

109 patients with antiphospholipid syndrome Previous thrombosis No thrombosis during anticoagulation No active haemorrhagic disorders

Authors

Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D’Angelo A, Tognoni G, Barbui T

Publication

J Thromb Haemost. 2005;3(5):848–853

Note

Vascular death, major thrombosis 9.3% (warfarin), 5.5% (ASS) Vascular death, major thrombosis or major hemorrhage 11.1% (warfarin), 9.1% (ASS) Death 5.6% (warfarin), 3.6% (ASS) Total thrombosis 11.1% (warfarin), 5.5% (ASS) Ischemic stroke n = 2 (warfarin), n = 2 (ASS) Transient ischemic attacks n = 2 (warfarin), n = 1 (ASS) Deep venous thrombosis n = 2 (warfarin), n = 0 (ASS) Pulmonary embolism n = 1 (warfarin), n = 0 (ASS) Superficial thrombophlebitis n = 1 (warfarin), n = 0 (ASS) Total hemorrhage 27.8% (warfarin), 14.6% (ASS) Major hemorrhage 3.7% (warfarin), 5.5% (ASS) Minor hemorrhage 27.8% (warfarin), 10.9% (ASS)

472

Antiphospholipid Syndrome: Warfarin

Trial

A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome

Substance

Warfarin to achieve an INR of 2.0–3.0 (moderate intensity, n = 56) Warfarin to achieve an INR of 3.1–4.0 (high intensity, n = 58) Concomitant medication: Aspirin was allowed

Result

High-intensity warfarin was not superior to moderate-intensity warfarin for thromboprophylaxis in patients with antiphospholipid antibodies and previous thrombosis

Patients

114 patients with antiphospholipid antibodies Previous thrombosis Not only IgM anticardiolipin antibodies No clinically significant bleeding or diathesis No thrombocytopenia <50,000/mm3 No intracranial hemorrhage, stroke, or gastrointestinal bleeding £ 3 months No pregnancy or planned pregnancy

Authors

Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ

Publication

N Engl J Med. 2003;349(12):1133–1138

Follow up

2.7 years (mean)

Note

Recurrent thrombosis 10.7% (high-intensity) 3.4% (moderate-intensity)

Adverse events

Major bleeding n = 3 (high-intensity), n = 4 (moderate-intensity) Any bleeding n = 14 (high-intensity), n = 11 (moderate-intensity) Myocardial infarction n = 1 (high-intensity), n = 0 (moderate-intensity) Deep vein thrombosis n = 1 (high-intensity), n = 0 (moderate-intensity)

Progressive Systemic Sclerosis

Corticosteroids

Trial

Intravenous dexamethasone pulse therapy in diffuse systemic sclerosis. A randomized placebo-controlled study

Substance

Intravenous 100 mg dexamethasone “pulse” therapy (n = 17) Placebo (dextrose, n = 18) 1×/every 6 months No information on concomitant medication

Result

Intravenous pulse dexamethasone treatment of diffuse systemic sclerosis seemed effective for skin and lung manifestations

Patients

25 patients with diffuse systemic sclerosis No patients with limited disease Not pretreated with any immunosuppressive drug or corticosteroids

Authors

Sharada B, Kumar A, Kakker R, Adya CM, Pande I, Uppal SS, Pande JN, Sunderam KR, Malaviya AN

Publication

Rheumatol Int. 1994;14(3):91–94

Note

Change of: Total skin score –4.5 (dexamethasone), +4.1 (placebo) Flexion index –0.8 (dexamethasone), +2.9 (placebo) Maximum oral opening –0.7 (dexamethasone), –0.5 (placebo) Extension index +1.6 (dexamethasone), –0.4 (placebo) Functional disability score –1.9 (dexamethasone), –0.6 (placebo) Frequency of Raynaud’s phenomenon –3.1×/day (dexamethasone), –1.6×/day (placebo) ESR (mm/h) –6.9 (dexamethasone), –1.6 (placebo) Vital Capacity +1.6% (dexamethasone), –0.1% (placebo) DLCO –15.8% (dexamethasone), –8.6% (placebo) Tidal Volume –0.6 (dexamethasone), +9.0 (placebo) FEV1 –2.0 (dexamethasone), –1.5 (placebo) Maximum mid-expiratory flow rate +1.7 (dexamethasone), +1.6 (placebo)

Adverse events

Infections n = 12 (dexamethasone), n = 6 (placebo)

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_6, © Springer-Verlag London Limited 2011

473

474

Progressive Systemic Sclerosis: Ambrisentan

ARIES-Trial

Ambrisentan for the treatment of pulmonary arterial hypertension: results of the Ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES), study 1 and 2. ARIES: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study

Substance

Placebo (n = 132) Ambrisentan dose: ARIES-1: 5 mg/day (n = 67) or 10 mg/day (n = 68) ARIES-2: 2.5 mg/day (n = 64) or 5 mg/day (n = 63) Concomitant medication: No bosentan No sitaxsentan No sildenafil No epoprostenol No iloprost No treprostinil

Result

Ambrisentan treatment of patients with pulmonary arterial hypertension improved exercise capacity. Ambrisentan was well tolerated. It was associated with a low risk of aminotransferase abnormalities

Patients

269 (Aries 1) and 215 (Aries 2) patients With pulmonary arterial hypertension, including (number not disclosed) secondary to connecitve tissue/autoimmune disease No patients with 6-min walk distance < 150 m No patients with 6-min walk distance > 450 m

Authors

Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group

Publication

Circulation. 2008;117(23):3010–3019, Epub May 27, 2008

Follow up

12 weeks

Note

Change of: ARIES 1 6-min walk distance: disance decreased (placebo), +31 m (5 mg ambrisentan), +51 m (10 mg ambrisentan) Improvements in World Health Organization functional class, Borg dyspnea score, and B-type natriuretic peptide ARIES 2 6-min walk distance: distance decreased (placebo), +32 m (2.5 mg ambrisentan), +45 m (5 mg ambrisentan) Improvements in time to clinical worsening, Short Form-36 score, Borg dyspnea score, and B-type natriuretic peptide

Progressive Systemic Sclerosis: Ambrisentan

Adverse events

475

ARIES 1 Death 3% (placebo), 1% (5 mg ambrisentan), 1% (10 mg ambrisentan) Hospitalization for PAH 3% (placebo), 3% (5 mg ambrisentan), 3% (10 mg ambrisentan) Withdrawal because of other PAH treatment 1% (placebo), 0% (5 mg ambrisentan), 1% (10 mg ambrisentan) Peripheral edema 10.4% (placebo), 26.9% (5 mg ambrisentan), 28.4% (10 mg ambrisentan) Nasal congestion 3.0% (placebo), 6.0% (5 mg ambrisentan), 10.4% (10 mg ambrisentan) Sinusitis 0% (placebo), 4.5% (5 mg ambrisentan), 4.5% (10 mg ambrisentan) Flushing 0% (placebo), 3.0% (5 mg ambrisentan), 1.5% (10 mg ambrisentan) Nasopharyngitis 1.5% (placebo), 7.5% (5 mg ambrisentan), 3.0% (10 mg ambrisentan) Abdominal pain 1.5% (placebo), 3.0% (5 mg ambrisentan), 3.0% (10 mg ambrisentan) Constipation 1.5% (placebo), 4.5% (5 mg ambrisentan), 6.0% (10 mg ambrisentan) Palpitations 3.0% (placebo), 0.0% (5 mg ambrisentan), 4.5% (10 mg ambrisentan) Dyspnea 3.0% (placebo), 6.0% (5 mg ambrisentan), 4.5% (10 mg ambrisentan) Headache 20.9% (placebo), 17.9% (5 mg ambrisentan), 19.4% (10 mg ambrisentan) ARIES 2 Death 5% (placebo), 3% (2.5 mg ambrisentan), 0% (5 mg ambrisentan) Hospitalization for PAH 14% (placebo), 5% (2.5 mg ambrisentan), 3% (5 mg ambrisentan) Withdrawal because of other PAH treatment 0% (placebo), 0% (2.5 mg ambrisentan), 0% (5 mg ambrisentan) Peripheral edema 10.8% (placebo), 3.1% (2.5 mg ambrisentan), 9.5% (5 mg ambrisentan) Nasal congestion 0% (placebo), 1.6% (2.5 mg ambrisentan), 4.8% (5 mg ambrisentan) Sinusitis 0% (placebo), 1.6% (2.5 mg ambrisentan), 1.6% (5 mg ambrisentan) Flushing 1.5% (placebo), 6.3% (2.5 mg ambrisentan), 4.8% (5 mg ambrisentan) Nasopharyngitis 0% (placebo), 0% (2.5 mg ambrisentan), 3.2% (5 mg ambrisentan) Abdominal pain 0% (placebo), 3.1% (2.5 mg ambrisentan), 3.2% (5 mg ambrisentan) Constipation 1.5% (placebo), 3.1% (2.5 mg ambrisentan), 1.6% (5 mg ambrisentan) Palpitations 1.5% (placebo), 6.3% (2.5 mg ambrisentan), 7.9% (5 mg ambrisentan) Dyspnea 3.1% (placebo), 1.6% (2.5 mg ambrisentan), 4.8% (5 mg ambrisentan) Headache 6.2% (placebo), 7.8% (2.5 mg ambrisentan), 12.7% (5 mg ambrisentan)

476

Progressive Systemic Sclerosis: Ambrisentan

ARIES-Trial

Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension ARIES: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study

Substance

Clinical trial: Placebo (n = 132) Ambrisentan dose: ARIES-1: 5 mg/day (n = 67) or 10 mg/day (n = 68) ARIES-2: 2.5 mg/day (n = 64) or 5 mg/day (n = 63) Concomitant medication: No bosentan No sitaxsentan No sildenafil No epoprostenol No iloprost No Ttreprostinil Long term extension (first 24 weeks): Fixed dose After week 24: Randomized treatment assignment remained blinded Dose adjustments were permitted per investigator discretion Available doses: 1, 2.5, 5, and 10 mg 2.5 mg ambrisentan, finishing year 2 n = 69 5 mg ambrisentan, finishing year 2 n = 126 10 mg ambrisentan, finishing year 2 n = 66

Result

Ambrisentan treatment over 2 years was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was well tolerated

Patients

269 (Aries 1) and 215 (Aries 2) patients With pulmonary arterial hypertension No patients with-min walk distance <150 m No patients with-min walk distance >450 m

Authors

Oudiz RJ, Galiè N, Olschewski H, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Harrison BC, Despain D, Dufton C, Rubin LJ; ARIES Study Group

Publication

J Am Coll Cardiol. 2009;54(21):1971–1981

Follow up

2 years

Progressive Systemic Sclerosis: Ambrisentan

Note

Year 1: Improvement of WHO class 17% (2.5 mg ambrisentan), 30% (5 mg ambrisentan), 38% (10 mg ambrisentan) No change of WHO class 72% (2.5 mg ambrisentan), 65% (5 mg ambrisentan), 48% (10 mg ambrisentan) Worsening of WHO class 11% (2.5 mg ambrisentan), 5% (5 mg ambrisentan), 15% (10 mg ambrisentan) Survival n = 81 (2.5 mg ambrisentan), n = 153 (5 mg ambrisentan), n = 81 (10 mg ambrisentan) Year 2: Improvement of WHO class 17% (2.5 mg ambrisentan), 31% (5 mg ambrisentan), 41% (10 mg ambrisentan) No change of WHO class 62% (2.5 mg ambrisentan), 58% (5 mg ambrisentan), 45% (10 mg ambrisentan) Worsening of WHO class 21% (2.5 mg ambrisentan), 11% (5 mg ambrisentan), 15% (10 mg ambrisentan) Survival n = 68 (2.5 mg ambrisentan), n = 121 (5 mg ambrisentan), n = 66 (10 mg ambrisentan) Change of (end of first year): 6 min Walking distrance +25 m (2.5 mg ambrisentan), +28 m (5 mg ambrisentan), +37 m (10 mg ambrisentan) Borg Dyspnoe index –0.08 (2.5 mg ambrisentan), –0.59 (5 mg ambrisentan), –0.51 (10 mg ambrisentan) Change of (end of second year): 6 min Walking distrance +7 m (2.5 mg ambrisentan), +23 m (5 mg ambrisentan), +28 m (10 mg ambrisentan) Borg Dyspnoe index +0.23 (2.5 mg ambrisentan), –0.33 (5 mg ambrisentan), –0.60 (10 mg ambrisentan)

477

478

Adverse events

Progressive Systemic Sclerosis: Ambrisentan

Right ventricular failure 3.1% (2.5 mg ambrisentan), 3.7% (5 mg ambrisentan), 5.2% (10 mg ambrisentan) Pulmonary hypertension 7.3% (2.5 mg ambrisentan), 2.1% (5 mg ambrisentan), 3.1% (10 mg ambrisentan) Acute respiratory failure 0.0% (2.5 mg ambrisentan), 1.1% (5 mg ambrisentan), 2.1% (10 mg ambrisentan) Cardiac arrest 1.0% (2.5 mg ambrisentan), 1.1% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Cardiorespiratory arrest 1.0% (2.5 mg ambrisentan), 1.1% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Pneumonia 1.0% (2.5 mg ambrisentan), 0.5% (5 mg ambrisentan), 1.0% (10 mg ambrisentan) Diarrhea 0.0% (2.5 mg ambrisentan), 1.1% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Dyspnea exacerbated 1.0% (2.5 mg ambrisentan), 0.5% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Hemorrhage intracranial 0.0% (2.5 mg ambrisentan), 0.0% (5 mg ambrisentan), 2.1% (10 mg ambrisentan) Hepatic enzyme increased 1.0% (2.5 mg ambrisentan), 0.0% (5 mg ambrisentan), 1.0% (10 mg ambrisentan) Hypoxia 0.0% (2.5 mg ambrisentan), 0.0% (5 mg ambrisentan), 2.1% (10 mg ambrisentan) Multiorgan failure 1.0% (2.5 mg ambrisentan), 0.5% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Pyrexia 0.0% (2.5 mg ambrisentan), 1.1% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Respiratory arrest 1.0% (2.5 mg ambrisentan), 0.0% (5 mg ambrisentan), 1.0% (10 mg ambrisentan) Sudden death 0.0% (2.5 mg ambrisentan), 0.5% (5 mg ambrisentan), 1.0% (10 mg ambrisentan) Syncope 2.1% (2.5 mg ambrisentan), 0.0% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Vomiting 0.0% (2.5 mg ambrisentan), 1.1% (5 mg ambrisentan), 0.0% (10 mg ambrisentan) Event free ALT/AST > 3× upper normal limit 98.2% (all patients, year 1), 96.1% (all patients, year 2) Death 14% (2.5 mg ambrisentan), 11% (5 mg ambrisentan), 8% (10 mg ambrisentan)

Progressive Systemic Sclerosis: Azathioprine

479

Trial

Experience with azathioprine in systemic sclerosis associated with interstitial lung disease

Substance

Azathioprine + low-dose prednisone No information on the dosages used No information on concomitant medication

Result

Azathioprine had an effect on dyspnea and on lung function parameters in this open study of patients with interstitial lung disease in systemic sclerosis

Patients

11 patients with systemic sclerosis + interstitial lung disease FVC > 70% of the predicted and declining Nonsmokers

Authors

Dheda K, Lalloo UG, Cassim B, Mody GM

Publication

Clin Rheumatol. 2004;23(4):306–9. Epub April 14, 2004

Follow up

18 months

Note

FVC predicted 54.25 (baseline), 63.38 (12 months), 60.0 (18 months) Patients improved during follow up n = 5 Patients remained stable during follow up n = 3 Mean dyspnea score (n = 8), improved from a baseline of 1.55, 0.50 (12 months), 0.43 (18 months)

Adverse events

Nausea n = 1 Leukopenia n = 1 Death n = 1 (unknown cause) Carcinoma tongue n = 1 Pulmonary tuberculosis n = 1

480

Progressive Systemic Sclerosis: Azathioprine + Cyclophosphamide

FAST-Trial

A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral Azathioprine for the treatment of pulmonary fibrosis in scleroderma FAST: Fibrosing Alveolitis in Skleroderma Trial

Substance

Induction therapy: 20 mg Prednisolone on alternate days + 6 × 600 mh/sqm cyclophosphamide (CYC)/4 weeks Maintenance therapy: 2.5 mg/kg azathioprine (AZA)/day Started with 50 mg/day Increate to full dosage within 4 weeks (n = 22) Placebo (n = 23) Pretreatement: No prior AZA or CYC therapy for >3 months No oral prednisolone ³10 mg/day ³3 months

Result

Azathioprine treated patients versus did not improve significantly as compared to placebo treated patients. There was a trend toward better FVC values among azathioprine treated patients

Patients

45 patients with systemic sclerosis (SSc) and SSc-associated pulmonary fibrosis High resolution computer tomograph: ³5% extend of the disease or ground glass attenuation or thoracoscopic lung biopsy No treatment with AZA or CYC or high-dose oral corticosteroid therapy (30 mg of prednisolone), for >3 months

Authors

Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh NJ, Foley NM, Pearson SB, Emery P, Veale DJ, Denton CP, Wells AU, Black CM, du Bois RM

Publication

Arthritis Rheum. 2006;54(12):3962–3970

Follow up

1 year

Note

Improvement on serial HRCT 40% (Aza), 20% (placebo) Change of: FVC (% predicted) +2.4 (Aza), –3.0 (placebo) DLCO (% predicted) –3.3 (Aza), –3.2 (placebo) TLC (% predicted) –1.6 (Aza), –2.4 (placebo) FEV1 (% predicted) +1.7 (Aza), –2.7 (placebo) Coefficient of gas transfer (% predicted) +0.2 (Aza), –4.8 (placebo) Dyspnea score (mean) +1.05 (Aza), +0.6 (placebo)

Adverse events

Nausea 36.4% (Aza), 0% (placebo) Mood disturbance 18.2% (Aza), 0% (placebo) Oral ulcers 13.6% (Aza), 0% (placebo) Rash 13.6% (Aza), 0% (placebo) Abdominal findings 9.1% (Aza), 0% (placebo) Diarrhoea 9.1% (Aza), 0% (placebo) Dyspepsia 4.5% (Aza), 0% (placebo) Respiratory tract infection 13.6% (Aza), 17.4% (placebo) Hematuria (baseline) 13.6% (Aza), 17.4% (placebo) Hematuria (end of follow up) 45.5% (Aza), 26.1% (placebo)

Progressive Systemic Sclerosis: Bosentan

481

Trial

Effects of the dual endothelin-receptor antagonist Bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study

Substance

2 × 62.5 mg bosentan/day (after 4 weeks then 2 × 125 mg/day, n = 21) Placebo (n = 11) Prior medication: Stop any of treatments within 1 month of screening No epoprostenol within 1 month No glibenclamide or ciclosporin within 1 month Concomitant medication: Warfarin: 71% (bosentan), 73% (placebo) Diltiazem: 29% (bosentan), 18% (placebo) Amlodipine: 14% (bosentan), 36% (placebo)

Result

Bosentan increased exercise capacity and improved hemodynamics in patients with pulmonary hypertension

Patients

32 patients with pulmonary hypertension Primary or associated with scleroderma Functional classes III–IV (WHO classification) Despite previous treatment with vasodilators, anticoagulants, diuretics, cardiac glycosides, or supplemental oxygen Baseline 6-min walking distance 150–500 m Mean pulmonary artery pressure > 25 mmHg Pulmonary capillary wedge pressure < 15 mmHg Pulmonary vascular resistance > 240 dyn s/cm5

Authors

Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ

Publication

Lancet. 2001;358(9288):1119–1123

Follow up

20 weeks

Note

Change of: 6 min walk test (m, week 12) +70 (bosentan), –6 (placebo) 6 min walk test (m, week 20) +77 (bosentan), –15 (placebo) Cardiac index (L/min/m2) +0.5 (bosentan), –0.5 (placebo) Pulmonary vascular resist. (dyn s/cm5) –223 (bosentan), +191 (placebo) Pulmonary artery pressure (mmHg) –1.6 (bosentan), –5.1 (placebo) Mean right arterial apressure (mmHg) –1.3 (bosentan), +4.9 (placebo) Improvement to WHO class II 43% (bosentan), 9% (placebo)

482

Progressive Systemic Sclerosis: Bosentan

Trial

Bosentan therapy for pulmonary arterial hypertension

Substance

Placebo (n = 69) 2 × 62.5 mg/day for 4 weeks Followed by Bosentan 2 × 125/day (n = 74) or Bosentan 2 × 250 mg/day (n = 70) for a minimum of 12 weeks Concomitant medication: Antithrombotic agents: 72% (placebo), 69% (125 mg bosentan), 71% (250 mg bosentan) Diuretics: 46% (placebo), 54% (125 mg bosentan), 56% (250 mg bosentan) Calcium-channel blockers: 52% (placebo), 45% (125 mg bosentan), 44% (250 mg bosentan) Supplemental oxygen at screening visit: 33% (placebo), 26% (125 mg bosentan), 31% (250 mg bosentan)

Result

Bosentan was beneficial and well tolerated in patients with pulmonary arterial hypertension

Patients

213 patients with pulmonary arterial hypertension WHO class III or IV Despite anticoagulant treatment Primary or associated with connective-tissue disease 6 min walk test 150–450 m Pulmonary artery pressure ³25 mmHg Capillary wedge pressure ³15 mmHg Pulmonary vascular resistance 240 dynx s/cm5

Authors

Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G

Publication

N Engl J Med. 2002;346(12):896–903

Follow up

16 weeks

Progressive Systemic Sclerosis: Bosentan

Note

Improvement WHO III =>II 28% (placebo), 38% (125 mg bosentan), 34% (250 mg bosentan) Improvement WHO III =>I 0% (placebo), 3% (125 mg bosentan), 1% (250 mg bosentan) Clinical worsening 20% (placebo), 7% (125 mg bosentan), 6% (250 mg bosentan) Death 3% (placebo), 1% (125 mg bosentan), 0% (250 mg bosentan) Hospitalisation or discontinuation for pulmonary arterial hypertension 13% (placebo), 4% (125 mg bosentan), 4% (250 mg bosentan) Lack of clinical improvement leading to discontinuation 1% (placebo), 0% (125 mg bosentan), 0% (250 mg bosentan) Worsening of pulmonary arterial hypertension leading to discontinuation 7% (placebo), 4% (125 mg bosentan), 3% (250 mg bosentan) Receipt of Epoprostenol 4% (placebo), 3% (125 mg bosentan), 3% (250 mg bosentan) Borg dyspnoea index +0.4 (placebo) –0.1 (bosentan 2 × 125) –0.6 (bosentan 2 × 250 mg)

Adverse events

Headache 19% (placebo), 19% (125 mg bosentan), 23% (250 mg bosentan) Dizziness 19% (placebo), 12% (125 mg bosentan), 10% (250 mg bosentan) Worsening of symptoms of pulmonary arterial hypertension 19% (placebo), 9% (125 mg bosentan), 6% (250 mg bosentan) Cough 12% (placebo), 5% (125 mg bosentan), 6% (250 mg bosentan) Dyspnoea 10% (placebo), 3% (125 mg bosentan), 7% (250 mg bosentan) Syncope 6% (placebo), 8% (125 mg bosentan), 10% (250 mg bosentan) Flushing 4% (placebo), 9% (125 mg bosentan), 9% (250 mg bosentan) Abnormal hepatic function 3% (placebo), 4% (125 mg bosentan), 14% (250 mg bosentan)

483

484

Progressive Systemic Sclerosis: Bosentan

RAPIDS-1-Trial

Digital ulcers in systemic sclerosis: prevention by treatment with Bosentan, an oral endothelin receptor antagonist RAPIDS: RAndomized Placebo-controlled study on prevention of Ischemic Digital ulcers in Scleroderma

Substance

2 × 62.5 mg bosentan/day (n = 79) for 4 weeks Increased to 2 × 125 mg bosentan/day Placebo (n = 43) Concomitant medication: Continue treatment with oral vasodilating and immunosuppressive drugs Receiving calcium channel blockers 58.1% (placebo), 41.8% (bosentan) ACE inhibitors/Angiotensin II rec. antag. 25.6% (placebo), 25.3% (bosentan) No treatment with parenteral prostanoids within the previous 3 months

Result

Bosentan was effective in preventing new digital ulcers and improving hand function in patients with systemic sclerosis

Patients

122 systemic sclerosis patients with digital ulcers 38% diffuse scleroderma, 62% had limitedscleroderma Body weight > 40 kg

Authors

Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E, Rich E, Carpentier P, Molitor J, Seibold JR, Hsu V, Guillevin L, Chatterjee S, Peter HH, Coppock J, Herrick A, Merkel PA, Simms R, Denton CP, Furst D, Nguyen N, Gaitonde M, Black C

Publication

Arthritis Rheum. 2004;50(12):3985–3993

Follow up

16 weeks

Note

New ulcers/patient 1.4 (bosentan), 2.7 (placebo) New digital ulcers (% of the patients) 58% (bosentan), 61% (placebo) ³4 new ulcers/patient with ulcers at baseline 13% (bosentan), 42% (placebo) Study completed n = 37 (placebo), n = 66 (bosentan) No difference in the healing of existing ulcers

Progressive Systemic Sclerosis: Bosentan

Adverse events

Headache 16.3% (placebo), 16.5% (bosentan) Liver function tests abnormal 0% (placebo), 11.4% (bosentan) Upper respiratory tract infection 14.0% (placebo), 8.9% (bosentan) Vomiting 9.3% (placebo), 8.9% (bosentan) Diarrhoea 2.3% (placebo), 8.9% (bosentan) Infected skin ulcer 4.7% (placebo), 7.6% (bosentan) Arthralgia 16.3% (placebo), 6.3% (bosentan) Pain in limb 9.3% (placebo), 6.3% (bosentan) Fatigue 7.0% (placebo), 5.1% (bosentan) Nasopharyngitis 7.0% (placebo), 5.1% (bosentan) Edema lower limb 7.0% (placebo), 5.1% (bosentan) Flushing 2.3% (placebo), 5.1% (bosentan) Constipation 0% (placebo), 5.1% (bosentan) Oesophageal reflux aggravated 0% (placebo), 5.1% (bosentan) Other 72.1% (placebo), 83.5% (bosentan) Serious adverse events: Ventricular tachycardia n = 0 (placebo), n = 2 (bosentan) Palpitations n = 0 (placebo), n = 1 (bosentan) Dyspnea n = 1 (placebo), n = 1 (bosentan) Acute high-altitude sickness n = 1 (placebo), n = 0 (bosentan) Vomiting n = 1 (placebo), n = 0 (bosentan) Esophagitis n = 1 (placebo), n = 0 (bosentan) Digital ischemia n = 1 (placebo), n = 0 (bosentan)

485

486

Progressive Systemic Sclerosis: Bosentan

BREATHE-1Trial

Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions BREATH: Bosentan: Randomised Trial of Endothelin Receptor antagonist Therapy for Pulmonary Arterial Hypertension

Substance

2 × 62.5 mg Bosentan/day for 4 weeks Up-titration 2 × 125 or 2 × 250 mg for 8 or 12 weeks (n = 44) Placebo (n = 22) Followed by open label extension (n = 64) Bosentan monotherapy n = 40 Addition of prostanoids n = 1 Discontinued n = 19

Result

Short-term bosentan treatment patients with pulmonary arterial hypertension secondary to connective tissue disease with the subsequent addition of other PAH treatments, if required, was safe for long-term treatment and had a positive effect on outcome

Patients

66 patients with PAH Secondary to connective tissue disease (CTD) World Health Organization (WHO) functional class III–IV 6-min walk test distance 150–500 m Pulmonary arterial pressure >25 mmHg Pulmonary vascular resistance 0.240 dyn s/cm5 Pulmonary capillary wedge pressure < 15 mmHg (right heart catheterisation) No patients with vital capacity < 70% predicted PAH/SSc n = 52 SLE n = 8 Overlap syndrome n = 4 CTD (unclassified) n = 2

Authors

Denton CP, Humbert M, Rubin L, Black CM

Publication

Ann Rheum Dis. 2006;65(10):1336–1340. Epub June 22, 2006

Follow up

12–16 weeks, 1.6 years (mean) open label extension

Note

6-min walk distance at the end of the study +19.5 m (bosentan), –2.6 m (placebo) Epoprostenol as add-on treatment 16% Epoprostenol 14% after discontinuation of bosentan Survival 85.9% (bosentan 1 year) 73.4% (bosentan 2 year) Event free survival n = 29 (bosentan), n = 16 (placebo)

Adverse events

Dizziness 18.2% (bosentan), 4.5% (placebo) Lower limb oedema 18.2% (bosentan), 4.5% (placebo) Headache 15.9% (bosentan), 22.7% (placebo) Fatigue 13.6% (bosentan), 0% (placebo) Abnormal hepatic function 11.4% (bosentan), 9.1% (placebo)

Progressive Systemic Sclerosis: Bosentan

Trial

Improvement of vascular endothelial function using the oral endothelin receptor antagonist Bosentan in patients with systemic sclerosis

Substance

Bosentan (2 × 62.5 mg/day, n = 12) Untreated control patients (n = 12) Concomitant medication: Vasoactive and immunosuppressive therapy was continued

Result

Bosentan improved endothelial function without affecting hemodynamic parameters or endothelial activation-related processes

Patients

systemic sclerosis (SSc) Patients Pulmonary hypertension and/or Digital ulcers Decreased brachial artery ultrasound derived flow-mediated dilation (FMD%)

Authors

Sfikakis PP, Papamichael C, Stamatelopoulos KS, Tousoulis D, Fragiadaki KG, Katsichti P, Stefanadis C, Mavrikakis M

Publication

Arthritis Rheum. 2007;56(6):1985–1993

Follow up

4 weeks

Note

Change of: Flow-mediated dilation +5.3% (bosentan), 0% (control) Systolic blood pressure (mmHg) –3 (bosentan), –4 (control) Diastolic blood pressure (mmHg) –6 (bosentan), –6 (control) Reactive hyperaemia +15% (bosentan), –12% (control) Nitro–glycerine–induced dilation +5.7% (bosentan), +5.3% (control) Augmentation index –2.5% (bosentan), +0.3% (control) Forearm blood flow (mL/min/100 mL) +0.2 (bosentan), –0.1 (control) Peripheral flow reserve –0.3 (bosentan), –0.1 (control) ICAM–1 (ng/mL) +76 (bosentan), –67 (control) E–selectin (ng/mL) +6 (bosentan), +2 (control) VEGF (pg/mL) –19 (bosentan), –20 (control) Endothelin 1 (pg/mL) 0 (bosentan), –0.4 (control)

487

488

Progressive Systemic Sclerosis: Bosentan

BUILD-1-Trial

BUILD-1: a randomized placebo-controlled trial of Bosentan in idiopathic pulmonary fibrosis BUILD: Bosentan Use in Interstitial Lung Disease

Substance

Oral bosentan 62.5 mg twice daily for 4 weeks Increased to 125 mg twice daily thereafter (n = 74) Placebo (n = 84) Concomitant medication: No immunosuppressive drugs No cytotoxic drugs Prednisone £15 mg or equivalent No calcineurin inhibitors, fluconazole, and glyburide

Result

Bosentan treated patients with idiopathic pulmonary fibrosis did not show superiority over placebo. A trend in delayed time to death or disease progression, and improvement in quality of life, was observed with bosentan

Patients

Please note: trial presented because of lack of trials in patients with pulmonary fibrosis secondary to connective tissue disease 158 patients with idiopathic pulmonary fibrosis Demonstrated by HRCT Diagnosis £3 years before enrolment Baseline 6 min walking distance between 150 and 499 m FVC ³50% predicted DLCO ³30% predicted RV > 120% FEV1/FVC ³65% Echocardiographic pulmonary hypertension (systolic pulmonary pressure > 50 mmHg or tricuspid) Regurgitation velocity > 3.2 m/s No severe congestive heart failure PaO2 ³55 mmHg

Authors

King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, Stähler G, Leconte I, Roux S, Raghu G

Publication

Am J Respir Crit Care Med. 2008;177(1):75–81

Follow up

12 months

Note

Change of: 6-min walk test –52 m (bosentan), –34 m (placebo) Disease progression or death 22.5% (bosentan), 36.1% (placebo) Death n = 3 (bosentan), n = 3 (placebo) Study not completed 33.8% (Bosentan), 28.6% (placebo) Acute decompensation of idiopathic pulmonary fibrosis n = 0 (bosentan), n = 3 (placebo) FVC –6.4% (bosentan), –7.7% (placebo) DLCO –4.3% (bosentan), –5.8% (placebo)

Adverse events

Cough 17.6% (bosentan), 27.4% (placebo) Worsening of idiopathic pulmonary fibrosis 16.2% (bosentan), 23.8% (placebo) Exacerbation of dyspnoea 13.5% (bosentan), 19.0% (placebo) Elevations in alanine aminotransferase 20.5% (bosentan), 0% (placebo)

Progressive Systemic Sclerosis: Bosentan

Trial

Long-term experience of Bosentan for treating ulcers and healed ulcers in systemic sclerosis patients

Substance

2 × 62.5 mg/day for 28 days and a Maintenance dose of 2 × 125 mg

Result

Bosentan treatment of systemic sclerosis patients was a safe long-term alternative for treating the recurrence of skin ulcers

Patients

15 SSc patients suffering from digital ulcers Diffuse cutaneous SSc 33.3% Limited cutaneous SSc 66.6%

Authors

García de la Peña-Lefebvre P, Rodríguez Rubio S, Valero Expósito M, Carmona L, Gámir Gámir ML, Beltrán Gutiérrez J, Díaz-Miguel C, Orte Martínez J, Zea Mendoza AC

Publication

Rheumatology (Oxford). 2008;47(4):464–466. Epub February 7, 2008

Follow up

Median 24.7 months

Note

Change of: Modified Rodnan skin score –1.8 Oral opening –3.4 mm Mean hand flexion +1.5 mm Mean hand extension –0.3 mm Mean grip strength –5.4 mmHg No. of ulcers –1.4 No. of healed ulcers –0.4 Number of Raynaud’s phenomenon episodes –1.7 Duration of Raynaud’s phenomenon episodes –34.8 min Raynaud’s phenomenon VAS –50.0 mm Overall disease VAS (mm) +14.0 Arthritis impact measurement scales –0.6 Scleroderma health assessment questionnaire –0.1

Adverse events

Increase of transaminases (<3 × normal values), n = 3 Myocardial infarction n = 1 Headache n = 1 Nasal congestion n = 2 Discomfort n = 1 Anaemia n = 2 Infection of ulcers n = 5 Decrease of 1–2 points of haemoglobin n = 6

489

490

Progressive Systemic Sclerosis: Bosentan

Trial

No effects of Bosentan on microvasculature in patients with limited cutaneous systemic sclerosis

Substance

Bosentan, 2 × 62.5 mg 4 weeks Followed by 2 × 125 mg 12 weeks Concomitant medication: No prior use of bosentan Reliable method of contraception No prostanoids therapy during the last month No sympathectomy £12 months Calcium channel antagonists, ketanserin, angiotensin converting enzyme inhibitors were continued at a stable dosage

Result

Bosentan treatment of patients with limited cutaneous systemic sclerosis did not lead to structural improvement of micro-vascular system and function in this short-time mechanistic pilot study

Patients

15 patients with limited cutaneous SSc Digital pitting scars and/or ulceration No current smoking or smoking £4 weeks

Authors

Hettema ME, Zhang D, Stienstra Y, Smit AJ, Bootsma H, Kallenberg CG

Publication

Clin Rheumatol. 2009;28(7):825–833. Epub April 7, 2009

Follow up

16 weeks with a follow-up period of 4 weeks

Note

Change of: Baseline flux (arbitrary units) –2.42 Plateau flux (arbitrary units) +7.3 Absolute increase (arbitrary units) +9.8 ACh-mediated vasodilatation –31.3% SNP-mediated vasodilatation 22.8 Plateau flux (arbitrary units) 29.1 Absolute increase (arbitrary units) –2.6 Sodium nitroprusside-mediated vasodilatation –151.3% Number of capillaries –0.5/3 mm

Progressive Systemic Sclerosis: Chlorambucil

Trial

Immunosuppression with Chlorambucil, versus placebo, for scleroderma. Results of a three-year, parallel, randomized, double-blind study

Substance

Placebo (n = 32) 0.05 mg/kg chlorambucil/day (n = 33) 0.075 mg/kg chlorambucil/day after 6 months 0.010 mg/kg chlorambucil/day after 1 year Concomitant medication: No immunosoppressive drugs >3 months Prednisolone £15 mg

Result

3 years of treatment with chlorambucil did not improve signs and symptoms of this scleroderma population

Patients

65 SSc patients Creatinine < 2 mg/dL pO2 > 55 torr

Authors

Furst DE, Clements PJ, Hillis S, Lachenbruch PA, Miller BL, Sterz MG, Paulus HE

Publication

Arthritis Rheum. 1989;32(5):584–593

Follow up

3 years

Note

Change of: Skin Score (max. 30) –1.12 (chlorambucil), –0.27 (placebo) Weight (kg) –0.39 (chlorambucil), –0.31 (placebo) DLCO (% of normal) –1.73 (chlorambucil), –2.51 (placebo) TLC (% of normal) +0.72 (chlorambucil), –0.64 (placebo) FVC (% of normal) –0.14 (chlorambucil), –0.35 (placebo) FEV (% of normal) –0.25 (chlorambucil), +0.17 (placebo) Creatinine clearance, mL/min –2.92 (chlorambucil), –4.55 (placebo) Serum creatinine (mg%) +0.01 (chlorambucil), –0.01 (placebo) Proteinuria (mg/24 h) +5.66 (chlorambucil), –2.70 (placebo) Tender joint count –0.06 (chlorambucil), –0.60 (placebo)

Adverse events

Lack of benefit n = 4 (chlorambucil), n = 5 (placebo) Leucopenia n = 21 (chlorambucil), n = 5 (placebo) Thrombocytopenia n = 3 (chlorambucil), n = 1 (placebo) Gastrointestinal effects n = 4 (chlorambucil), n = 4 (placebo) Infections n = 6 (chlorambucil), n = 1 (placebo) Aplastic anaemia n = 0 (chlorambucil), n = 1 (placebo) Death n = 9 (chlorambucil), n = 13 (placebo) Cancer n = 0 (chlorambucil), n = 3 (placebo)

491

492

Progressive Systemic Sclerosis: Ciclosporine

Trial

Ciclosporine in systemic sclerosis. Results of a 48-week open safety study in ten patients

Substance

1 mg/kg ciclosporine/day (n = 10) Placebo (n = 13) Background medication: Hypertension ³ACE inhibitor and/or decrease dosage CsA Prior treatment: No anti-metabolite treatment £3 months No immunosuppressive treatment £3 months No colchicine £3 months No ACE inhibitors £3 months

Result

Skin thickening decreased significantly in ciclosporin treated patients, while cardiac and pulmonary involvement remained unchanged. Adverse events were frequent and dose associated

Patients

23 systemic sclerosis patients Duration of cutaneous involvement < 60 months ³21 years of age No arterial hypertension (CsA group) No pO2 £55 torr

Authors

Clements PJ, Lachenbruch PA, Sterz M, Danovitch G, Hawkins R, Ippoliti A, Paulus HE

Publication

Arthritis Rheum. 1993;36(1):75–83

Follow up

48 weeks

Note

Change of: Skin Score –2.9 (CsA), –0.3 (placebo) Joint count –5.7 (CsA), –5.1 (placebo) Creatinine Clearance (mL/min) –27 (CsA), –11 (placebo) Serum creatinine (mg/dL) +0.2 (CsA), +0.07 (placebo) Total lung capacity (%) +0.5 (CsA), –3.1 (placebo) Vital capacity (%) –1.2 (CsA), –1.4 (placebo) DLCO (%) +1.7 (CsA), –2.9 (placebo)

Adverse events

Hypertrichosis n = 6 (CsA) Tinnitus n = 1 (CsA) Gastrointestinal upset n = 1 (CsA) Rise in serum creatinine > 30% n = 8 (CsA) Arterial hypertension n = 2 (CsA) Coccidiodiodmmycosis n = 1 (CsA)

Progressive Systemic Sclerosis: Colchicine

Trial

Long-term evaluation of Colchicine in the treatment of scleroderma

Substance

Colchicine At the maximum tolerated individual doses Mean dose 10.1 mg/week Range 6–21 mg/week

Result

Colchicine treatment improved symptoms of scleroderma within 3 months

Patients

19 patients with Scleroderma Raynaud phenomenon n = 19 Esophageal involvement n = 18 CREST syndrome n = 4 Progress. System Sclerosis n = 15

Authors

Alarcon-Segovia D, Ramos-Niembro F, Ibanez de Kasep G, Alcocer J, Tamayo RP

Publication

J Rheumatol. 1979;6(6):705–712

Follow up

19–57 months (mean 39 months)

Note

Percentage of patients with improvement of: Grip strength 17% Finger palm distance 11% Mouth opening 13% Reappearance of hair 19% Skins elasticity 19% Raynaud’s phenomenon 19% Digital pitting microinfarcts 9% Dysphagia 14% Pulmonary function tests 9% Skin biopsy 17% Time on treatment before improvement: Grip strength 8.1 month Finger palm distance 10.0 month Mouth opening 13.0 month Reappearance of hair 19.6 month Skins elasticity 7.5 month (observer’s evaluation), 6.0 month (patient’s evaluation)

Adverse events

No significant adverse events Increased alkaline phosphatase (frequently) No leukopenia No gastrointestinal adverse events

493

494

Progressive Systemic Sclerosis: Cyclophosphamide

Trial

Cyclophosphamide and low-dose Prednisone therapy in patients with systemic sclerosis (scleroderma), with interstitial lung disease

Substance

Oral cyclophosphamide (1–2 mg/kg/day) + low dose prednisone (<10 mg/day) Concomitant medication: No information provided Pre-treatment: No information provided

Result

Cyclophosphamide and low-dose prednisone therapy improved lung function in patients with systemic sclerosis with interstitial lung disease

Patients

14 patients with scleroderma and interstitial lung disease Disease duration 23.1 months Diffuse cutaneous scleroderma n = 9 Limited cutaneous scleroderma n = 4 SSc without scleroderma n = 1 Active alveolitis proven by BAL Min 2 standard deviation increase in the absolute number of macrophages, neutrophils and/or eosinophils

Authors

Silver RM, Warrick JH, Kinsella MB, Staudt LS, Baumann MH, Strange C

Publication

J Rheumatol. 1993;20(5):838–844

Follow up

24 months

Note

FVC (% predicted) 51.4 (baseline), 56.1 (6 months), 58.3 (12 months), 63.6 (24 months) DLCO (% predicted) 54.5 (baseline), 55.0 (6 months), 51.9 (12 months), 47.9 (24 months)

Adverse events

Leucopenia n = 2 Thrombopenia n = 1 Pneumonia n = 1 Hemorrhagic cystitis n = 2 Related malignancy n = 1

Progressive Systemic Sclerosis: Cyclophosphamide

Trial

Intravenous Cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma

Substance

750 mg/sqm Cyclophosphamide monthly i.v. pulse therapy (n = 8) for 12 months Oral 2–2.5 mg/kg Cyclophosphamide/day (n = 8) Concomitant medication: 10 mg Prednisone/day Calcium channel blockers as needed H2 blockers as needed Omeprazole as needed

Result

Cyclophosphamide pulse therapy was effective in suppressing active alveolitis as demonstrated by ground glass appearance on HRCT

Patients

16 patients with SSc and an Alveolitis detected by computer tomography No pulmonary hypertension Non smokers

Authors

Davas EM, Peppas C, Maragou M, Alvanou E, Hondros D, Dantis PC

Publication

Clin Rheumatol. 1999;18(6):455–461

Follow up

12 months

Note

Change of (12 months): FEV1 –1.1% (oral), +2.5% (i.v.) FVC +1.0% (oral), +7.5% (i.v.) TLC 0% (oral), +6.7% (i.v.) DLCO –11.8% (oral), +21.5% (i.v.) HRCT score (following Wells et al.): Baseline 25% (oral), +34.2% (i.v.) 6 months 31.5% (oral), +30% (i.v.) 12 months 31.5% (oral), +11.7% (i.v.) Grade I (ground glass appearance) n = 3 (oral), n = 8 (i.v.) Grade II (ground glass and reticular appearance) n = 1 (oral), n = 0 (i.v.) Grade III (reticular appearance) n = 4 (oral), n = 1 (i.v.)

Adverse events

Leucopenia n = 3 (oral) Alopecia n = 1 (oral) Few, self limiting episodes of nausea and vomiting (i.v.)

495

496

Progressive Systemic Sclerosis: Cyclophosphamide

Trial

Cyclophosphamide with low or high dose Prednisolone for systemic sclerosis lung disease

Substance

Low doses of prednisolone (<10 mg/day, n =12) High doses of 1 mg/kg/day prednisolone (max. 60 mg/day, n = 16) Tapered by 5 mg/day on alternating days each 2 weeks Concomitant medication: Intravenous pulses of 500 mg/m2 cyclophosphamide Mesna in three seperate doses

Result

A combination of i.v. pulse cyclophosphamide with high doses of prednisolone was effective in improving the clinical, physiological, and radiological evolution of systemic sclerosis related interstitial lung disease

Patients

28 patients with systemic sclerosis Related interstitial lung disease (ILD) With FVC < 70% of predicted FEV1/FVC > 70% of predicted No other disease affecting the lung

Authors

Pakas I, Ioannidis JP, Malagari K, Skopouli FN, Moutsopoulos HM, Vlachoyiannopoulos PG

Publication

J Rheumatol. 2002;29(2):298–304

Follow up

12 months

Note

CT-Scan findings: Ground glass –5.7% (high dose), –1.1% (low dose) Reticular pattern –0.3% (high dose), +5.9% (low dose) Interstitial disease score –6.0% (high dose), +4.8% (low dose) Pulmonary function tests: TLC (% predicted) +5.1% (high dose), –1.0% (low dose) FVC (% predicted) +12.4% (high dose), –0.7% (low dose) DLCO (% predicted) +7.3% (high dose), +0.9% (low dose) Skin involvement score –5.4 (high dose), –0.7% (low dose)

Adverse events

Death from end stage ILD during n = 1 (low dose) No patient developed leucopoenia or other cytopenia No patient developed scleroderma related renal crisis Nausea and vomiting, typically lasting for 1–3 days respiratory tract infections n = 3 (low dose)

Progressive Systemic Sclerosis: Cyclophosphamide

Trial

Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis

Substance

1,000 mg/m2 i.v. Cyclophosphamide/month for 6 months + 25 mg Prednisone/day for 1 month Followed by 5 mg Prednisone/day for the remaining 5 months Pre-treatment: No cytotoxic drugs No biologic £12 months

Result

Cyclophosphamide pulse regimen seemed to stabilize alveolitis in the majority of cases useful in SSc patients to control disease evolution in the lung

Patients

23 patients with SSc Diffuse SSc n = 17 Limited SSc n = 6 Alveolitis detected by bronchoalveolar lavage cell analysis Recent deterioration in FVC

Authors

Giacomelli R, Valentini G, Salsano F, Cipriani P, Sambo P, Conforti ML, Fulminis A, De Luca A, Farina G, Candela M, Generini S, De Francisci A, Tirri E, Proietti M, Bombardieri S, Gabrielli A, Tonietti G, Cerinic MM

Publication

J Rheumatol. 2002;29(4):731–736

Follow up

6 months

Note

FVC no change n = 13 FVC Improvement (>15% increase) n = 8 FVC decline n = 2 DLCO Improvement n = 15 DLCO no change n = 4 DLCO decline n = 4 Ground-glass aspect in HRCT stable n = 8 Ground-glass aspect in HRCT improvement n = 10 Ground-glass aspect in HRCT diffusion to other segments n = 5 Bronchioalveolar lavage: Recovery 53% (Baseline), 49% (6 months) Cells/ml 460,000 (Baseline), 285,000 (6 months) Macrophages 62% (Baseline), 78% (6 months) Lymphocytes 16% (Baseline), 12% (6 months) Neutrophils 4% (Baseline), 3% (6 months) Basophils 0% (Baseline), 0.5% (6 months) Eosinophils 0.4% (Baseline), 1% (6 months)

Adverse events

Mild nausea n = 4

497

498

Progressive Systemic Sclerosis: Cyclophosphamide

Trial

Systemic sclerosis and interstitial lung disease: a pilot study using pulse intravenous methylprednisolone and Cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function

Substance

6 pulses of i.v.15 mg/kg Cyclophosphamide + i.v. 10 mg/kg Methylprednisolone The first three pulses were given at three weekly intervals The remaining three pulses were administered at four weekly intervals Concomitant medication: Proton pump inhibitor or H2 antagonist Patients were advised to drink 3 L of fluid on the day of the pulse 3 × 400 mg mesna tablets, 1 h pre-CYC and 4 and 12 h post-CYC Metoclopramide or granisetron Amphoteracin Lisinopril (typically 2.5 mg daily)

Result

I.v. cyclophosphamide of patients with systemic sclerosis stabilized lung disease. Stop or reduction of treatment resulted in deterioration of lung function in the majority of patients

Patients

14 consecutive patients with SSc and lung involvement A HRCT scan was performed If the TLC was <80% of the predicted Or DLCO was <75% of the predicted + Deterioration of DLCO and FVC Abnormal HRCT: ground glass

Authors

Griffiths B, Miles S, Moss H, Robertson R, Veale D, Emery P

Publication

J Rheumatol. 2002;29(11):2371–2378

Follow up

12–54 months

Note

Modified Rodnan skin score 17 ³13 HRCT scan scores improved or stabilized n = 13 DLCO remained stable Deterioration in DLCO 26 months 67% of patients experienced

Adverse events

Death of cerebral hemorrhage n = 1 Death of generalized SSc n = 1 Death of chest infection n = 1

Progressive Systemic Sclerosis: Cyclophosphamide

Trial

Effects of oral Cyclophosphamide and Prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis

Substance

Oral 2–2.5 mg/kg Cyclophosphamide/day + 30 mg Methylprednisolone/every other day Tapered by 2.5 mg every 6 weeks until 2.5 mg/every other day

499

Previous treatment: No DMARDs No NSAIDs Result

Combination therapy with cyclophosphamide plus prednisolone of patients suffering from early diffuse systemic sclerosis was effective

Patients

13 patients with early diffuse SSc Disease duration was <2 years None of the patients was previously treated with DMARDs All of them had diffuse Cutaneous involvement FVC ³50% of predicted DLCO ³40% of No congestive heart failure No chronic obstructive lung disease

Authors

Apras S, Ertenli I, Ozbalkan Z, Kiraz S, Ozturk MA, Haznedaroglu IC, Cobankara V, Pay S, Calguneri M

Publication

Arthritis Rheum. 2003;48(8):2256–2261

Follow up

12 months

Note

Change of: Skin Score, median 48 (baseline), 32 (post treatment) ESR (mm/h) 52.3 (baseline), 17.2 (post treatment) White blood cell count (no/mm3) 8,300 (baseline), 6,290 (post treatment) Creatinine clearance (mL/min) 77.4 (baseline), 103.1 (post treatment) FVC (% of predicted) 76.4 (baseline), 86.2 (post treatment) DLCO (% of predicted) 64.3 (baseline), 76.3 (post treatment)

Adverse events

No toxic effects

500

Progressive Systemic Sclerosis: Cyclophosphamide

The Scleroderma Cyclophosphamide versus placebo in scleroderma lung disease Lung Study Substance

Oral cyclophosphamide (Cyc, £2 mg/kg/day, n = 79) Placebo (n = 79) Prednisone £10 mg/day Previous medications: No oral cyclophosphamide No ³2 i.v. cyclophosphamide No DMARDs

Result

Oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnoea, thickening of the skin, and the health-related quality of life

Patients

158 patients with scleroderma Restrictive lung physiology Dyspnoea (Mahler dyspnoea index grade II) FVC 45–85% of the predicted DLCO ³30% of the predicted Non smokers ³6 months Evidence of inflammatory interstitial lung disease: Bronchoalveolar-lavage: neutrophilia ³3% and/or eosinophilia of ³2% or HRCT: ground-glass opacity

Authors

Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M; Scleroderma Lung Study Research Group

Publication

N Engl J Med. 2006;354(25):2655–2666

Follow up

12 months

Progressive Systemic Sclerosis: Cyclophosphamide

Note

Change of (12 months): FVC (% of predicted) –1.0 (Cyc), –2.6 (placebo) Total lung capacity (% of predicted) –0.3 (Cyc), –2.8 (placebo) DLCO (% of predicted) –4.2 (Cyc), –3.5 (placebo) HAQ –0.11 (Cyc), +0.16 (placebo) SF36 score: Physical component +0.7 (Cyc), –1.9 (placebo) Mental component +2.9 (Cyc), +0.1 (placebo) Skin-thickness score: Total score –3.6 (Cyc), –0.9 (placebo) Difffuse –5.3 (Cyc), –1.7 (placebo) Limited –0.8 (Cyc), +0.2 (placebo)

Adverse events

Year 1: Hematuria n = 9 (Cyc), n = 3 (placebo) Leucopenia n = 19 (Cyc), n = 0 (placebo) Neutropenia n = 7 (Cyc), n = 0 (placebo) Anemia n = 2 (Cyc), n = 0 (placebo) Pneumonia n = 5 (Cyc), n = 1 (placebo) Death n = 2 (Cyc), n = 3 (placebo) Year 2: Hematuria n = 1 (Cyc), n = 2 (placebo) Leucopenia n = 0 (Cyc), n = 0 (placebo) Neutropenia n = 0 (Cyc), n = 0 (placebo) Anemia n = 0 (Cyc), n = 1 (placebo) Pneumonia n = 1 (Cyc), n = 0 (placebo) Death n = 4 (Cyc), n = 3 (placebo)

501

502

Progressive Systemic Sclerosis: Cyclophosphamide

Trial

Oral Cyclophosphamide improves pulmonary function in scleroderma patients with fibrosing alveolitis: experience in one center

Substance

Oral 2 mg/kg cyclophosphamide/day for 1 year + 25 mg Prednisone/day for 3 months Then tapered to 5 mg/day

Result

Oral cyclophosphamide treatment of scleroderma patients with active alveolitis was effective in ameliorating and/or stabilizing lung function, with beneficial effects lasting up to 1 year

Patients

33 scleroderma patients With active alveolitis: Presence of areas of ground-glass attenuation’ on HRCT Recent deterioration in lung function Decline TC ³ 7% Decline DLCO ³ 7% No pulmonary hypertension (right ventricular sistoli pressure >40 mmHg)

Authors

Beretta L, Caronni M, Raimondi M, Ponti A, Viscuso T, Origgi L, Scorza R

Publication

Clin Rheumatol. 2007;26(2):168–172. Epub April 14, 2006

Follow up

24 months

Note

After 12 months: Improvement of DLCO 63.6% Stabilisation of DLCO 24.2% Deterioration of DLCO 12.1% Improvement of VC 45.5% Stabilisation of VC 42.4% Deterioration of VC 12.1% Change of (24 months): DLCO +0.26 mmol/min/kPa DLCO +6.9% predicted VC +0.06 l VC +4% predicted Response of DLCO dependent on initial radiological Grading (Wells): Grade I: 76.2% improvement, 0% deterioration Grade II: 50.0% improvement, 40.0% deterioration Grade III: 0.0% improvement, 0.0% deterioration Response of VC dependent on initial radiological Grading (Wells): Grade I: 52.4% improvement, 9.5% deterioration Grade II: 40.0% improvement, 10.0% deterioration Grade III: 0.0% improvement, 50.0% deterioration

Adverse events

Reduction of white blood cell count < 3,000/mm3 n = 7 Alopecia n = 1 Amenorrhea n = 4 Haemorrhagic cystitis n = 0

Progressive Systemic Sclerosis: Cyclophosphamide vs. Azathioprine

503

Trial

A randomized unblinded trial of Cyclophosphamide vs. Azathioprine in the treatment of systemic sclerosis

Substance

Oral 2 mg/kg cyclophosphamide/day for 12 months Then maintained on 1 mg/kg/day (Cyc, n = 30) 2.5 mg/kg oral azathioprine/day for 12 months Then maintained on 2 mg/kg/day (Aza, n = 30) Concomitant medication: 15 mg Prednisone/day Tapered every month by 2.5 mg to 0 Reliable anticonception Previous treatment: No DMARDs Prednisolone in some patients NSAIDs in some patients

Result

Cyclophosphamide treatment of patients with systemic sclerosis had a significantly higher effect than treatment with azathioprine on skin, lung function and joint pain

Patients

60 patients with early, diffuse systemic sclerosis Disease duration £12 months No obstructive lung disease No nephritis No increased creatinine No increased transaminases

Authors

Nadashkevich O, Davis P, Fritzler M, Kovalenko W

Publication

Clin Rheumatol. 2006;25(2):205–212. Epub October 14, 2005

Follow up

18 months

Note

Change of (month 19): Modified Rodnan skin score –9.47 (Cyc), +0.2 (Aza) Attack frequency of Raynaud’s phenomenon –1.59/day (Cyc), +0.41/day (Aza) ESR (mm/h) –14.6 (Cyc), +1.3 (Aza) FVC (% predicted) +3.3 (Cyc), –11.1 (Aza) DLCO (% predicted) 0.0 (Cyc), –11.6 (Aza) Patients with arthralgias –19 (Cyc), –5 (Aza)

Adverse events

Considerable hair loss n = 3 (Cyc), n = 0 (Aza) Dyspepsia n = 4 (Cyc), n = 2 (Aza) Leukopenia n = 5 (Cyc), n = 2 (Aza) Nausea n = 0 (Cyc), n = 3 (Aza) Otitis media n = 0 (Cyc), n = 1 (Aza)

504

Progressive Systemic Sclerosis: Cyclophosphamide

The Scleroderma Effects of 1-year treatment with Cyclophosphamide on outcomes lung study at 2 years in scleroderma lung disease Substance

Oral Cyclophosphamide (£2 mg/kg/day, n = 79) Placebo (n =79) Prednisone £10 mg/day Treatment was discontinued after 12 months Previous medications: No oral Cyclophosphamide No ³2 i.v. Cyclophosphamide No DMARDs Treatment during the second year: Finishing year 2: n = 57 (placebo) n = 56 (Cyc) Any off study drug n = 14 (placebo) n = 10 (Cyc) Prednisone (³10 mg) n = 12 (average dose: 11.6 mg, Placebo), n = 10 (average dose: 14.0 mg, Cyc) Cyclophosphamide n = 2 (average dose: 72.5 mg), n = 0 (Cyc) No patients received azathioprine or mycophenolate

Result

After stop of 1 year treatment with cyclophosphamide lung function, skin scores, dyspnoea and health status/disability improved for several months. However, except for a sustained impact on dyspnoea, all of these effects waned and were no longer apparent at 24 months

Patients

158 patients with scleroderma Restrictive lung physiology Dyspnoea (Mahler Dyspnoea Index Grade II) FVC 45–85% of the predicted DLCO ³30% of the predicted Non smokers ³6 months Evidence of inflammatory interstitial lung disease: Bronchoalveolar-lavage: neutrophilia ³3% and/or eosinophilia of ³2% or HRCT: ground-glass opacity

Authors

Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM, Goldin J, Arriola E, Strange C, Bolster MB, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel D, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M, Khanna D, Li N, Li G; Scleroderma Lung Study Research Group

Publication

Am J Respir Crit Care Med. 2007;176(10):1026–1034. Epub August 23, 2007

Progressive Systemic Sclerosis: Cyclophosphamide

Follow up

24 months

Note

Dissipation of beneficial effects on pulmonary function and health status after 18 months Dissipation of beneficial effects on skin improvements after 12 months Positive effect on dyspnoea persisted through 24 months FVC <70% predicted n = 40 (Cyc), n = 37 (placebo) FVC ³70% predicted n = 29 (Cyc), n = 35 (placebo)

Adverse events

No leukopenia No neutropenia Hematuria n = 1 (Cyc), n = 2 (placebo) Anemia n = 2 (Cyc), n = 1 (placebo) Pneumonia n = 1 (Cyc), n = 0 (placebo) Death n = 4 (Cyc), n = 3 (placebo)

505

506

Progressive Systemic Sclerosis: Cyclophosphamide

The scleroderma Treatment of scleroderma-interstitial lung disease with Cyclophosphamide lung study is associated with less progressive fibrosis on serial thoracic high-resolution CT scan than placebo: findings from the scleroderma lung study Substance

Oral cyclophosphamide (£2 mg/kg/day, n = 79) Placebo (n =79) Prednisone £10 mg/day Treatment was discontinued after 12 months Previous medications: No oral cyclophosphamide No ³2 i.v. cyclophosphamide pulses No DMARDs

Result

Treatment of scleroderma-interstitial lung disease with cyclophosphamide was associated with treatment-related improvement in fibrosis scores on HRCT scans, which correlated with other pulmonary parameters

Patients

158 patients with scleroderma Restrictive lung physiology Dyspnoea (Mahler Dyspnoea Index Grade II) FVC 45–85% of the predicted DLCO ³30% of the predicted Non smokers ³6 months Evidence of inflammatory interstitial lung disease: Bronchoalveolar-lavage: neutrophilia ³ 3% and/or eosinophilia of ³2% or HRCT: ground-glass opacity

Authors

Goldin J, Elashoff R, Kim HJ, Yan X, Lynch D, Strollo D, Roth MD, Clements P, Furst DE, Khanna D, Vasunilashorn S, Li G, Tashkin DP

Publication

Chest. 2009;136(5):1333–1340

Follow up

1 year

Note

Fibrosis worse n = 14 (Cyc), n = 26 (placebo) Fibrosis not worse n = 35 (Cyc), n = 23 (placebo) Ground-glass opacities worse n = 13 (Cyc), n = 16 (placebo) Ground-glass opacities not worse n = 36 (Cyc), n = 33 (placebo) Honeycomb cysts worse n = 3 (Cyc), n = 3 (placebo) Honeycomb cysts not worse n = 46 (Cyc), n = 46 (placebo)

Progressive Systemic Sclerosis: D-Penicillamine

Trial

D-Penicillamine therapy and interstitial lung disease in scleroderma. A long-term follow-up study

Substance

750 mg/day D-Penicillamine (range 250 –1,250 mg/day, n = 17) 12.5 mg Prednisone (range 7.5–30 mg/day, n = 10) Background therapy: Colchicine n = 2 (D-penicillamine), n = 3 (placebo) NSAIDs if needed

Result

D-Penicillamine treatment of patients with scleroderma associated interstitial lung disease had a beneficial effect

Patients

27 scleroderma patients With progressive disease Pre-treated with D-Penicillamine for min. 6 months Min. 2 lung function measurements before

Authors

de Clerck LS, Dequeker J, Francx L, Demedts M

Publication

Arthritis Rheum. 1987;30(6):643–650

Follow up

Mean 4.7 years (range 0.75–11.0a, D-penicillamine) Mean 4.6 years (range 1.75–6.5a, prednisone)

Note

DLCO >10% lower than the initial value n = 3 (D-penicillamine), n = 5 (placebo) Change of (start – end of study): DLCO/Lung volume +1.2% (D-penicillamine), –14.4% (placebo) DLCO +0.5% (D-penicillamine), –7.9% (placebo) TLC –2.1% (D-penicillamine), +0.2% (placebo) FEV1/FVC –3.3% (D-penicillamine), –0.5% (placebo)

507

508

Progressive Systemic Sclerosis: D-Penicillamine

Trial

High-dose versus low-dose D-Penicillamine in early diffuse systemic sclerosis: analysis of a 2-year, double-blind, randomized, controlled clinical trial

Substance

High-dose D-penicillamine (750–1,000 mg/day, n = 66) Low-dose D-penicillamine (125 mg every other day, n = 68) Concomitant medication: Corticosteroids, £10 mg of prednisone/day (or equivalent) Safe contraceptive measures Previous medication: D-penicillamine, azathioprine, cyclophosphamide, methotrexate, chlorambucil, paraaminobenzoic acid, colchicine, or captopril had to be discontinued ³1 month

Result

The effectivity of high and low-dose D-penicillamine was not different concerning of the skin score and the frequencies of scleroderma renal crisis and mortality in patients with systemic scelosis High-dose D-penicillamine patients suffered from four times more adverse events leading to withdrawal

Patients

134 SSc patients Early disease £18 months Diffuse Cutaneous scleroderma into a 2-year No other rheumatic disease Nolocalized scleroderma, serious No organ involvement: DLCO <45% predicted Serum creatinine ³2.0 mg/dL Proteinuria >500 mg/24 hours Intractable malabsorption

Authors

Clements PJ, Furst DE, Wong WK, Mayes M, White B, Wigley F, Weisman MH, Barr W, Moreland LW, Medsger TA Jr, Steen V, Martin RW, Collier D, Weinstein A, Lally E, Varga J, Weiner S, Andrews B, Abeles M, Seibold JR

Publication

Arthritis Rheum. 1999;42(6):1194–1203

Follow up

24 months

Progressive Systemic Sclerosis: D-Penicillamine

Note

509

Physician’s global assessment: Improved 86% (low dose), 59% (high dose) Change of: Rodnan Skin Score –6.7 (low dose), –4.9 (high dose) DLCO (% predicted) –2.9% (low dose), –0.5% (high dose) FVC (% predicted) +4% (low dose), +4.9% (high dose) HAQ Disability Index (0–3.0 scale) –0.19 (low dose), –0.13 (high dose) Creatinine clearance (mL/min) –1 (low dose), –11 (high dose) Tender joint count (0–8 joints) –0.73 (low dose), –0.29 (high dose) CK (% of upper limit of normal) +9% (low dose), +47% (high dose) Weight (kg) +0.4 (low dose), +0.4 (high dose) Left hand spread (mm) –4 (low dose), –9 (high dose) Right hand spread (mm) –1 (low dose), –10 (high dose) Left fist closure (mm) –5 (low dose), –4 (high dose) Right fist closure (mm) –8 (low dose), –3 (high dose) Oral aperture (mm) +3 (low dose), +1 (high dose) New onset of organ involvement during follow up: Lung n = 5/20 (low dose), n = 3/13 (high dose) Heart n = 5/33 (low dose), 5/24 (high dose) Kidney (chronic) n = 3/36 (low dose), n = 2/32 (high dose) Muscle n = 7/34 (low dose), n = 7/28 (high dose) Joint n = 7/23 (low dose), n = 8/17 (high dose)

Adverse events

Withdrawal because of adverse events n = 4 (low dose), n = 16 (high dose) Proteinuria (>1 g) n = 1 (low dose), n = 7 (high dose) Rash n = 0 (low dose), n = 3 (high dose) Myasthennia gravis n = 0 (low dose), n = 1 (high dose) Low platelets n = 1 (low dose), n = 2 (high dose) Flu symptoms n = 1 (low dose), n = 1 (high dose) Stomatitis n = 1 (low dose), n = 2 (high dose) Death n = 3 (low dose), n = 1 (high dose)

510

Progressive Systemic Sclerosis: Methotrexate

Trial

Comparison of Methotrexate with placebo in the treatment of systemic sclerosis: a 24-week randomized double-blind trial, followed by a 24-week observational trial

Substance

15 mg MTX (increase to 25 mg/week if needed, n = 17) Placebo (n = 12) Concomitant medication: Corticosteroids £10 mg/day Non-steroidal antiinflammatory drugs Analgesics were permitted Nifedipene was permitted Ketanserine was permitted Cimetidine was permitted Omeprazole was permitted at stable doses All ³8 weeks prior trial entry

Result

Low-dose methotrexate was more effective than placebo in patients with active systemic sclerosis

Patients

29 scleroderma patients with a patient career <3 years from the first rememberable skin thickening Patients with longer disease duration were also included if they had experienced a progression of skin thickening Persistent digital ulcerations, or a Deterioration in pulmonary function during the last 6 months

Authors

van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB

Publication

Br J Rheumatol. 1996;35(4):364–372

Follow up

24 weeks

Note

Change of: Total skin score –0.7 (MTX), +1.2 (placebo) Extension index right (mm) –2.1 (MTX), –1.2 (placebo) Extension index left (mm) –0.8 (MTX), 0.3 (placebo) Grip strength right (mmHg) 18.8 (MTX), 12.9 (placebo) Grip strength left (mmHg) –0.5 (MTX), –2.8 (placebo) Oral opening (mm) –0.7 (MTX), –0.2 (placebo) General health (0–100 mm VAS) 4.5 (MTX), –1.0 (placebo) Lung Fibrosis n = 5 (MTX), n = 4 (placebo) TLC (% predicted) –1.1 (MTX), –0.5 (placebo) VC (% predicted) –2.7 (MTX), –1.7 (placebo) DLCO –0.03 (MTX), –0.01 (placebo) Cardiac involvement n = 4 (MTX), n = 3 (placebo) Creatinine clearance rate (mL/min) +4.0 (MTX), –3.0 (placebo) Oesophageal n = 13 (MTX), n = 8 (placebo) ESR (Westergren, mm/h) –0.71 (MTX), +2.2 (placebo)

Adverse events

Progression of cardiopulmonary, gastrointestinal and nephrological manifestations n = 1 (placebo), n = 0 (MTX) Renal failure due to scleroderma renal crisis n = 1 (placebo), n = 1 (MTX) Severe headache n = 0 (placebo), n = 2 (MTX) Death of cardiorespiratory n = 0 (placebo), n = 1 (MTX) Myocardial infarction n = 0 (placebo), n = 1 (MTX) Pancytopenia n = 0 (placebo), n = 1 (MTX) Liver enzyme abnormalities n = 0 (placebo), n = 6 (MTX)

Progressive Systemic Sclerosis: Methotrexate

Trial

A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma

Substance

10 mg/week MTX (n = 35) Dosage was increased to a max. 15 mg/week in steps of 2.5 mg every 4 weeks Placebo (n = 36)

511

Concomitant medication: Practicing appropriate birth control Prednisone at a £15 mg/day or equivalent stable within the last 2 months Previous medication: No current or past use of MTX No immunosuppressive therapy currently or within the last 3 months Result

Treatment of early diffuse SSc with methotrexate was tendentially superior to placebo

Patients

71 patients with diffuse SSc Disease duration <3 years UCLA skin score ³5 (maximum possible score = 30) No overlap syndrome No mixed connective tissue disease No morphea, or linear scleroderma No AST or bilirubin level >2 times the upper limit of normal No nsulin-dependent diabetes mellitus No uncontrolled hypertension or severe congestive heart failure Forced expiratory volume in 1 s ³40% DLCO ³40%

Authors

Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, Smith CD, Chalmers IM, Hong P, O’Hanlon D, Kaminska E, Markland J, Sibley J, Catoggio L, Furst DE

Publication

Arthritis Rheum. 2001;44(6):1351–1358

Follow up

12 months

512

Note

Progressive Systemic Sclerosis: Methotrexate

Change of (all patients): UCLA Skin Score –2.1 (MTX), –0.3 (placebo) Rodnan skin score –6.3 (MTX), –1.1 (placebo) Physician`s global assessment –0.9 (MTX), –0.3 (placebo) Change of (intent to treat analysis): UCLA Skin Score –1.3 (MTX), –0.7 (placebo) Rodnan skin score –4.1 (MTX), +1.1 (placebo) Physician`s global assessment –0.2 (MTX), –0.2 (placebo) Patient global assessment (VAS 10-cm) 0.0 (MTX), –0.4 (placebo) DLCO (% predicted) –3.7 (MTX), –7.7(placebo) After 12 months: Oral opening (mm) 38.7 (MTX), 35.1 (placebo) HAQ pain (0–3) 1.1 (MTX), 1.0 (placebo) HAQ disability (0–3) 1.2 (MTX), 1.2 (placebo) Functional index (0–33) 8.3 (MTX), 7.5 (placebo) Grip strength right (mmHg) 160 (MTX), 146 (placebo) Grip strength left (mmHg) 156 (MTX), 142 (placebo) Flexion index right (mm) 68 (MTX), 84 (placebo) Flexion index (mm) 65 (MTX), 82 (placebo) DLCO (% predicted) 75.7 (MTX), 61.8 (placebo) Patient global assessment (VAS 10-cm) 4.2 (MTX), 4.3 (placebo)

Progressive Systemic Sclerosis: Mycophenolate Mofetil

Trial

A pilot study of Mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral low-dose Glucocorticoids in severe early systemic sclerosis

Substance

Three consecutive daily i.v. 15 mg/kg Methylprednisolone pulses Followed by five additional monthly i.v. 15 mg/kg Methylprednisolone pulses Mycophenolate mofetil (2 × 0.5 g/day for 1 week; then 2 × 1 g/day) Oral prednisolone (5–10 mg/day) Concomitant medication: ACE inhibitors in case of hypertension No other DMARDs Previous medication: Glucosteroids 25% Methotrexate 7% ACE inhibitors 14%

Result

The combination of mycophenolate mofetil, i.v. methylprednisolone and low-dose glucocorticoids achieved good clinical, functional and radiological results in patients suffering from severe early systemic sclerosis

Patients

16 systemic sclerosis patients Modified Rodnan total skin score ³15 n = 9 Active interstitial lung disease n = 7 DLCO £75% of the predicted + Ground glass opacity on HRCT Or broncho alveolar lavage: ³15% lymphocytes, ³3% eosinophiles, ³1% eosinophiles Disease duration <3a (first non-Raynaud manifestation) Total skin score ³15 No scleroderma associated renal crisis No serum creatinine ³2 mg/dL No vital capacity £50% No left ventricular ejection fraction £40% No DLCO £70%

Authors

Vanthuyne M, Blockmans D, Westhovens R, Roufosse F, Cogan E, Coche E, Nzeusseu Toukap A, Depresseux G, Houssiau FA

Publication

Clin Exp Rheumatol. 2007;25(2):287–292

Follow up

12 months

513

514

Note

Progressive Systemic Sclerosis: Mycophenolate Mofetil

All patients: Total skin score responders 69% Responders of HAQ 50% Interstitial lung’s disease patients: DLCO responders 71% FEV responders 86% VC responders 83% 6 min walking distance responders 14% Ground glass appearance –1.53 Consoldation areas (HRCT) –0.57 Interlobular thickening (HRCT) 0.0 Honeycombing –0.29 Skin patients: Total skin score 56% Change of (all patients): Total skin score –7 HAQ –0.5 SHAQ (VAS 1, Raynaud) –10 SHAQ (VAS 2, finger ulcers) –10 SHAQ (VAS 3, gastrointestinal) –6 SHAQ (VAS 4, lung) –3 SHAQ (VAS 5, overall) –16 SHAQ (VAS 6, pain) –18 CRP (mg/dL) –1.5 Change of (Interstitial lung’s disease patients): VC +345 mL, +10% of the predicted FEV1 +376 mL, +14% of the predicted DLCO +13% of the predicted 6-min walking distance +61 m Change of (skin patients): Total skin score –8

Adverse events

Enterocolitis n = 1 Varicella zoster virus n = 1 Bronchitis n = 4 Diarrhoea n = 4 Nausea n = 1 Vertigo n = 1 Renal crisis n = 0 Hypertension n = 4

Progressive Systemic Sclerosis: 5-Fluorouracil

Trial

5-fluorouracil in the treatment of scleroderma: a randomized, double-blind, placebo-controlled international collaborative study

Substance

12 mg/kg 5-fluorouracil/day for four doses (max. 1,000 mg/day, n = 26) Followed by 4 × 6 mg/kg (£800 mg/day) every 2 days Placebo (n = 20) Concomitant medication: Corticosteroids for inflammatory conditions (myositis, pericarditis) Previous medication: No D-Penicillamine for 6 months No colchicine

Result

There was a modest benefit of 5 FU, but no improvement of visceral functions, in this open trial of patients with scleroderma

Patients

70 patients with limited SSc with evidence of visceral disease or digital ulcerations PA, Villarreal I, Nolte C, Menajovsky BL, Escudero EE, Blackburn WD, Alarcón GS, Subauste CP

Publication

Ann Rheum Dis. 1990;49(11):926–928

Follow up

6 months

Note

Change of: Total skin score –1.7 (placebo), –5.8 (5-FU) Skin weight (g) –0.7 (placebo), –3.7 (5-FU) Oral opening (mm) –1.4 (placebo), –0.2 (5-FU) Flexion index (mm) –2.2 (placebo), –0.7 (5-FU) Extension index (mm) –0.65 (placebo), –2.2 (5-FU) Functional score –3.3 (placebo), –2.1 (5-FU) Global assessment 0.9 (placebo), 1.52 (5-FU) Raynaud’s score 0.0 (placebo), –0.44 (5-FU) Ulcer (number) 0.25 (placebo), –0.1 (5-FU) Oesophageal involvement (score) –0.1 (placebo), 0.0 (5-FU) Lung involvement (score) 0.2 (placebo), –0.2 (5-FU) Heart involvement (score) 0.15 (placebo), –0.23 (5-FU) Muscle involvement (score) 0.0 (placebo), 0.04 (5-FU)

Adverse events

Haemocytopenia 5% (placebo), 46% (5-FU) Leukopenia 5% (placebo), 42% (5-FU) Thrombocytopenia 0% (placebo), 4% (5-FU) Gastrointestinal symptoms 40% (placebo), 96% (5-FU) Angina pectoris 0% (placebo), 4% (5-FU) Pruritus 0% (placebo), 4% (5-FU) Total (patients) 50% (placebo), 96% (5-FU)

515

516

Progressive Systemic Sclerosis: Etanercept

Trial

Efficacy and safety of Etanercept in the treatment of scleroderma-associated joint disease

Substance

50 mg etanercept/week or or 2 × 25 mg etanercept/week Concomitant medication: NSAIDs n = 18 MTX (dose range 2.5–25 mg/week) n = 15 HCQ n = 5 Prednisone (dose range 0.5–15 mg/day) n = 9 Minocycline n = 2

Result

Etanercept was effective in scleroderma associated synovitic disease

Patients

12 patients with limited systemic sclerosis + 6 patients with systemic sclerosis Inflammatory joint involvement

Authors

Lam GK, Hummers LK, Woods A, Wigley FM

Publication

J Rheumatol. 2007;34(7):1636–1637

Follow up

Treatment duration 2–66 months

Note

Positive result and decreasing synovitis n = 15 Sustained remission n = 1 Change of: HAQ –0.3 Skin score –2.69 DLCO –5.1% FVC –1.4%

Adverse events

No oportunistic infections Lupus like syndrome n = 1

Progressive Systemic Sclerosis: Rituximab

Trial

Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histo-pathological study

Substance

2 × 1,000 mg rituximab administered day 0 and day 15 Concomitant medication: Low-dose prednisolone £10 mg/day at stable dose for ³12 weeks Disease-modifying antirheumatic drugs (except methotrexate) stopped ³12 weeks 15 mg Methotrexate/week was continued

Result

Rituximab was well-tolerated and seemed to have some efficacy for skin disease in diffuse cutaneous systemic sclerosis

Patients

8 patients with diffuse cutaneous systemic sclerosis Disease duration £4 years Modified Rodnan skin score ³14 Disease activity score ³3 FVC >50% DLCO >40% Left ventricular ejection fraction >40%

Authors

Smith VP, Van Praet JT, Vandooren BR, Vander Cruyssen B, Naeyaert JM, Decuman S, Elewaut D, de Keyser F

Publication

Ann Rheum Dis. 2010;69(1):193–197

Follow up

24 weeks

Note

Change of: Total skin score –10.5 DLCO (% of normal) –0.3 Lung vital capacity (% of normal) –4.5 Forced expiratory volume (% of normal) –6.9 Systolic pulmonary artery pressure (mmHg) –1.0 Left ventricular ejection fraction (% of normal) –2.6 Creatinine clearance (mL/min per 1.73 m2) +8.8 Total SF-36 +9.9 HAQ-DI –0.1 HAQ –0.1 Disease activity score –3.4 Change of (histology): Hyalinised collagen score was 60 (Baseline), 28 (after treatment, week 12), 7.1 (normal reference) Myofibroblast positivity was 4/7 (Baseline), 2/7(after treatment, week 12), 0/8(normal reference)

Adverse events

Coronary artery bypass surgery n = 1 Lowgrade fever occurring 2 weeks after the second infusion n = 1 Infectious exacerbation of existing polyposis nasi n = 1 Initiation of antihypertensive therapy n = 1 Nausea and of depressive mood n = 1

517

518

Progressive Systemic Sclerosis: Rituximab

Trial

B cell depletion with Rituximab in patients with diffuse cutaneous systemic sclerosis

Substance

2 × 1,000 mg Rituximab, administered 2 weeks apart Concomitant medication: No immunosuppressive drugs (methotrexate n = 1 later in the study) Prednisone £10 mg/day No premedication Infusion reactions: Corticosteroids Acetaminophen Diphenhydramine

Result

Rituximab treatment had little effect on the levels of systemic sclerosis associated autoantibodies. Rituximab treatment had no significant beneficial effect on skin disease. Treatment was safe and well tolerated

Patients

15 patients with diffuse cutaneous systemic sclerosis First non-Raynaud’s disease manifestation within 18 months of trial entry DLCO >50% of the predicted FVC >50% of the predicted No significant cardiac arrhythmia Ejection fraction >40%

Authors

Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel PA, Simms RW

Publication

Arthritis Rheum. 2009;60(2):578–583

Follow up

12 months

Note

Change of: Modified Rodnan skin thickness score +0.5 Forced vital capacity (% of predicted) +3.5 (6 months) DLCO (% of predicted) –0.9 (6 months) HAQ disability index –0.12 Visual analogue scale –0.17 Sedimentation rate, mm/hour –10.9 mm/h Change of immunoglobulins levels (units/mL): IgM –21 IgG –0.85 IgA +4

Adverse events

Frequent infusion reactions n = 7 Mild hypotension n = 2 Urinary tract infection n = 1 Dental abscess n = 1 Flushing n = 1 Fatigue n = 1 Nausea/abdominal cramping n = 1 Rigors n = 1 Hand tingling n = 1

Progressive Systemic Sclerosis: Plasma Exchange

519

Trial

Treatment of progressive systemic sclerosis by plasma exchange: long-term results in 40 patients

Substance

Plasma exchange 30.7 sessions (range 1–110) Centrifugation or filtration Replacement solution: Beginning 500 mL gelantine 4% albumine 70% of the patients Fresh frozen plasma 5% of the patients Mixture albumine – fresh frozen plasma 25% of the patients Exchange volume 2.8 l (range 0.3–4.6 L) 0.5–1 mg/kg prenisone with exchange n = 21 2 mg/kg cyclophosphamide n = 9 Chloraminophen n = 2 Previous medication: Colchicine n = 12 Anti-malarial drugs n = 9 D-Penicillamine n = 9 Factor XIII n = 11 Corticosteroids n = 19 Cyclophosphamide n = 5 Nitrated derivates n = 1 Nifedipine n = 9 Captopril n = 4 Surgical sympathectomy n = 3 Concomitant medication: Colchicine n = 4 Anti-malarial drugs n = 5 D-Penicillamine n = 0 Factor XIII n = 1 Corticosteroids n = 21 Cyclophosphamide n = 9 Nitrated derivates n = 0 Nifedipine n = 3 Captopril n = 1 Surgical sympathectomy n = 0

Result

Plasma exchange was effective in 52% of the patients with progressive systemic sclerosis but the effect was only short term

520

Progressive Systemic Sclerosis: Plasma Exchange

Patients

40 patients with scleroderma Indication for plasma exchange: Necrosis of the limb n = 9 Lung involvement n = 9 Raynaud`s syndrome n = 5 Joint involvement n = 5 Cardiac involvement n = 4 Sicca syndrome n = 3 Renal involvement n = 1 Retinal vasculitis n = 1 Malabsorption n = 1

Authors

Guillevin L, Amoura Z, Merviel P, Pourrat J, Bussel A, Sobel A, Khuy T, Houssin A, Alcalay D, Stroumza P et al

Publication

Int J Artif Organs. 1990;13(2):125–129

Follow up

14 years

Note

Positive effect on: Scleroderma n = 8/13 (3 months), 2/13 (12 months), 1/11 (>12 months) Necrosis of limbs n = 4/9 (3 months), 0/9 (12 months), 0/9 (>12 months) Lung involvement n = 4/9 (3 months), 0/9 (12 months), 0/9 (>12 months) Raynaud’s phenomenon n = 3/5 (3 months), 0/5 (12 months), 0/9 (>12 months) Joint involvement n = 4/5 (3 months), 0/5 (12 months), 1/5 (>12 months) Cardiac involvement n = 2/4 (3 months), 0/4 (12 months), 0/4 (>12 months) Sicca syndrome n = 0/3 (3 months), 0/3 (12 months), 0/3 (>12 months) Retinal vasculitis n = 0/1 (3 months), 0/1 (12 months), 0/1 (>12 months) Renal involvement n = 0/1 (3 months), 0/1 (12 months), 0/1 (>12 months) Malabsorption n = 1/1 (3 months), 0/1 (12 months), 0/1 (>12 months)

Adverse events

Venous thrombosis n = 3 Vagal neuralgia/syncope n = 12 Fever n = 5 Allergic reactions n = 4 Aggravated skin lesions n = 3

Progressive Systemic Sclerosis: Stem Cell Transplantation

521

Trial

Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease

Substance

Priming (n = 40) 4 g/m2 cyclophosphamide + G-CSF n = 29 Cyclophosphamide alone n =1 G-CSF alone n = 10 Conditioning (n = 37) Cyclophosphamide 150–200 mg/kg n = 19 Cyclophosphamide 120 mg/kg + anti-thymocyte globulin +8 Gy total body iradiationI n = 9 Cyclophosphamide 200 mg/kg + anti-thymocyte globulin n = 4 Cyclophosphamide 200 mg/kg + CAMPATH-1 n = 2 Cyclophosphamide 200 mg/kg + total lymphoid irradiation n = 1 Other chemotherapy n = 2 (busulphan, cyclophosphamide with anti-thymocyte globulin; carmustine, fludarabine, and thiotepa)

Result

Stem cell transplantation in systemic sclerosis had a marked impact on skin score and a trend towards stabilisation of lung involvement. A higher procedure related mortality rate from compared with patients with breast cancer and non-Hodgkin’s lymphoma was observed

Patients

41 patients Predominantly diffuse skin disease Limited disease n = 4 Clinical overlap Disease duration >3 years A high risk of further progression and mortality Absence of severe irreversible internal organ damage Patients with limited scleroderma with no life threatening pulmonary fibrosis or pulmonary hypertension Organ involvement of patients: Lung 76% Pulmonary hypertension 19% Arterial hypertension 8% Raynaud’s phenomenon 93% Renal 14% Oesophageal 58% Gastrointestinal 11%

Authors

Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, Finke J, Peter HH, van Laar J, Breedveld FC, Fibbe WE, Farge D, Gluckman E, Locatelli F, Martini A, van den Hoogen F, van de Putte L, Schattenberg AV, Arnold R, Bacon PA, Emery P, Espigado I, Hertenstein B, Hiepe F, Kashyap A, Kötter I, Marmont A, Martinez A, Pascual MJ, Gratwohl A, Prentice HG, Black C, Tyndall A

Publication

Ann Rheum Dis. 2001;60(6):577–584

522

Progressive Systemic Sclerosis: Stem Cell Transplantation

Follow up

4 years

Note

Skin score improvement >25% (compared to baseline) 69% Skin score deterioration in 7% VC improved (>15%) 16% VC deteriorated (>15%) 24% DLCO improved (>15%) 9% DLCO deteriorated (>15%) 39% Serum creatinine increase 57% Death 27% 17% related to the procedure Direct organ toxicity n = 4 Haemorrhage n = 2 Infection/neutropenic fever n = 1

Reasons of death Day 0 Sudden cardiac death and survival time Day 0 Neutropenic fever, pneumonia Day 0 Thrombopenia, pulmonary hemorrhagia Day 0 Disease progression Day 11 Diffuse alveolar haemorrhage Day 28 Interstit. Pneumonitis Day 40 Central nervous system bleeding Day 79 Interstitial pneumonitis Day 217 Pulmonary hypertension Day 242 Disease progression Day 527 Superior vena cava obstruction

Progressive Systemic Sclerosis: Autologous Stem Cell Transplantation

523

Trial

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study

Substance

Mobilization: 16 mcg/kg/day s.c. G-CSF to mobilized PBSCs First apheresis day 4 CD34-selection using a Isolex 300i device (Baxter, Irvine, CA) Autologous HC grafts were stored for treating engraftment failure or severe immunodeficiency after Induction therapy: Fractionated total body irradiation 800 cGy 120 mg/kg Cyclophosphamide 90 mg/kg equine antithymocyte globulin 1 mg/kg Methylprednisolone I.v. together with ATG 0.5 mg/kg/day Prednisone om the start of conditioning to day 30 after hematopoietic cell transplantation Tapered over 1 month Graft transmission: CD34-selected autologous graft was infused 5 mcg/kg/day G-CSF day 0 until neutrophil count ³0.5 × 109/L for 3 days Infection prophylaxis: Trimethoprimsul Famethoxazole Acyclovir Fluconazole

Result

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation lead to a major reduction of the dermal fibrosis

Patients

34 patients with diffuse Cutaneous SSc Disease duration £4 years Modified Rodnan skin score ³16 Significant visceral organ involvement Decrease of DLCO ³15% within 6 months Decrease of FVC ³15% within 6 months

Authors

Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, Mayes MD, McDonagh KT, McLaughlin B, Molitor JA, Nelson JL, Shulman H, Storb R, Viganego F, Wener MH, Seibold JR, Sullivan KM, Furst DE

Publication

Blood. 2007;110(4):1388–1396. Epub April 23, 2007

Follow up

Max 5–8 years

524

Note

Progressive Systemic Sclerosis: Autologous Stem Cell Transplantation

Survival first year n = 27 Change of (final evaluation): mRSS –22.08 mHAQ –1.03 Dermal fibrosis rate –3.1 DLCO –6.04% FVC +2.11% Creatinine (mg/dL) +0.25 Ejection fraction –2.37%

Adverse events

Fatal pulmonary toxicity n = 2 Renal crisis n = 6 Dialysis required n = 2 Supraventricular arrhythmia n = 2 Heart failure n = 2 Hypothyreoidism n = 1 Myelodysplastic syndrome n = 1 Death n = 12 Treatment related n = 8 Disease related n = 4 Infections: EBV 3.7% HSV 11.1% CMV 25.9% VZV 22.2% BK Virus 3.7% Bacteraemia 40.7 Urinary tract infections 11.1% Osteomyelitis 3.7% Cellulitis 3.7% Aspiration pneumonia 3.7% Aspergillus flavus 3.7%

Raynaud’s Phenomenon

Diltiazem

Trial

A randomized double-blind trial of Diltiazem in the treatment of Raynaud’s phenomenon

Substance

1 Week placebo prior to randomization Diltiazem 3 × 120 mg/day Placebo Cross over after 2 weeks No information on concomitant medication and precise numbers in each group

Result

Diltiazem in the treatment of Raynaud’s phenomenon was effective, especially in patients with idiopathic vasospastic disease

Patients

16 patients with Raynaud’s phenomenon progressive systemic sclerosis n = 7, rheumatoid arthritis n = 2, systemic lupus erythematosus n = 1, idiopathic Raynaud’s phenomenon n = 6

Authors

Kahan A, Amor B, Menkes CJ

Publication

Ann Rheum Dis. 1985;44(1):30–33

Follow up

4 weeks

Note

Marked or moderate improvement n = 9 (diltiazem), n = 3 (placebo) Frequency of attacks/2 weeks: All patients 18.9 (placebo), 12.6 (diltiazem) Idiopathic Raynaud’s phenomenon patients 16.3 (placebo), 8.5 (diltiazem) PSS + RA + SLE patients 20.4 (placebo), 15.1 (diltiazem) Severity of attacks (VAS 0–10): All patients 6.2 (placebo), 4.2 (diltiazem) Idiopathic Raynaud’s phenomenon patients 5.4 (placebo), 2.6 (diltiazem) PSS + RA + SLE patients 6.6 (placebo), 5.1 (diltiazem)

Adverse events

Headache n = 2 (diltiazem), n = 0 (placebo) Flushing n = 2 (diltiazem), n = 0 (placebo) Dizziness n = 1 (diltiazem), n = 0 (placebo) Nausea n = 2 (diltiazem) n = 1 (placebo) Ankle oedema n = 1 (diltiazem), n = 0 (placebo) Light-headedness n = 0 (diltiazem), n = 1 (placebo)

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_7, © Springer-Verlag London Limited 2011

525

526

Raynaud’s Phenomenon: Diltiazem

Trial

A double-blind placebo-controlled crossover randomized trial of Diltiazem in Raynaud’s phenomenon

Substance

Diltiazem 3 × 60 mg/day Placebo No information on the concomitant medication Initial basel line observation 4 weeks study first phase 4 weeks cross over

Result

Diltiazem was effective the treatment of intermittent digital vasospasm

Patients

30 patients with bilateral Raynaud’s phenomenon Secondary disease n = 9 Systemic sclerosis n = 4 Mixed connective tissue disease n = 4 SLE n = 2

Authors

Rhedda A, McCans J, Willan AR, Ford PM

Publication

J Rheumatol. 1985;12(4):724–727

Follow up

10 weeks

Note

Drop out n = 8 Change of: Frequency of attacks (attacks/month) – 4.6 (placebo first), –22.9 (after change to diltiazem), –12.0 (diltiazem first), 0.0 (after change to placebo) Duration of attacks (min/month) –159.7 (placebo first), – 443.6 (after change to diltiazem), –230.8 (diltiazem first), +27.7 (after change to placebo)

Adverse events

Headache n = 1 (diltiazem), n = 0 (placebo) Rash n = 1 (diltiazem), n = 0 (placebo)

Raynaud’s Phenomenon: Diltiazem

527

Trial

Inefficacy of Diltiazem in the treatment of Raynaud’s phenomenon with associated connective tissue disease: a double-blind placebo-controlled study

Substance

3 × 60 mg diltiazem/day (n = 14) Placebo (n = 14) for 2 weeks Patient groups were crossed over after 2 weeks No information on concomitant medication

Result

Diltiazem treatment in Raynaud’s phenomenon patients was inefficient

Patients

15 patients suffering from Raynaud’s syndrome with associated connective tissue disorder SLE n = 8 Systemic sclerosis n = 4 Mixed connective tissue disease n = 1

Authors

da Costa J, Gomes JA, Espirito Santo J, Queirós M

Publication

J Rheumatol. 1987;14(4):858–859

Follow up

4 weeks

Note

Number of vasospastic attacks improved n = 12 (diltiazem), n = 11 (placebo) Patient assessed drug as effective n = 4 (diltiazem), n = 6 (placebo) Digital rheography improved n = 8 (diltiazem), n = 7 (placebo)

528

Raynaud’s Phenomenon: Glycerol Trinitrate

Trial

Topical Glyceryl trinitrate as adjunctive treatment in Raynaud’s disease

Substance

1% glyceryl trinitrate ointment Placebo Applied to one hand only for 6 weeks, contralateral hand as internal control Cross over for another 6 weeks Backgound medication: 10 mg Guanethidin/day n = 3 1–2 g Methyldopa/day n = 10

Result

The frequency and severity of attacks and of size of ulcers were lower with topical glyceryl trinitrate compared to placebo in Raynaud’s disease associated with connective tissue disease

Patients

17 patients with bilateral Raynaud’s disease Secondary to ‘collagen’ disease Systemic sclerosis n = 13 SLE n = 3 RA n = 1 Oral sympatholytic agents at the maximum levels patients could tolerate

Authors

Franks AG Jr

Publication

Lancet. 1982;1(8263):76–77

Follow up

12 weeks

Note

Reduction of number of Raynaud’s attacks n = 13 (glyceryl trinitrate), n = 6 (placebo) Reduction of Severity of Raynaud’s attacks n = 11 (glyceryl trinitrate), n = 1 (placebo) Size of ulcerations improved n = 7 (glyceryl trinitrate), n = 1 (placebo)

Adverse events

Headache Postural hypotension Abnormal sensations in the untreated hand (no frequencies were listed)

Raynaud’s Phenomenon: Iloprost

Trial

Prolonged increase in digital blood flow following iloprost infusion in patients with systemic sclerosis

Substance

Three 8-h infusions of iloprost (2 ng/kg/min) on consecutive days

529

Concomitant medication: Vaso-active drugs (channelcalcium antagonists, anti-platelet activity, non-steroidal anti-inflammatory agents) discontinued ³2 weeks before admission Result

Digital blood flow increased and number of cutaneous lesions decreased following an infusion of iloprost given for 8 h on three consecutive days, with effects persisting for 10 weeks

Patients

13 patients with Raynaud’s phenomenon secondary to systemic sclerosis

Authors

Rademaker M, Thomas RH, Provost G, Beacham JA, Cooke ED, Kirby JD

Publication

Postgrad Med J. 1987;63(742):617–620

Follow up

10 weeks

Note

Subjective improvement n = 9 Cutaneous lesions n = 26 (onset), n = 14 (2 weeks), n = 7 (10 weeks) Decrease of digital peripheral vascular resistance n = 9

530

Raynaud’s Phenomenon: Iloprost

Trial

Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud’s phenomenon in systemic sclerosis

Substance

2.0 mg/kg/min iloprost for 8 h (n = 11) Placebo (n = 9) No information on concomitant medication and on cross-over schedule

Result

Iloprost significantly reduced the number and the severity of attacks compared with placebo

Patients

29 patients with severe Raynaud’s phenomenon Systemic sclerosis n = 26 Ideopathic Raynaud’s pnenomenon n = 3

Authors

McHugh NJ, Csuka M, Watson H, Belcher G, Amadi A, Ring EF, Black CM, Maddison PJ

Publication

Ann Rheum Dis. 1988;47(1):43–47

Follow up

6 weeks

Note

No. of attacks a week –30% (iloprost) –2% (placebo) Duration –9% (iloprost) +26% (placebo) Severity –20% (iloprost) –1% (placebo) Painful attacks –16% (iloprost) –11% (placebo)

Adverse events

Headache n = 18 (iloprost) Facial flushing n = 6 (iloprost) Nausea n = 14/26 (iloprost) Vomiting n = 7 (iloprost) Diarrhoea n = 5 (iloprost)

Raynaud’s Phenomenon: Iloprost

531

Trial

Comparison of intravenous infusions of Iloprost and oral Nifedipine in treatment of Raynaud’s phenomenon in patients with systemic sclerosis: a double-blind randomized study

Substance

Iloprost i.v. 0.5 ng/kg/min, increased by 0.5 ng/kg/min every 15 min to max. 2.0 ng/kg/min for 8 h on 3 consecutive days + 1 single infusion at week 8 (n = 12) Nifedipine 30 mg/day, increased to 60 mg/day after 4 weeks (n = 11) Concomittant therapy: Adequate contraception

Patients

23 patients with Raynaud’s phenomenon associated with systemic sclerosis Typical for systemic sclerosis on capillaroscopy of the fingernail fold

Result

Iloprost and nifedipine were both beneficial in the treatment of Raynaud’s phenomenon. nifedipine associated adverse events were common. Short-term infusions of iloprost provided long-lasting relief of symptoms. Side effects occurred only during the infusions and were dose dependent

Authors

Rademaker M, Cooke ED, Almond NE, Beacham JA, Smith RE, Mant TG, Kirby JD

Publication

BMJ. 1989;298(6673):561–564

Follow up

16 weeks

Note

Change of: Number of skin lesions –2.9 (iloprost), –2.9 (nifedipine) Number of attacks –55.4% (iloprost), –41.5% (nifedipine) Severity of attacks –34.6% (iloprost), –31.5% (nifedipine) Duration of attacks –46.8% (iloprost), –44.7% (nifedipine)

Adverse events

Headache Nausea Vomiting >50% (iloprost)

532

Raynaud’s Phenomenon: Iloprost

Trial

A double-blind, randomized, multicentre comparison of two doses of intravenous Iloprost in the treatment of Raynaud’s phenomenon secondary to connective tissue diseases

Substance

Iloprost 0.5 ng/kg/min (n = 28, low dose) Iloprost 2 ng/kg/min (n = 27, standard dose) 10 mL/h with increments of 10 mL/h every 15 minutes until infusion rates reached 0.5 ng/kg/min and 2 ng/kg/min respectively No information on concomitant medication

Patients

55 Patients with Raynaud’s phenomenon >7 attacks/week Systemic sclerosis n = 32 Limited cutaneous scleroderma n = 11 Mixed connective tissue disease n = 5 Rhueumatoid arthritis n = 1 Sjoegren’s syndrome n = 1 Childhood dermatomyositis n = 1 No definite diagnosis n = 3

Result

0.5 and 2 ng iloprost/kg/min reduced severity of Raynaud’s phenomenon and encouraged ulcer healing. Low dose was associated with fewer side effects and was better tolerated

Authors

Torley HI, Madhok R, Capell HA, Brouwer RM, Maddison PJ, Black CM, Englert H, Dormandy JA, Watson HR

Publication

Ann Rheum Dis. 1991;50(11):800–804

Follow up

8 weeks

Note

Ulcer healing 44% (standard dose), 39% (low dose) New lesions n = 3 (standard dose) n = 6 (low dose) Patients’ subjective improvement 41% (standard dose), 68% (low dose) Change of (week 8): Frequency of Raynaud’s attacks –28% (standard dose), –37% (low dose) Duration of Raynaud’s attacks –20 min (standard dose), –46 min (low dose) Severity of Raynaud’s attacks (VAS) –23 (standard dose), –10 (low dose)

Adverse events

Flushing n = 3 (low dose), n = 3 (standard dose) Headache n = 8 (low dose), n = 20 (standard dose) Nausea n = 1 (low dose), n = 13 (standard dose) Vomiting n = 0 (low dose), n = 8 (standard dose) Diarrhoea n = 0 (low dose), n = 7 (standard dose) Abdominal cramps n = 0 (low dose), n = 6 (standard dose) Painful eyes n = 0 (low dose), n = 1 (standard dose) Dizziness n = 0 (low dose), n = 2 (standard dose) Drowsiness n = 1 (low dose), n = 0 (standard dose) Tingling fingers n = 1 (low dose), n = 3 (standard dose) Patients reporting any side effect n = 9 (low dose), n = 21 (standard dose)

Raynaud’s Phenomenon: Iloprost

Trial

Placebo-controlled study showing therapeutic benefit of Iloprost in the treatment of Raynaud’s phenomenon

Substance

3 × 0.5 ng/kg/min iloprost over 6 h (increase every 30 min to max. 2 ng/kg/min) Placebo Cross over after 6 weeks Previous therapy: Nivedipine n = 7 (benefit n = 2) Naftidroyfuryl n = 1 (benefit n = 1) PGE1 n = 5 (benefit n = 2) Oxerutins n = 1 (benefit n = 0) Thymoxamine n = 2 (benefit n = 1) Sympathectomy n = 3 (benefit n = 1) Evening primase oil n = 1 (benefit n = 1) Nicotinic acid n = 5 (benefit n = 2)

Result

Treatment with iloprost reduced the frequency and duration of Raynaud’s phenomenon attacks

Patients

13 patients with Raynaud’s phenomenon Primary Raynaud phenomenon n = 8 Systemic sclerosis n = 4 Mixed connective tissue disease n = 1

Authors

Kyle MV, Belcher G, Hazleman BL

Publication

J Rheumatol. 1992;19(9):1403–1406

Follow up

2 × 6 weeks

Note

Change of (week 6): Frequency of attacks –24.5 (placebo), –44.4 (iloprost) Duration of attacks –54.3 (placebo), –12.2 (iloprost) Severity of attacks +0.1 (placebo), –9.5 (iloprost)

Adverse events

Headache n = 5 Flushing n =2 Nausea n = 4 Vomiting n = 1 Diarrhoea n = 2

533

534

Raynaud’s Phenomenon: Iloprost

Trial

Intravenous Iloprost treatment of Raynaud’s phenomenon and ischemic ulcers secondary to systemic sclerosis

Substance

I.v. iloprost (0.5–2.0 ng/kg/min, n = 18) by continuous infusion for 6 h on 5 consecutive days Placebo (n = 17) No information on concomitant medication

Result

Iloprost was effective in the treatment of digital ulcers in systemic sclerosis and was associated with evidence of prolonged physiologic improvement

Patients

35 patients with Raynaud’s phenomenon secondary to systemic sclerosis With digital ischemic ulcerations n = 11 ³8 symptomatic episodes of Raynaud’s phenomenon/week

Authors

Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP

Publication

J Rheumatol. 1992;19(9):1407–1414

Follow up

10 weeks

Note

Complete healing of all cutaneous lesions 86% (iloprost), 0% (placebo) Critical ischemic temperature 21.6 => 17.8 (iloprost), 21.4 => 20.1 (placebo) Change of: Duration of attacs (min) +2 min (iloprost), –13.4 (placebo) Severity of attacks (VAS 0–4) –0.17 (iloprost), –0.27 (placebo) Recovery (°C/min) +0.29 (iloprost), +0.10 (placebo)

Adverse events

Headache 100% (iloprost), 47% (placebo) Nausea 78% (iloprost), 6% (placebo) Pain 50% (iloprost), 0% (placebo) Vomiting 50% (iloprost), 0% (placebo) Vasodilatation 33% (iloprost), 0% (placebo) Injection-site reaction 28% (iloprost), 1% (placebo) Diarrhoea 17% (iloprost), 0% (placebo) Dizziness 17% (iloprost), 24% (placebo) Abdominal pain 17% (iloprost), 0% (placebo) Myalgia 11% (iloprost), 0% (placebo) Chest pain 11% (iloprost), 0% (placebo)

Raynaud’s Phenomenon: Iloprost

535

Trial

Intravenous Iloprost infusion in patients with Raynaud’s phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study

Substance

Sequential, 6-h i.v. infusions of iloprost (0.5–2.0 ng/kg per min, n = 64) Placebo (n = 67) Prior use of nifedipine n = 26

Patients

131 patients with systemic sclerosis (101 women, 30 men) Min. 8 attacks/week ³1 finger cutaneous ischemic lesion

Result

Iloprost was effective as short-term treatment of severe Raynaud’s phenomenon in patients with systemic sclerosis

Authors

Wigley FM, Wise RA, Seibold JR, McCloskey DA, Kujala G, Medsger TA Jr, Steen VD, Varga J, Jimenez S, Mayes M, Clements PJ, Weiner SR, Porter J, Ellman M, Wise C, Kaufman LD, Williams J, Dole W

Publication

Ann Intern Med. 1994;120(3):199–206

Follow up

9 weeks

Note

Physician’s overall assessment: Great improvement 12.5% (iloprost), 4.5% (placebo) Improved 48.4% (iloprost), 22.4% (placebo) Same 32.8% (iloprost), 56.7% (placebo) Worse 6.3% (iloprost), 16.4% (placebo) Change of: Raynaud severity score –34.8% (iloprost), –19.7% (placebo) Frequency of Raynaud attacks –39.1% (iloprost), –22.2% (placebo) Number of Raynaud attacks – 44.86% (iloprost), –27.21% (placebo) Global Raynaud severity score 34.8% (iloprost), 19.7% (placebo) Physician’s overall rating 52.4% (iloprost), 27.4% (placebo) HAQ –6.71% (iloprost), +9.17% (placebo)

536

Adverse events

Raynaud’s Phenomenon: Iloprost

Headache 84% (iloprost), 31% (placebo) Flushing 50% (iloprost), 9% (placebo) Nausea 45% (iloprost), 16% (placebo) Jaw pain 23% (iloprost), 3% (placebo) Diarrhoea 20% (iloprost), 3% (placebo) Vomiting 19% (iloprost), 3% (placebo) Injection-site reactions 14% (iloprost), 0% (placebo) Abdominal pain 11% (iloprost), 9% (placebo) Dizziness 8% (iloprost), 10% (placebo) Myalgia 8% (iloprost), 0% (placebo) Nausea and vomiting 8% (iloprost), 1% (placebo) Injection-site pain 8% (iloprost), 1% (placebo) Dyspepsia 6% (iloprost), 6% (placebo) Paresthesia 6% (iloprost), 1% (placebo) Dry mouth 5% (iloprost), 1% (placebo) Flatulence 5% (iloprost), 1% (placebo) Hypertonia 5% (iloprost), 0% (placebo) Injection-site inflammation 5% (iloprost), 1% (placebo) Back pain 5% (iloprost), 1% (placebo) Phlebitis 5% (iloprost), 0% (placebo) Arthralgia 3% (iloprost), 1% (placebo) Chills 3% (iloprost), 3% (placebo) Circumoral paresthesia 3% (iloprost), 0% (placebo) Taste perversion 3% (iloprost), 1% (placebo) Amblyopia 2% (iloprost), 1% (placebo) Asthenia 2% (iloprost), 1% (placebo) Eructation 2% (iloprost), 0% (placebo) Gastrointestinal disorder 2% (iloprost), 0% (placebo) Hyperkinesia 2% (iloprost), 0% (placebo) Hypotension 2% (iloprost), 0% (placebo) Postural hypotension 2% (iloprost), 1% (placebo) Abnormal liver function 2% (iloprost), 0% (placebo) Neck pain 2% (iloprost), 0% (placebo) Increased sweating 2% (iloprost), 1% (placebo) Arrhythmia 0% (iloprost), 3% (placebo) Dysonea 0% (iloprost), 3% (placebo) Injection-site eodema 0% (iloprost), 1% (placebo) Peripheral oedema 0% (iloprost), 3% (placebo) Chest pain 0% (iloprost), 1% (placebo) Vertigo 0% (iloprost), 1% (placebo)

Raynaud’s Phenomenon: Iloprost

537

Trial

Oral Iloprost as a treatment for Raynaud’s syndrome: a double-blind multicenter placebo-controlled study

Substance

2 × 50 E –150 µg oral iloprost (n = 32) Placebo (n = 31) Both applied for 10 days 14 days washout of vasoactive substances

Result

Oral administration of Iloprost displayed a trend in favor of iloprost in this short-term follow-up study

Patients

63 Patients with Raynaud’s syndrome secondary to systemic sclerosis

Authors

Belch JJ, Capell HA, Cooke ED, Kirby JD, Lau CS, Madhok R, Murphy E, Steinberg M

Publication

Ann Rheum Dis. 1995;54(3):197–200

Follow up

10 days treatment + 14 days follow up

Note

Global opinion: Samptoms unchanged 60% (placebo) Symptoms improved 60% (iloprost) Change of duration of Raynaud’s attacks: End of treatment –24% (placebo), –40% (iloprost) After 2 weeks follow up –25% (placebo), –25% (iloprost) Change of painful attacks: End of treatment –23 (placebo), +1 (iloprost) After 2 weeks follow up –7 (placebo), –27 (iloprost) Change of severity of Raynaud’s attacks: End of treatment –1 (placebo), –6 (iloprost) After 2 weeks follow up 0 (placebo), –9 (iloprost) Change of severity of Raynaud’s attacks: End of treatment –1% (placebo), –6% (iloprost) After 2 weeks follow up 0% (placebo), –9% (iloprost)

Adverse events

Headache leading to withdrawal n = 3 (iloprost), n = 0 (placebo) Headache, flushing, and nausea 97% (iloprost), 61% (placebo)

538

Raynaud’s Phenomenon: Iloprost

Trial

Oral Iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study

Substance

2 × 50 µg iloprost/day orally (n = 157) Placebo (n = 151) Previous medication: No prostanoid therapy (including misoprostol) £ 2 months No prior ciclosporin

Result

Oral iloprost treatment of Raynaud’s phenomenon secondary to scleroderma was equally effective as placebo

Patients

308 with scleroderma (272 women, 36 men, mean age 49 years) With Raynaud’s phenomenon Min. 6 Raynaud attacks/week

Authors

Wigley FM, Korn JH, Csuka ME, Medsger TA Jr, Rothfield NF, Ellman M, Martin R, Collier DH, Weinstein A, Furst DE, Jimenez SA, Mayes MD, Merkel PA, Gruber B, Kaufman L, Varga J, Bell P, Kern J, Marrott P, White B, Simms RW, Phillips AC, Seibold JR

Publication

Arthritis Rheum. 1998;41(4):670–677

Follow up

12 weeks

Note

Graded response: Improvement in duration of Raynaud’s phenomenon attacks >50% 45.9% (iloprost), 41.7% (placebo) Improvement in duration of Raynaud’s phenomenon attacks >50% 24.8% (iloprost), 24.5% (placebo) Improvement in Raynaud’s condition score >50% 35.0% (iloprost), 24.5% (placebo) Change of: Duration of Raynaud attacks, minutes –24.06% (iloprost), –21.13% (placebo) Frequency of Raynaud attacks –24.12% (iloprost), –15.38% (placebo) Raynaud’s condition score –29.18% (iloprost), –21.46 (placebo)

Raynaud’s Phenomenon: Iloprost

Adverse events

Headache 67.3% (iloprost), 28.9% (placebo) Flushing 31.4% (iloprost), 6.0% (placebo) Nausea 22.4% (iloprost), 11.4% (placebo) Dizziness 18.6% (iloprost), 9.4% (placebo) Diarrhoea 13.5% (iloprost), 10.7% (placebo) Skin ulcers 11.5% (iloprost), 13.4% (placebo) Asthenia 10.9% (iloprost), 5.4% (placebo) Abdominal pain 9.6% (Iloprost), 3.4% (placebo) Myalgia 9.0% (iloprost), 6.0% (placebo) Vascular disorde 8.3% (iloprost), 9.4% (placebo) Cough increase 8.3% (iloprost), 8.7% (placebo) Pain 7.7% (iloprost), 12.8% (placebo) Dyspepsia 7.7% (iloprost), 8.7% (placebo) Infection 7.1% (iloprost), 6.7% (placebo) Rhinitis 7.1% (iloprost), 5.4% (placebo) Flu syndrom 7.1% (iloprost), 4.7% (placebo) Upper respiratory infection 6.4% (iloprost), 7.4% (placebo) Vomiting 6.4% (iloprost), 6.4% (placebo) Arthralgias 5.8% (iloprost), 4.7% (placebo) Trismus 5.1% (iloprost), 1.3% (placebo) Sinusitis 3.2% (iloprost), 6.0% (placebo)

539

540

Raynaud’s Phenomenon: Iloprost

Trial

Oral Iloprost in Raynaud’s phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, dose-comparison study

Substance

Placebo (n = 35) Oral iloprost 50 µg (n = 33) Oral iloprost 100 µg (n = 35) No information on concomittant medication

Result

Oral iloprost was effective with regard to duration and frequency of attacks in Raynaud’s phenomenon secondary to systemic sclerosis

Patients

103 patients with Raynaud’s phenomenon Secondary to systemic sclerosis

Authors

Black CM, Halkier-Sørensen L, Belch JJ, Ullman S, Madhok R, Smit AJ, Banga JD, Watson HR

Publication

Br J Rheumatol. 1998;37(9):952–960

Follow up

12 weeks

Note

Improvement 44% (placebo), 57% (iloprost 50 µg), 64% (iloprost 100 µg) Healing of digital cutaneous lesions n = 1/7 (placebo), n = 1/8 (iloprost 50 µg), n = 3/7 (iloprost 100 µg) Change of: Duration of Raynaud’s attacks –9% (placebo), –60% (iloprost 50 µg), –60% (iloprost 100 µg) Frequency of Raynaud’s attacks –15% (placebo), –46% (iloprost 50 µg), –50% (iloprost 100 µg) Raynaud’s condition score –15% (placebo), –38% (iloprost 50 µg), –60% (iloprost 100 µg)

Adverse events

Headache 40% (placebo), 79% (50 µg iloprost), 86% (100 µg iloprost) Flushing 17% (placebo), 27% (50 µg iloprost), 46% (100 µg iloprost) Nausea 3% (placebo), 30% (50 µg iloprost), 37% (100 µg iloprost) Flu syndrome 31% (placebo), 9% (50 µg iloprost), 14% (100 µg iloprost) Dizziness 17% (placebo), 6% (50 µg iloprost), 14% (100 µg iloprost) Vomiting 6% (placebo), 9% (50 µg iloprost), 20% (100 µg iloprost) Diarrhoea 3% (placebo), 9% (50 µg iloprost), 20% (100 µg iloprost) Pain in extremity 3% (placebo), 12% (50 µg iloprost), 14% (100 µg iloprost) Ashenia 3% (placebo), 9% (50 µg iloprost), 14% (100 µg iloprost) Dyspepsia 9% (placebo), 9% (50 µg iloprost), 9% (100 µg iloprost) Rash 3% (placebo), 6% (50 µg iloprost), 14% (100 µg iloprost) Trismus 0% (placebo), 6% (50 µg iloprost), 17% (100 µg iloprost) Infection 11% (placebo), 9% (50 µg iloprost), 3% (100 µg iloprost) Pharyngitis 0% (placebo), 12% (50 µg iloprost), 6% (100 µg iloprost) Any adverse events 80% (placebo), 86% (50 µg iloprost), 97% (100 µg iloprost) Treatment discontinuation due to adverse events 6% (placebo), 27% (50 µg iloprost), 51% (100 µg iloprost)

Raynaud’s Phenomenon: Iloprost

Trial

Effects of long-term cyclic Iloprost therapy in systemic sclerosis with Raynaud’s phenomenon. A randomized, controlled study

Substance

I.v. infusions of iloprost (2 ng/kg/min on 5 consecutive days over a period of 8 h/day and subsequently for 8 h on one day every 6 weeks, n = 29) Nifedipine (40 mg/day for os, n = 17)

Result

In systemic sclerosis patients suffering from Raynaud’s phenomenon, cyclic intravenous iloprost infusions were able to control vasospastic disease. It also seemed to reduce the skin score

Patients

46 patients with systemic sclerosis and Raynaud’s phenomenon

Authors

Scorza R, Caronni M, Mascagni B, Berruti V, Bazzi S, Micallef E, Arpaia G, Sardina M, Origgi L, Vanoli M

Publication

Clin Exp Rheumatol. 2001;19(5):503–508

Follow up

12 months

Note

Change of: Reduced the skin score –4.0 (iloprost), +1.34 (nifedipine) Raynaud’s phenomenon severity score –0.95 (iloprost), –0.75 (nifedipine) DLCO (% of the predicted normal value) –2.8 (iloprost), –13.0 (nifedipine) Total skin score –12.2 (iloprost), +6.3 (nifedipine)

Adverse events

Headache 100% (ilomedin), 24% (nifedipine) Nausea, Vomiting 83% (ilomedin), 0% (nifedipine) Jaw pain 69% (ilomedin), 0% (nifedipine) Myalgia 34% (ilomedin), 0% (nifedipine) Diarrhoea 28% (ilomedin), 0% (nifedipine) Chills 17% (ilomedin), 0% (nifedipine) Hypotension 14% (ilomedin), 29% (nifedipine) Arrythmia 7% (ilomedin), 0% (nifedipine) Hyperkinesia 3% (ilomedin), 0% (nifedipine) Tachycardia 0% (ilomedin), 6% (nifedipine)

541

542

Raynaud’s Phenomenon: Iloprost

Trial

Comparison between Iloprost and Alprostadil in the treatment of Raynaud’s phenomenon

Substance

I.v. 8–30 µg iloprost/day (n = 11) 20 µg alprostadil/h (n = 10), cyclically 5 consecutive days, followed by 1 day every 30 days No information on concomitant medication

Result

Iloprost and alprostadil were both effective in conective tissue diseaseassociated Raynaud’s phenomenon, without significant differences in either clinical efficacy or circulating biomarkers

Patients

21 women with connective tissue disease-associated Raynaud’s phenomenon + ³3 Raynaud’s attacks/s ± Digital ischemic changes

Authors

Marasini B, Massarotti M, Bottasso B, Coppola R, Papa ND, Maglione W, Comina DP, Maioli C

Publication

Scand J Rheumatol. 2004;33(4):253–256

Follow up

60 days

Note

Raynaud’s phenomenon improved in 45% (iloprost), 90% (alprostadil) Improvement of ulcers in 60% (iloprost), 40% (alprostadil) Change of: Skin score –2.2 (iloprost), +1.2 (alprostadil) Circulating von Willebrand factor –6.2% (iloprost), –9.4% (alprostadil) Tissue plasminogen activation –0.9 (iloprost), +1.6 (alprostadil) Thrombomodulin –0.6 (iloprost), +0.2 (alprostadil) Pro-collagen N terminal peptide –0.1 (iloprost), +0.2 (alprostadil)

Adverse events

Headache n = 6 (iloprost), n = 0 (alprostadil) Nausea n = 3 (iloprost), n = 0 (alprostadil) Vomiting n = 1 (iloprost), n = 0 (alprostadil) Injection-site reaction n = 0 (iloprost), n = 1 (alprostadil)

Raynaud’s Phenomenon: Iloprost

543

Trial

Low versus high-dose Iloprost therapy over 21 days in patients with secondary Raynaud’s phenomenon and systemic sclerosis: a randomized, open, single-center study

Substance

2 ng/kg body weight per minute (n = 25) Low-dose (0.5 ng/kg/min), intravenous iloprost administration (n = 25) Applied for 6 h daily over 21 days No information on concomitant medication

Result

Low-dose Iloprost was equally effective as high-dose iloprost in long-term treatment and was very effective in the therapy of digital ulcers

Patients

50 patients with SSc Stable immunosuppression or vasoactive therapies for 3 months Current smokers, patients with a history of gastric ulcer £3 months Cardiac ejection fraction <25% No severe organ involvement or other uncontrolled disease: Angina pectoris Severe anaemia Coagulopathies Azotemia Cerebral infarction during the last 6 months Malignant diseases

Authors

Kawald A, Burmester GR, Huscher D, Sunderkötter C, Riemekasten G

Publication

J Rheumatol. 2008;35(9):1830–1837. Epub July 15, 2008

Follow up

12 months

Note

Reduction of digital ulcers 76.2% (high dose), 61.0% (low dose) Reduction in frequency of Raynaud’s phenomenon 46% (high dose), 42% (low dose) Reduction in duration of Raynaud’s phenomenon 70% (high dose), 68% (low dose) Modified Rodnan skin score unchanged after 1 year (both regimen) No Response 12% (both regimen)

Adverse events

Flushing 48% (high dose), 40% (low dose) Headache 24% (high dose), 12% (low dose) and GI symptoms like nausea or vomiting 12% (high dose), 4% (low dose)

544

Raynaud’s Phenomenon: Nifedipine

Trial

Controlled trial of Nifedipine in the treatment of Raynaud’s phenomenon

Substance

Nifedipine 4 × 10 mg/day (n = 8) Placebo (n = 8) Cross over after 2 weeks No concomitant vasoactive substance

Result

Nifedipine was effective in 12 out of 17 patients

Patients

Patients with moderate to severe Raynaud’s phenomenon n = 17 Idiopathic Raynaud’s phenomenon n = 5 Systemic sclerosis n = 11 Min. 1 attack/day

Authors

Smith CD, McKendry RJ

Publication

Lancet. 1982;2(8311):1299–1301

Follow up

6 weeks

Note

Patient sore of effectiveness +1.3 (placebo), 5.3 (nifedipine) Change of: Frequency of attacks – 0.3 (placebo), –1.5 (nifedipine) Severity of attacks +0.6 (placebo), –2.4 (nifedipine)

Adverse events

Flushing n = 5 (nifedipine), n = 1 (placebo) Headache n = 4 (nifedipine), n = 0 (placebo) Sensation of light headed n = 3 (nifedipine), n = 0 (placebo) Ankle swelling n = 3 (nifedipine), n = 0 (placebo)

Raynaud’s Phenomenon: Nifedipine

Trial

Controlled double-blind trial of Nifedipine in the treatment of Raynaud’s phenomenon

Substance

3 × 20 mg nifedipine/day Placebo Patient groups were crossed over after 2 weeks and crossed back after another 2 weeks No information on concomitant medication

Result

Treatment of patients suffering from Raynaud’s phenomenon with nifedipine lead to a decrease in the frequency of attacks and moderate improvement in symptoms

Patients

15 Raynaud patients Systemic sclerosis n = 9 SLE n = 1 No systemic disease n = 5 Bilateral episodes

Authors

Rodeheffer RJ, Rommer JA, Wigley F, Smith CR

Publication

N Engl J Med. 1983;308(15):880–883

Follow up

4 weeks

Note

Moderate or marked improvement 60% (nifedipine), 13% (placebo) Minimal improvement, change, or worse 40% (nifedipine), 87% (placebo) Attack rate/2 weeks 14.7 (nifedipine), 10.8 (placebo)

Adverse events

Headache 80% (nifedipine), 20% (placebo) Lightheadness 33%(nifedipine), 7% (placebo)

545

546

Raynaud’s Phenomenon: Nifedipine

Trial

A randomized double-blind cross-over trial of Nifedipine in the treatment of primary Raynaud’s phenomenon

Substance

2 × 5 mg nifedipine/day (dose increased to 2 × 15 mg/day within 3 weeks) Placebo No concomitant medication for Raynaud’s phenomenon was allowed

Result

Nifedipine was effective in primary Raynaud’s phenomenon in most patients but side effects are common

Patients

23 women with primary Raynaud’s phenomenon Disease duration >2 years

Authors

Corbin DO, Wood DA, Macintyre CC, Housley E

Publication

Eur Heart J. 1986;7(2):165–170

Follow up

4 weeks

Note

Number of attacks of Raynaud’s phenomenon 2.3 (nifedipine) 5.0 (placebo) Systolic blood pressure 109.5/68.1 (nifedipine) 109.6/68.6 (placebo) Drug compliance: Good n = 10 (45 mg nifedipine), n = 0 (30 mg nifedipine), n = 3 (15 mg nifedipine), n = 15 (placebo) Moderate n = 5 (45 mg nifedipine), n = 2 (30 mg nifedipine), n = 0 (15 mg nifedipine), n = 6 (placebo) Poor n = 0 (45 mg nifedipine), n = 2 (30 mg nifedipine), n = 0 (15 mg nifedipine), n = 2 (placebo)

Adverse events

Headache 26% (nifedipine), 9% (placebo) Ankle swelling 22% (nifedipine), 0% (placebo) Flushing 52% (nifedipine), 0% (placebo) Palpitations 9% (nifedipine), 0% (placebo) Nausea 17% (nifedipine), 4% (placebo) Paraesthesia 35% (nifedipine), 0% (placebo) Dizziness 13% (nifedipine), 0% (placebo) Chest pain 0% (nifedipine), 0% (placebo)

Raynaud’s Phenomenon: Nifedipine

Trial

Nifedipine in the treatment of Raynaud’s phenomenon in patients with systemic sclerosis

Substance

3 ×10 mg nifedipine (n = 5) Placebo (n = 5) After a 2 week wash ourt period Patient groups were crossed over after 6 weeks

Result

Patients with idiopathic Raynaud’s phenomenon responded better to nifedipine than patients with disease secondary to systemic sclerosis

Patients

10 patients with Raynaud’s phenomenon Secondary to systemic sclerosis

Authors

Meyrick Thomas RH, Rademaker M, Grimes SM, MacKay A, Kovacs IB, Cook ED, Bowcock SM, Kirby JD

Publication

Br J Dermatol. 1987;117(2):237–241

Follow up

6 weeks

Note

Duration of Raynaud’s attacks (min) 29.7 (placebo), 18.7 (nifedipine) Number of attacks/day 1.6 (placebo), 1.3 (nifedipine) Percentage of mild attacks 32.4 (placebo), 50.3 (nifedipine) Percentage of moderate attacks 48.9 (placebo), 37.2 (nifedipine) Percentage of severe attacks 18.7 (placebo), 12.5 (nifedipine) Percentage of pain free attacks 49.5 (placebo), 59.3 (nifedipine)

547

548

Raynaud’s Phenomenon: Sildenafil

Trial

Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilatory therapy

Substance

2 × 50 mg sildenafil/day Placebo b.i.d. for 4 weeks Fixed-dose, crossover study, 1 week wash out period in between the two treatment periods All vasoactive substances were stopped before the trial Concomittant substances for rheumatological disease remained unchanged

Result

2 × 50 mg sildenafil/day was an effective and well-tolerated treatment in patients with Raynaud’s phenomenon

Patients

16 patients with symptomatic secondary Raynaud’s phenomenon Resistant to vasodilatory therapy with at least two agents Regular occurrence of painful Raynaud attacks Systemic sclerosis, n = 14 Mixed connective tissue disease, n = 2 No connective tissue disease, n = 2

Authors

Fries R, Shariat K, von Wilmowsky H, Böhm M

Publication

Circulation. 2005;112(19):2980–2985

Follow up

9 weeks

Note

Frequency of Raynaud attacks 35 (Sildenafil), 52 (placebo) Cumulative attack duration 581 min (Sildenafil), 1,046 min (placebo) Mean capillary flow velocity +0.31 (Sildenafil), +0.07 (placebo)

Adverse events

Headache n = 1 (Sildenafil) Muscle pain n = 1 (Sildenafil) Swelling of the nasal mucosa n = 1 (Sildenafil) Transient facial sensation of heat n = 3 (Sildenafil) Mild nausea n = 2 (Sildenafil) No significant effect of Sildenafil on blood pressure and heart rate

Dermato/Polymyositis

Corticosteroids

Trial

Childhood dermatomyositis: clinical course of 36 patients treated with low doses of corticosteroids

Substance

Low doses of corticosteroids (prednisolone 1 mg/kg/day, n = 36) Additional treatment with DMARDs (n = 13) Ciclosporin (n = 4) Methotrexate (n = 2) i.v. Immunoglobulins (n = 2) Methotrexate + ciclosporine (n = 1)

Patients

36 patients with juvenile dermatomyositis Diagnosed according the criteria of Bohan and Peter

Result

28 children treated with corticosteroids had a favourable outcome

Authors

Tabarki B, Ponsot G, Prieur AM, Tardieu M

Publication

Eur J Paediatr Neurol. 1998;2(4):205–211

Follow up

Mean 4.9 years

Note

No functional impairment 78% Inactive disease but with persisting disabilities 8% Active disease despite several years of treatment 8.3% Dystrophic calcifications 42% Outcome (according Bowyer et al.): Type 1: Monophasic course of the disease 39% Type 2: Polyphasic course 39% Type 3: Persistent active disease 8% Type 4: Inactive disease with muscular impairment 14%

Adverse events

None reported

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_8, © Springer-Verlag London Limited 2011

549

550

Dermato/Polymyositis: Azathioprine

Trial

Azathioprine with prednisone for polymyositis. A controlled, clinical trial

Substance

15 mg (material and methods) or 60 mg (abstract) prednisone/day alone (n = 8) Prednisone + 2 mg/kg azathioprine/day (Aza, n = 8) Prednisone dose was adjusted according to clinical criteria, creatinine kinase, manual muscle strength testing Concomitant medication: No information was provided Drug changes were permitted

Result

Normalization of the CK was not consistent with disease control. Type II fiber atrophy was more marked in women than in men (P < 0.03)

Patients

16 patients with polymyositis

Authors

Bunch TW, Worthington JW, Combs JJ, Ilstrup DM, Engel AG

Publication

Ann Intern Med. 1980;92(3):365–369

Follow up

3 months

Note

Time to normal CK 53.5 days (prednisone), 69.4 days (Aza + prednisone) Change of: Muscle strength score +1.1 (prednisone), +6.5 (Aza + prednisone) Inflammation score +1.79 (prednisone), +1.65 (Aza + prednisone)

Adverse events

Nausea n = 0 (prednisone), n = 1 (Aza + prednisone) Diverticulitis n = 1 (prednisone), n = 0 (Aza + prednisone) Pneumonitis n = 0 (prednisone), n = 1 (Aza + prednisone) Leukopenia n = 0 (prednisone), n = 1 (Aza + prednisone)

Dermato/Polymyositis: Azathioprin

Trial

Prednisone and azathioprine for polymyositis: long-term follow up

Substance

Prednisone alone (n = 8) Prednisone + 2 mg/kg Azathioprine/day (n = 8) Prednisone dose was adjusted according to clinical criteria, creatinine kinase, manual muscle strength testing Concomitant medication: No information was provided Drug changes were permitted

Result

Comparing prednisolone monotherapy versus azathioprine – prednisone combination therapy of polymyositis revealed no significant differences after 3 months. Functional disability improved more in the combination therapy group on long term follow up

Patients

16 patients with polymyositis

Authors

Bunch TW

Publication

Arthritis Rheum. 1981;24(1):45–48

Follow up

Approximately 3 years

Note

Average prednisone dose 1.6 mg/day (prednisone), –1.5 mg/day (Aza + prednisone) Change of: Functional grade disability 8.7 mg/day (prednisone), 1.6 mg/day (Aza + prednisone)

Adverse events

CMV infection n = 0 (prednisone), n = 1 (Aza + prednisone) Death (ruptured berry aneurysma) n = 1 (prednisone), n = 0 (Aza + prednisone) Leucocyte count > 3,000/mm3 n = 0 (prednisone), n = 1 (Aza + prednisone)

551

552

Dermato/Polymyositis: Cyclosphosphamide

Trial

Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with Polymyositis/Dermatomyositis

Substance

Cyclophosphamide (300–800 mg/m2), 6 × every 4 weeks Oral prednisolone (0.5–1 mg/kg/day) for 2 weeks and gradually tapered Concomittant therapy isoniazid and sulfamethoxazole-trimethoprim to prevent Pneumocystis jiroveci pneumonia or TBC

Result

Treatment with i.v. cyclophosphamide of patients with Polymyositis/ Dermatomyositis-associated interstitial pneumonia improved symptoms, pulmonary function tests and HRCT findings

Patients

17 patients with Polymyositis/Dermatomyositis Or amyopathic dermatomyositis With progressive interstitial pneumonia, based on chest X-ray and HRCT

Authors

Yamasaki Y, Yamada H, Yamasaki M, Ohkubo M, Azuma K, Matsuoka S, Kurihara Y, Osada H, Satoh M, Ozaki S

Publication

Rheumatology (Oxford). 2007;46(1):124–130. Epub June 4, 2006

Follow up

24 months

Note

Improvement in their dyspnoea n = 17 No more dyspnoea n = 11 Oxygen Reqirement n = 6 (before), n = 1 (after) ³10% improvement of vital capacity n = 8 ³10% reduction of vital capacity n = 9 Flare-up of interstitial pneumonia or myositis n = 2 Extent of abnormal lesions in HRCT –11% Vital capacity +19%

Adverse events

Infection with Mycobacterium avium n = 3 Herpes zoster infection n = 9 Azospermia n = 1

Dermato/Polymyositis: Immunoglobulins

Trial

A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis

Substance

Immunoglobulins (IVIG, 2 g/kg/month, n = 8) Placebo (n = 7) Patient groups were crossed over after 3 months Concomittant 25 mg prednisolone Concomittant DMARDs were continued

Result

High-dose intravenous immunoglobulins treatment for refractory dermatomyositis was safe and effective

Patients

15 dermatomyositis patients (age 18 to 55 years) Biopsy-proven, treatment-resistant Progressive muscle weakness Unresponsive to corticosteroids or DMARDs

Authors

Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S

Publication

N Engl J Med. 1993;329(27):1993–2000

Follow up

6 months

Note

Major improvement n = 0 (placebo), n = 9 (IVIG) Mild improvement n = 3 (placebo) n = 2 (IVIG) No change n = 0 (placebo), n = 0 (IVIG) Worsening of their condition n = 5 (placebo), n = 0 (IVIG) Change of: Improvement in sores of muscle strength n = 8 (IVIG), n = 0 (placebo) Muscle-strength scores increased from +10.3 (IVIG)

Adverse events

None reported

553

554

Dermato/Polymyositis: Immunoglobulins

Trial

Results and long-term follow-up of intravenous immunoglobulin infusions in chronic, refractory Polymyositis: an open study with 35 adult patients

Substance

Six infusions of i.v. immunoglobulins at 1 mg/kg (mean dose 32.7 mg/day) Concomittant corticosteroids were continued After the patients had received conventional therapy

Result

70% of the patients with chronic, refractory Polymyositis improved upon i.v. immunoglobulin treatment. After discontinuation of the immunoglobulin therapy and during 3 years of follow up the efficacy remained stable in 50% of the patients

Patients

35 adult white patients with chronic, refractory Polymyositis (20 female, 15 male, mean age 43.5 years)

Authors

Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, Maisonobe T, Eymard B, Herson S

Publication

Arthritis Rheum. 2002;46(2):467–474

Follow up

4 years

Note

i.v. Immunoglobulin responders (n = 25): British Medical Research Council score +14.5 Muscle disability scale score –12.7 CK level –1590 U/L Mean dose of steroids 32.7 mg/day ³ 21.9 mg/day i.v. Immunoglobulin non responders (n = 10): British Mmedical research council score +13.5 Muscle disability scale score –7.4 CK Levels –940 U/L Mean dose of steroids 29.8 mg/day ³ 25.8 mg/day

Adverse events

Total n = 29 Mild headache n = 4 Fever with shivering and sweating n = 3

Dermato/Polymyositis: Methotrexate

Trial

Methotrexate treatment of recalcitrant childhood dermatomyositis

Substance

20 mg/m2 MTX

555

Concomittant medication: 2 mg/kg prednisone/day Additional treatment 3 weeks of plasmapheresis and 3 months of tolmetin in 1, 4 weeks of hydroxychloroquine in the other n = 2 Result

Methotrexate in combination with prednisone was an effective treatment of recalcitrant childhood dermatomyositis. Recurrence of disease activity after withdrawal of methotrexate suggests that the drug may have a suppressive, rather than a remittive, effect

Patients

16 patients with recalcitrant dermatomyositis

Authors

Miller LC, Sisson BA, Tucker LB, DeNardo BA, Schaller JG

Publication

Arthritis Rheum. 1992;35(10):1143–1149

Follow up

9.5 months–28 months

Note

Regaining muscle strength n = 12 Prednisone dosage could eventually be tapered to £5 mg/day n = 11 Normal CK levels after 2 weeks Normal serum aldolase 8 weeks

Adverse events

Anaemia (hematocrit 23–33%) 19% Poor compliance 6% Cellulitis 12.5% Pneumonia 6% Opportunistic infection 6% Abdominal pain mild-moderate 69% Abdominal pain severe 6% Diarrhoea 31% Nausea and vomiting 6% Transient elevations of SGOT and SGPT 50% Stomatitis 8% Persistent elevation of SGOT and SGPT 8% Decreased pulmonary diffusion capacity 8%

556

Dermato/Polymyositis: Methotrexate

Trial

Low-dose methotrexate administered weekly is an effective corticosteroidsparing agent for the treatment of the cutaneous manifestations of dermatomyositis

Substance

Oral Methotrexate 2.5–7.5 mg/week, increased as needed (range 2.5–30 mg/week) Patients needed to avoid the sun Concomitant 1% hydrocortisone ointment

Result

Low-dose oral methotrexate administered weekly was effective in treatment of the cutaneous manifestations of dermatomyositis and frequently enabled a reduction or discontinuation of corticosteroid therapy

Patients

13 patients with dermatomyositis According the criteria of Bohan and Peter

Authors

Kasteler JS, Callen JP

Publication

J Am Acad Dermatol. 1997;36(1):67–71

Follow up

3–22 months

Note

Free of all cutaneous manifestations of dermatomyositis n = 4 MTX allowed reduction of other therapies n = 13

Adverse events

Nausea n = 6

Dermato/Polymyositis: Methotrexate

Trial

The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids

Substance

10–20 mg/m2/week methotrexate (MTX, max. 25 mg/week, n = 31) + aggressively tapered 2 mg/kg corticosteroids (max. 75 mg/day) Only corticosteroid treated patients (n = 22) Flare: Dose of prednisone was increased until control was achieved

557

Additional DMARD treatment: Azathioprine 3.2% (patients), 0% (controls) Ciclosporin A 3.2% (patients), 0% (controls) Cyclophosphamide 3.2% (patients), 4.6% (controls) Hydroxychloroquine 19.4% (patients), 36.4% (controls) Methotrexate 27.2% (controls) Result

Methotrexate in conjunction with an aggressively tapered course of prednisone seemed more effective as traditional long-term corticosteroid therapy for children with dermatomyositis. The cumulative dose of corticosteroids was lower with methotrexate

Patients

31 consecutive children with dermatomyositis (patients) 22 patients with incident cases of juvenile dermatomyositis (controls)

Authors

Ramanan AV, Campbell-Webster N, Ota S, Parker S, Tran D, Tyrrell PN, Cameron B, Spiegel L, Schneider R, Laxer RM, Silverman ED, Feldman BM

Publication

Arthritis Rheum. 2005;52(11):3570–3578

Follow up

48 months

Note

Change of: Time to discontinue corticosteroids 10 months (MTX), 27 months (control) Increase of BMI 2.0 kg/m2 (MTX) 2.8 kg/m2 (control) Height velocity +4.1 cm/a (MTX), +2.8 cm/a (control) Rash at 3 years 22% (MTX), 33% (control) Rash at 4 years 24% (MTX), 40% (control)

Adverse events

Cataract n = 3 (MTX), n = 8 (control) Spinal fracture n = 1 (MTX), n = 2 (control) Elevated liver enzymes n = 6 (MTX), n = 3 (control) Infections n = 3 (MTX, Shigelles, fungal vaginitis, cellulitis), n = 0 (control)

558

Dermato/Polymyositis: Methotrexate vs. Ciclosporine

Trial

Ciclosporin A versus Methotrexate in the treatment of polymyositis and dermatomyositis

Substance

0.5–1 mg/kg/day Prednisone, tapered after week 4 If patients did not respond after 3 weeks 7.5–15 mg methotrexate/week (MTX, n = 17) 3–3.5 mg/kg/day ciclosporine A (CsA, n = 19)

Patients

36 patients (20 with Dermatomyositis, 16 with Polymyositis) No inclusion body myositis Manual muscle test Grade 3 in min two muscle groups Elevated CK levels Non responsive to 0.5–1 g/kg prednisolone over 3 weeks

Result

Treatment of polymyositis or dermatomyositis with methotrexate or ciclosporin A added to corticosteroids was associated with an improvement of clinical and laboratory findings

Authors

Vencovský J, Jarosová K, Machácek S, Studýnková J, Kafková J, Bartůnková J, Nemcová D, Charvát F

Publication

Scand J Rheumatol. 2000;29(2):95–102

Follow up

6 months

Note

Muscle endurance and functional test improved 33% (MTX), 47% (CsA) Muscle endurance and functional test unchanged 60% (MTX), 37% (CsA) Clinical assessment improved 73% (MTX), 58% (CsA) Clinical assessment unchanged 20% (MTX), 37% (CsA) Patient’s global assessment improved 67% (MTX), 68% (CsA) Patient’s global assessment unchanged 27% (MTX), 21% (CsA) Change of: CK (Nkat/l) –39.53 (MTX), –13.6 (CsA) Myoglobulin (mcg/l) –483 (MTX), –285 (CsA) CRP (mg/l) –7.8 (MTX), –3.7 (CsA) ANA positivity –3% (MTX), –10% (CsA)

Adverse events

Pancytopenia n = 1 (MTX), n = 0 (CsA) Gut perforation n = 1 (MTX), n = 0 (CsA) Acute alveolitis n = 1 (MTX), n = 0 (CsA) Petechiae n = 1 (MTX), n = 0 (CsA) Hypertension n = 1 (MTX), n = 3 (CsA) Rash n = 1 (MTX), n = 0 (CsA) Creatinine elevation n = 0 (MTX), n = 1 (CsA) Pneumonia n = 0 (MTX), n = 1 (CsA) Bronchitis n = 0 (MTX), n = 1 (CsA) Bronchopneumonia n = 0 (MTX), n = 1 (CsA)

Dermato/Polymyositis: Mycophenolate Mofetil

Trial

Mycophenolate mofetil as an effective corticosteroid-sparing therapy for recalcitrant dermatomyositis

Substance

2 × 500–1,000 mg Mycophenolate mofetil/day (max. 3 g/day)

559

Concomitant medication: Methotrexate was allowed Prednisone was allowed Result

Mycophenolate mofetil treatment of patients with dermatomyositis may be an effective corticosteroid-sparing therapy

Patients

12 patients with dermatomyositis Skin lesions recalcitrant to traditional therapies or Developed toxic effects

Authors

Edge JC, Outland JD, Dempsey JR, Callen JP

Publication

Arch Dermatol. 2006;142(1):65–69

Note

Improvement in both cutaneous and muscular symptoms within 4 to 8 weeks n = 10

Adverse events

B-cell lymphoma n = 1 Abnormal levels of hepatic enzymes n = 1 Leucopenia n = 2 Fatigue n = 1

560

Dermato/Polymyositis: Anti-TNF

Trial

Possible role for tumor necrosis factor inhibitors in the treatment of resistant dermatomyositis and polymyositis: a retrospective study of eight patients

Substance

3 mg/kg Infliximab (n = 1) weeks 0, 2, 6, every 8 weeks thereafter 2 × 25 mg Etanercept/week (n = 6) Or both, sequential (n = 1)

Result

Anti-TNF treatment of patients with refractory dermatomyositis or polymyositis may be useful in some cases

Patients

8 patients with dermatomyositis or polymyositis Classification criteria of Bohan and Peter Refractory to corticosteroids and DMARDs (Oral and intravenous corticosteroids, intravenous immunoglobulin and immunosuppressant’s, methotrexate, azathioprine, mycophenolate mofetil, and leflunomide)

Authors

Efthimiou P, Schwartzman S, Kagen LJ

Publication

Ann Rheum Dis. 2006;65(9):1233–1236. Epub February 13, 2006

Follow up

3–20 months

Note

Favorable response n = 6 (Improved motor strength and decreased fatigue) None responders n = 2

Dermato/Polymyositis: Etanercept

Trial

Use of Etanercept in the treatment of dermatomyositis: a case series

Substance

2 × 25 mg Etanercept/week

Result

TNF-alpha inhibition by Etanercept was not effective, suggesting that a broad immunosuppressive therapy is needed to treat dermatomyositis

Patients

Five patients with active DM Despite DMARD and/or NSAID treatment Muscle weakness Elevated muscle enzymes Elevated creatine kinase Elevated lactate dehydrogenase

Authors

Iannone F, Scioscia C, Falappone PC, Covelli M, Lapadula G

Publication

J Rheumatol. 2006;33(9):1802–1804

Follow up

3 months

Note

All patients experienced an exacerbation of disease, with increase of muscle weakness, elevation of muscle enzyme levels, and unchanged rash Treatment with Etanercept was stopped After receiving a combination of methotrexate and azathioprine, disease manifestations improved in all patients CK +468.8 U/L LDH +75.8 U/L Prednisone dose +1 mg/day Muscle weakness upper limb +0.8 Muscle weakness lower limb +0.8

561

562

Dermato/Polymyositis: Rituximab

Trial

Rituximab in the treatment of dermatomyositis: an open-label pilot study

Substance

Four intravenous infusions of 100 mg/sqm (first three patients) 375 mg/sqm (n = 4) Rituximab Given at weekly intervals Premedication with acetaminophen and diphenhydramine Previous corticosteroid treatment was continued at stable doses or tapered Previous DMARD treatment was continued at stable doses or tapered

Result

Rituximab was effective in this open-label study in patients with dermatomyositis refractory to other immunomodulatory treatment

Patients

Seven adult patients with dermatomyositis Patients had failed to ³1 therapy (corticosteroids, ciclosporin A, methotrexate, IVIG, or other immunosuppressive therapy) Average muscle strength of <75%

Authors

Levine TD

Publication

Arthritis Rheum. 2005;52(2):601–607

Follow up

36–52 weeks

Note

Major clinical improvement n = 7 (evident after min. 4 weeks) Muscle strength increasing by 36–113% Return of symptoms n = 4 Maintained increased muscle strength at 52 weeks n = 2 CK levels (range) 128–5,600 units/L => 57–1,168 units/L FVC improvement n = 2 Improvement of hair grow after alopecia n = 2

Adverse events

Shortness of breath and hypertension n = 1 Cellulitis (grade 3) n = 1

Dermato/Polymyositis: Rituximab

563

Trial

A pilot trial of Rituximab in the treatment of patients with dermatomyositis

Substance

Rituximab (1 g each) 2 weeks apart Without peri-infusional steroids Continue treatment with topical corticosteroids or immunomodulators Continue oral corticosteroids Continue antimalarial agents, mycophenolate mofetil, methotrexate, azathioprine at stable doses

Result

Rituximab treatment had modest effects on muscle disease and limited effects on skin disease

Patients

Eight adult patients with dermatomyositis Two of the following criteria: Symmetrical weakness Muscle biopsy features consistent with DM Elevation of muscle enzyme levels Electromyographic evidence of muscle inflammation Skin biopsy findings consistent with DM mild muscle disease: Modified Medical Research Council Manual Muscle Test (MMT) score < 85 Elevation of CPK (>400 U/L) Aldolase (>8.0 U/L) Dermatomyositis Skin Severity Index (DSSI) score > 2 No cardiac or pulmonary disease, active infection, hepatitis B, hepatitis C, HIV, malignancies

Authors

Chung L, Genovese MC, Fiorentino DF

Publication

Arch Dermatol. 2007;143(6):763–767

Follow up

24 weeks

Note

Partial remission n = 3 Dermatomyositis Skin Severity Index –9.5% None of the subjective assessments changed substantially CK levels: Stable values n = 3 Increasing n = 1 Change of: CK level +17.80% Aldolase levels +15.13%

Adverse events

No serious infections Mild infusion reactions (headache, transient hypertension, congestion with facial flushing) n = 3 Increase in liver transaminase levels n = 1 (resolved with the discontinuation of azathioprine) Superficial skin infections (n = 2) Bronchitis (n = 3) Sinusitis (n = 2) Urinary tract infection (n = 1) Otitis media (n = 1) Death of metastatic cancer (n = 1)

564

Dermato/Polymyositis: Plasma Exchange

Trial

Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis

Substance

Plasma exchange (replacement of 1–1.5 volume of plasma with 5% albumin in saline, n = 13) Leukapheresis (removal of 5–10 × 109 lymphocytes, n = 13) Sham apheresis (3×/week, n = 13) 12 treatments given over a 1-month period Concomitant medication: Corticosteroid were continued Previous medication: Prednisone ³ 0.25 mg/kg/day for ³1 month Cytotoxic therapy n = 10 (plasma exchange), n = 9 (leukapheresis), n = 10 (Sham apharesis)

Result

Leukapheresis and plasma exchange were no more effective than sham apheresis as treatments for corticosteroid-resistant polymyositis or dermatomyositis

Patients

39 patients with definite polymyositis or dermatomyositis Biopsy proven Incomplete response to corticosteroids No inclusion body myositis ³16 years of age

Authors

Miller FW, Leitman SF, Cronin ME, Hicks JE, Leff RL, Wesley R, Fraser DD, Dalakas M, Plotz PH

Publication

N Engl J Med. 1992;326(21):1380–1384

Follow up

Mean 3.2 years

Note

Condition improved n = 3 (plasma exchange), n = 3 (leukapheresis), n = 3 (Sham apharesis) Condition deteriorated n = 1 (plasma exchange), n = 3 (leukapheresis), n = 0 (Sham apharesis) No change n = 9 (plasma exchange), n = 7 (leukapheresis), n = 10 (Sham apharesis) Taper Prednisone n = 1 (plasma exchange), n = 2 (leukapheresis), n = 0 (Sham apharesis) No significant differences among the three treatment groups in the final muscle strength or functional capacity of the patients

Adverse events

Require placement of central venous catheter to maintain venous access n = 0 (plasma exchange), n = 9 (leukapheresis), n = 0 (Sham apharesis) Major vasovagal episodes n = 0 (plasma exchange), n = 3 (leukapheresis), n = 0 (Sham apharesis) Clinical important citrate reactions n = 0 (plasma exchange), n = 2 (leukapheresis), n = 0 (Sham apharesis) Decline of hematocrit n = 0 (plasma exchange), n = 0 (leukapheresis), n = 1 (Sham apharesis)

Sjögren’s Syndrome

Hydroxychloroquine

Trial

Antimalarials in treatment of Sjogren’s syndrome

Substance

300 mg/day chloroquine for 3 weeks than 150 mg/day or 800 mg/day hydroxychloroquine for 3 weeks than 400 mg/day No information on concomitant medication

Result

Treatment of Sjögren’s syndrome with hydroxychloroquine was effective

Patients

25 patients with Sjögren’s Syndrome Duration of ocular symptoms 2–20a

Authors

Heaton JM

Publication

Br Med J. 1959;1(5136):1512–1513

Follow up

4–22 weeks

Note

Patients failed to improve n = 6 Patients improving n = 14 Patients with great improvement n = 4 3 patients stopped because of adverse events No change of Schirmer’s test Subjective amelioration

Adverse events

Total patients with adverse events n = 6 Nausea n = 4 Diarrhoea n = 3 Malaise n = 1

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_9, © Springer-Verlag London Limited 2011

565

566

Sjögren’s Syndrome: Hydroxychloroquine

Trial

Hydroxychloroquine treatment for primary Sjögren’s syndrome: a two year double blind cross over trial

Substance

2 × 200 mg hydroxychloroquine/day (HCQ => Placebo, n = 10) Placebo (Placebo => HCQ, n = 9) Groups were crossed over after 1 year Drug treatment at entry: Tear substitutes n = 10 Salvia substitutes n = 2 Sedatives n = 6 NSAIDs n = 4 Anti-hypertensive drugs n = 4 Anti-convulsant drugs n = 2 L-Thyroxine n = 2 Insulin n = 2 Calcium carbonate n = 3 Lactulose n = 3 Previous medication: No corticosteroids No immunosuppressive drugs £3 months prior study inclusion

Result

Hydroxychloroquine treatment of patients suffering from Sjögren’s syndrome did not have worstwhile clinical benefit

Patients

19 patients with Sjögren’s syndrome Median disease duration 3.0 a No immunosuppressive prior drug treatment No retinitis pigmentosa No RA, SLE, systemic sclerosis, or mixed connective tissue disease

Authors

Kruize AA, Hene RJ, Kallenberg CGM, van Bijsterveld A, van der Heijden A, Kater L, Bijlsma JWJ

Publication

Ann. Rheum Dis. 1993;52:360–364

Follow up

2 years

Sjögren’s Syndrome: Hydroxychloroquine

Note

Study not completed n = 4 (HCQ => placebo), n = 4 (placebo => HCQ) Received corticosteroids, because of progressive PNP n = 1 (HCQ => placebo), n = 1 (placebo => HCQ) Burkitt’s Lymphoma n = 1 (HCQ => Placebo), n = 0 (Placebo => HCQ) Tears lysozyme concentration (µg/ml): Entry 1,555 (HCQ => placebo), 1,145 (placebo => HCQ) 1 year 1,630 (HCQ => placebo), 1,345 (placebo => HCQ) 2 years 1,590 (HCQ => placebo), 1,320 (placebo => HCQ) Tear lactoferrin concentration (mm precipitation): Entry 8.1 (HCQ => placebo), 6.3 (placebo => HCQ) 1 year 8.7 (HCQ => placebo), 8.4 (placebo => HCQ) 2 years 10.7 (HCQ => placebo), 7.2 (placebo => HCQ) Schirmer’s test (mm/5 min): Entry 8.4 (HCQ => placebo), 7.8 (placebo => HCQ) 1 year 6.8 (HCQ => placebo), 8.1 (placebo => HCQ) 2 years 8.9 (HCQ => placebo), 7.0 (placebo => HCQ) Break up time (s): Entry 1.9 (HCQ => placebo), 4.8 (placebo => HCQ) 1 year 2.6 (HCQ => placebo), 3.5 (placebo => HCQ) 2 years 2.5 (HCQ => placebo), 1.5 (placebo => HCQ) Rose Bengal test (score 0–9): Entry 3.7 (HCQ => placebo), 3.9 (placebo => HCQ) 1 year 5.7 (HCQ => placebo), 5.4 (placebo => HCQ) 2 years 5.7 (HCQ => placebo), 6.1 (placebo => HCQ) Abnormal/normal scintigraphy (Technecium): Entry n = 4/1 (HCQ => Placebo), n = 3/2 (placebo => HCQ) 1 year n = 4/1 (HCQ => Placebo), n = 3/2 (placebo => HCQ) 2 years n = 4/1 (HCQ => Placebo), n = 3/2 (placebo => HCQ) Abnormal/normal scintigraphy (Gallium 67): Entry n = 4/1 (HCQ => placebo), n = 4/1 (placebo => HCQ) 1 year n = 4/1 (HCQ => placebo), n = 3/2 (placebo => HCQ) 2 years n = 4/1 (HCQ => placebo), n = 1/1 (placebo => HCQ) No differences comparing the groups for: Feeling of dryness in the eye, swelling of the salivary gland, fatigue, myalgia, arthralgia, inflammatory reaction of the eye lid

Adverse events

567

Psychological problems n = 0 (HCQ => placebo), n = 1 (placebo => HCQ) Moderate deterioration of liver function tests n = 0 (HCQ), n = 0 (placebo)

568

Sjögren’s Syndrome: Leflunomide

Trial

Safety and efficacy of Leflunomide in primary Sjögren’s syndrome: a phase II pilot study

Substance

20 mg leflunomide/day (no loading dose) No information on concomitant medication was provided

Result

The efficacy of leflunomide in the treatment of Sjögren`s syndrome was modest. The safety profile was fairly acceptable

Patients

15 patients with pSS with early and active disease Sicca complaints £60 months Diagnosis established (£36 months) ESR ³20 mm/hour Serum IgG ³15 mg/l No hepatic or renal impairment, severe infection or malignancy other than mucosa-associated lymphoid tissue lymphoma

Authors

van Woerkom JM, Kruize AA, Geenen R, van Roon EN, Goldschmeding R, Verstappen SM, van Roon JA, Bijlsma JW

Publication

Ann Rheum Dis. 2007;66(8):1026–1032. Epub 2007 Jan 12

Follow up

24 weeks

Note

VAS general health (0–100 mm) –7 VAS dry eyes (0–100 mm) +7 VAS sandy feeling (0–100 mm) +8 VAS dry mouth (0–100 mm) –15 VAS sleep disturbance due to dryness (0–100 mm) –5 Multidimensional Fatigue Inventory general fatigue –6 Zung depression score +4.5 ESR (mm/hour) –6 CRP (g/l) –1.9 Serum IgA (g/l) –0.5 Serum IgG (g/l) –3.4 Serum IgM (g/l) –0.4 Rheumatoid factor (U/l) –155 Schirmer test (mm/5 min) +3.7 Sialometry (ml/15 min) +0.1

Sjögren’s Syndrome: Leflunomide

Adverse events

Diarrhoea 47% GI discomfort 40% Anorexia 13% Oral ulcers 13% Hair loss 47% Headache 33% Fatigue/lethargy 20% Dysesthesia 13% Dizziness 26% Alcohol intolerance 6% Weight loss >2 kg 33% Dyspnoea 6% Increasing Transpiration 6% Increasing Conjunctivitis 13% Pharyngitis 13% Decreasing Libido 6% Mood changes 6% Decreasing taste 6% ALAT 1–2 × upper normal limits 13% ALAT 2 × upper normal limits 13% Increase of pre-existing arterial hypertension 13% LE skin lesions 33% Other skin lesions 20% Leukopenia (3–4 × 109/l) 26% Leukopenia (<3 × 109/l) 13% Anaemia <7.4 mmol/l 33%

569

570

Sjögren’s Syndrome: Methotrexate

Trial

Methotrexate in primary Sjögren’s syndrome

Substance

0.2 mg methotrexate/kg/week Concomitant medication: Oral and tear substitution was continued Previous medication: 2 months of washout of other therapeutics

Result

Methotrexate improved symptoms of Sjörgren’s syndrome in a substantial proportion of patients

Patients

18 patients with primary Sjögren’s syndrome Diagnosis according the EEC criteria Focus score on salvary gland biopsy >3/4 mm2

Authors

Skopouli FN, Jagiello P, Tsifetaki N, Moutsopoulos HM

Publication

Clin Exp Rheumatol. 1996;14(5):555–558

Follow up

12 months

Note

Subjective symptoms of dry eyes n = 7 (6 months), n = 6 (12 months) Subjective symptoms of dry eyes n = 7 (6 months), n = 7 (12 months) Improvement of dry cough n = 6 No improvement of dry cough n = 5 Improvement of arthralgia n = 8 (6 months), n = 4 (12 months) Improvement of fatigue n = 7 (6 months), n = 6 (12 months) Improvement of pupura n = 1 (6 months), n = 0 (12 months)

Adverse events

Persistent elevation of the hepatic transaminase levels n = 7 (=>reduction of MTX) Anaemia and Leucopoenia n = 2

Sjögren’s Syndrome: Mycophenolate

Trial

Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial

Substance

360 mg mycophenolate sodium/d, increased weekly up to 1,440 mg/day

571

Previous medication: No concomitant DMARDs £8 weeks prior randomization No Prednisolone (or equivalent) ³5 mg/day ³4 weeks prior randomization No secretagogues (Pilocarpine and Civemeline) or tricyclic antidepressants and anticholinergic drugs Result

Mycophenolate sodium improved signs and symptoms of patients with shorter disease duration

Patients

11 patients with pSS, active disease ESR >25 mm/hour IgG >1,500 mg/dl Autoantibodies (anti-SSA, SSB antibodies and/or rheumatoid factor)

Authors

Willeke P, Schlüter B, Becker H, Schotte H, Domschke W, Gaubitz M

Publication

Arthritis Res Ther. 2007;9(6):R115

Follow up

24 weeks

Note

Change of: Schirmer’s test (mm per 5 min) +2.4 Whole saliva (g per 5 min) +0.07 Swollen/Tender joint count 0.0 Erythrocyte sedimentation rate (mm/hour) +3.4 IgG (mg/dl) –0.124 IgM (mg/dl) –47 IgA (mg/dl) –70 Rheumatoid factor IgM (IU/ml) –96 Anti-SSA antibodies (U/ml) +0.029 Anti-SSB antibodies (U/ml) +0.103 VAS sicca syndrome (0–100 mm) –15.9 VAS arthralgia (0–100 mm) –14.6 VAS fatigue (0–100 mm) +1.9 Use of artificial teardrops (times per day) –2.1 Health assessment questionnaire score 0.0

Adverse events

Vertigo n = 1 Gastrointestinal complaints n = 4 Pneumonia n = 1 Herpes labialis n = 1 Common cold n = 2

572

Sjögren’s Syndrome: Pilocarpine

Trial

Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixeddose, multicenter trial. P92–01 Study group

Substance

Pilocarpine 4 × 2.5 mg/day (n = 121) Pilocarpine 4 × 5 mg/day (n = 127) Placebo tablets 4 times daily (n = 125) Concomitant medication used: Analgesic or anti-inflammatory drugs (aspirin, ibuprofen, naproxen, acetaminophen, and prednisone) Antirheumatic drugs (HCQ, MTX) Gastrointestinal tract agents (omeprazole) Hormonal replacement drugs (estrogen, medroxyprogesteron) Thyroid preparations (levothyroxine sodium)

Result

Pilocarpine treatment was well tolerated and lead to a significant improvement of sicca symptoms

Patients

373 Patients with Sjögren syndrome With at least one of the following: Auto-antibodies against SS-A or SS-B Rheumatoid factor or ANA ³1: Positive labial minor salivary gland biopsy sample Positive lip biopsy samples required a focus score >1 focus per 4 mm2 Clinically significant dry mouth and dry eye symptoms

Authors

Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, Salisbury PL III, Tran-Johnson TK, Muscoplat CC, Trivedi M, Goldlust B, Gallagher SC

Publication

Arch Intern Med. 1999;159(2):174–181

Follow up

12 weeks

Sjögren’s Syndrome: Pilocarpine

Note

Dry mouth improvement 61.3% (5-mg pilocarpine), 31.1% (Placebo group) Dry eyes, improvement 42.0% (5-mg pilocarpine), 26.1% (Placebo group) Salivary flow rates at onset (ml/min): Before dosing 0.11 (5-mg pilocarpine), 0.11 (Placebo group) 30 min after dosing 0.34 (5-mg pilocarpine), 0.12 (Placebo group) 60 min after dosing 0.34 (5-mg pilocarpine), 0.13 (Placebo group) 90 min after dosing 0.27 (5-mg pilocarpine), 0.13 (Placebo group) Follow up week 6: 60 min after dosing 0.33 (5-mg pilocarpine), 0.15 (Placebo group) Follow up week 12: 60 min after dosing 0.38 (5-mg pilocarpine), 0.17 (Placebo group)

Adverse events

573

Sweating 7.2% (placebo), 10.7% (2.5 mg pilocarpine), 43.3% (5 mg pilocarpine) Headache 24.8% (placebo), 20.7% (2.5 mg pilocarpine), 15.8% (5 mg pilocarpine Flu symptoms 8.8% (placebo), 13.2% (2.5 mg pilocarpine), 14.2% (5 mg pilocarpine) Nausea 8.8% (placebo), 12.4% (2.5 mg pilocarpine), 11.8% (5 mg pilocarpine) Rhinitis 5.6% (placebo), 7.4% (2.5 mg pilocarpine), 10.2% (5 mg pilocarpine) Dizziness 8.8% (placebo), 5.0% (2.5 mg pilocarpine), 0.2% (5 mg pilocarpine) Urinary frequency 1.6% (placebo), 10.7% (2.5 mg pilocarpine), 9.5% (5 mg pilocarpine)

574

Sjögren’s Syndrome: Etanercept

Trial

Etanercept in the treatment of patients with primary Sjögren’s syndrome: a pilot study

Substance

2 × 25 mg etanercept/week s.c. Concomitant medication: No concomitant DMARDs No corticosteroids

Result

Treatment of primary Sjögren’s syndrome with etanercept did not reduce sicca symptoms and other signs of the disease but may be beneficial in a small subgroup of Sjögren’s syndrome patients with severe fatigue

Patients

15 patients with well defined primary primary Sjögren’s syndrome Evidence of sublabial minor salivary gland biopsy indicated by a lymphocytic focus score >1 IgA-containing plasma cells percentage <70%

Authors

Zandbelt MM, de Wilde P, van Damme P, Hoyng CB, van de Putte L, van den Hoogen F

Publication

J Rheumatol. 2004;31(1):96–101

Follow up

24 weeks

Note

Change of VAS-Scores: General fatigue –2.7 (all patients), –2.1 (responders only) Physical fatigue –2.2 (all patients), –1.2 (responders only) Reduced activity –0.9 (all patients), +0.9 (responders only) Reduced motivation –0.9 (all patients), –0.2 (responders only) Mental fatigue –2.5 (all patients), –3.0 (responders only) ESR (mm/hour) –4 (all patients), –4 (responders only) CRP (mg/l) –1 (all patients), –1 (responders only) Gammaglobulin (g/l) 0 (all patients), +2 (responders only) Lymphocytic focus score (week 12) –0.73 (all patients), –0.54 (responders only) IgA% (week 12) –1.7 (all patients), –1.4 (responders only) IgM RF (U/l week 12) –5 (all patients), –14 (responders only)

Sjögren’s Syndrome: Etanercept

Trial

Etanercept in Sjögren`s Syndrome

Substance

2 × 25 mg Etanercept/week (n = 14) Placebo (n = 14)

575

Concomitant medication: Continue long-term medications No tricyclic antidepressants No anticholinergics Result

Etanercept was not effective in Sjögren`s Syndrome

Patients

28 patients with Sjögren`s Syndrome With oral and ocular dryness Evidence of active SS (elevated ESR or IgG levels)

Authors

Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA, Manny J, Baum BJ, Pillemer SR

Publication

Arthritis Rheum. 2004;50(7):2240–2245

Follow up

12 weeks Change of: Dry mouth (100-mm VAS) –2 (ETN), +3 (placebo) Dry eyes, by 100-mm VAS 1 (ETN), –0.5 (placebo) Schirmer I test, mm/5 min –0.75 (ETN), –0.50 (placebo) Van Bijsterveld score 0.0 (ETN), –0.25 (placebo) Total stimulated saliva flow (ml/min) –0.033 (ETN), –0.22 (placebo) IgG (mg/dl) +10 (ETN), –30 (placebo) ESR (mm/hour) –5.5 (ETN), +1.5 (placebo)

Note

576

Sjögren’s Syndrome: Infliximab

Trial

Infliximab in patients with primary Sjögren’s syndrome: a pilot stud

Substance

3 × Infliximab (3 mg/kg), at 0, 2, and 6 weeks Concomitant medication: No DMARDs £4 weeks before baseline No corticosteroids £4 weeks before baseline Continue artificial tears

Patients

16 primary Sjögren’s syndrome patients ESR >25mm/hour Hypergammaglobulinemia >1.4 g/l

Result

In patients with active primary Sjögren’s syndrome, a loading-dose regimen of 3 infusions of infliximab provided a fast and significant clinical benefit without major adverse reactions

Authors

Steinfeld SD, Demols P, Salmon I, Kiss R, Appelboom T

Publication

Arthritis Rheum. 2001;44(10):2371–2375

Follow up

14 weeks

Note

Change of: Patient’s Global assessment (0–100-mm VAS) –41.5 Patient’s assessment of pain –60.5 Physician’s Global assessment (0–100-mm VAS) –26.5 Tender joint count (0–64 joints) –5 Tender point count (0–18 tender points) –14.5 Global Fatigue (0–100-mm VAS) –32.5 Fatigue Questionnaire (0–3 scale) –2 ESR (mm/hour) –11 IgG (<1,000 mg/l) +0.23 White blood cell count (x1,000/mm3) +0.7 CD4+ cells/mm3 +37 CD8+ cells/mm3 +25 Dry eyes questionnaire (0–2 scale) –1 Fluorescein tear film breakup time (seconds/5 min) +2.5 Schirmer I test (mm/5 min) +1.5 Lissamine green staining (0–9 scale) –0.5 Dry mouth questionnaire (0–2 scale) –0.7 Speech test (“puttica”/2 min) +39.5 Unstimulated salivary flow (ml/min) +0.59

Adverse events

Facial erythema and dyspnoea n = 1 Mild respiratory tract infections n = 2 Develop any symptoms suggestive of SLE n = 1 (patient had already dsDNA antibodies before)

Sjögren’s Syndrome: Infliximab

TRIPSS-Trial

Inefficacy of Infliximab in primary Sjögren’s syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren’s Syndrome (TRIPSS) TRIPSS: Trial of Remicade in Primary Sjögren’s Syndrome

Substance

5 mg/kg Infliximab (n = 54) at weeks 0, 2, 6 Placebo (n = 49) Concomitant medication: No pilocarpine MTX, azathioprine, 6-mercaptopurine, hydroxychloroquine at stable doses Corticosteroids (£15 mg/day) at stable doses

Result

Infliximab in primary Sjögren’s syndrome was not effective

Patients

103 patients with pSS Positive for anti-Ro/SSA or anti-La/SSB Active disease: VAS >50/100mm evaluating: Joint pain Fatigue The most disturbing buccal, ocular, skin, vaginal, and bronchial dryness

Authors

Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puéchal X, Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J

Publication

Arthritis Rheum. 2004;50(4):1270–1276

Follow up

22 weeks

Note

Week 22: 30% decrease in two of three VAS-scores (see inclusion) 20.4% (placebo), 16.7% (IFX) 30% decrease in pain VAS 26.5% (placebo), 20.4% (IFX) 30% decrease in fatigue VAS 24.5% (placebo), 24.1% (IFX) 30% decrease in dryness VAS, 16.3% (placebo), 16.7% (IFX) Favourable response: Week 10: 26.5% (placebo), 27.8% (IFX) Week 22: 20.4% (placebo), 16.7% (IFX) Change of: Salivary flow rate (ml/min) +0.02 (placebo), +0.03 (IFX) Schirmer test (mm/5 min) +1.5 (placebo), +0.9 (IFX) Swollen joint count –0.3 (placebo), –0.4 (IFX) Tender joint count –2.3 (placebo), –2.4 (IFX) ESR (mm/hour) –0.9 (placebo), –0.8 (IFX) CRP (mg/l) –0.5 (placebo), –0.4 (IFX) Gamma globulin (g/l) 0.13 (placebo), 0.78 (IFX) IgG (g/l) +0.03 (placebo), +0.74 (IFX) IgA (g/l) +0.09 (placebo), +0.16 (IFX) IgM (g/l) +0.04 (placebo), +0.34 (IFX)

Adverse events

Total n = 1 (placebo), n = 6 (IFX) Infusion reactions n = 0 (placebo), n = 2 (IFX) Cutaneous facial eruption n = 0 (placebo), n = 1 (IFX) Autoimmune hepatitis n = 0 (placebo), n = 1 (IFX) Pneumococcal septicemia n = 0 (placebo), n = 1 (IFX) Breast cancer n = 0 (placebo), n = 1 (IFX) Polyclonal lymph node enlargement n = 1 (placebo), n = 0 (IFX)

577

578

Sjögren’s Syndrome: Rituximab

Trial

Rituximab treatment in patients with primary Sjögren’s syndrome: an open-label phase II study

Substance

Rituximab (once weekly 4 × 375 mg/m2) After pre-treatment with: 25 mg prednisone 2 mg clemastine 1 g acetaminophen Concomitant medication: No DMARDs No Corticosteroids

Result

Rituximab was effective in the treatment of primary Sjögren’s syndrome. A high incidence of human antichimeric antibodies and associated side effects was observed

Patients

15 patients with primary SS B cell hyperactivity (IgG > 15 g/l) Presence of auto-antibodies (IgM rheumatoid factor, anti-SSA/SSB) Disease duration <4 years Treatment with DMARDS (e.g., hydroxychloroquine, methotrexate, ciclosporin), and corticosteroids was not allowed during the study

Authors

Pijpe J, van Imhoff GW, Spijkervet FK, Roodenburg JL, Wolbink GJ, Mansour K, Vissink A, Kallenberg CG, Bootsma H

Publication

Arthritis Rheum. 2005;52(9):2740–2750

Follow up

12 weeks

Sjögren’s Syndrome: Rituximab

579

Note

Change of: Un-stimulated whole saliva (ml/min) +0.04 (primary SS), +0.01 (MALT/SS) Stimulated whole saliva (ml/min) +0.2 (primary SS), +0.01 (MALT/SS) Parotid stimulated secretion (ml/min) +0.06 (primary SS), +0.01 (MALT/SS) Na in parotid saliva (mmol/l) –11 (primary SS), 0 (MALT/SS) Schirmer’s test (mm/5 min) +5 (primary SS), +1 (MALT/SS) Rose bengal score –2 (primary SS), –2 (MALT/SS) Tear break-up time (s) +5 (primary SS), –1 (MALT/SS) General fatigue –9 (primary SS), –3 (MALT/SS) Physical fatigue –7 (primary SS), 0 (MALT/SS) Reduced activity –7 (primary SS), +1 (MALT/SS) Reduced motivation –5 (primary SS), 0 (MALT/SS) Mental fatigue –2 (primary SS), 0 (MALT/SS) SF-36 physical functioning +84 (primary SS), –5 (MALT/SS) SF-36 social functioning +12 (primary SS), +38 (MALT/SS) SF-36 role physical –2 (primary SS), 0 (MALT/SS) SF-36 role emotional 0 (primary SS), –65 (MALT/SS) SF-36 mental health +4 (primary SS), +8 (MALT/SS) SF-36 vitality +27 (primary SS), +10 (MALT/SS) SF-36 bodily pain +22 (primary SS), 0 (MALT/SS) SF-36 general health perception +17 (primary SS), +5 (MALT/SS) SF-36 health change +50 (primary SS), +50 (MALT/SS)

Adverse events

Infusion reaction n = 2 (primary SS), n = 0 (MALT/SS) Herpes zoster developed n = 1 (primary SS), n = 0 (MALT/SS) Human antichimeric antibodies n = 4 (primary SS), n = 0 (MALT/SS)

580

Sjögren’s Syndrome: Rituximab

Trial

Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications ofprimary Sjögren’s syndrome

Substance

375 mg/m2 Rituximab (RTX) infusions × 4 n = 1 4 375 mg/m2 Rituximab infusions × 6 n =1 2 × 1 g Rituximab infusions n = 1 Concomitant medication: Pretreatment with immunosmodulatory agents n = 9 Concomitant immunosuppressives n = 4

Result

Rituximab was effective and steroid sparing in patients with severe systemic manifestations of primary Sjögren’s syndrome in this retrospective study. It achieved complete remissions in four of five patients with lymphoma

Patients

16 patients with primary Sjögren’s syndrome according to the EuropeanAmerican consensus group criteria, with lymphoma or severe systemic complications Disease duration 16.3 years (mean) RTX prescribed for lymphoma n = 4 Refractory pulmonary disease with polysynovitis n = 2 Severe polysynovitis n = 2 Mixed cryoglobulinaemia n = 5 Thrombocytopenia n = 1 Mononeuritis multiplex n = 1

Authors

Seror R, Sordet C, Guillevin L, Hachulla E, Masson C, Ittah M, Candon S, Le Guern V, Aouba A, Sibilia J, Gottenberg JE, Mariette X

Publication

Ann Rheum Dis. 2007;66(3):351–357

Follow up

14.5 months (median)

Note

Remission of lymphoma 80% n = 4 Relapse of lymphoma n = 1 Efficacy for (examples): Systemic symptoms 82% Cutaneous vasculitis 100% Glandular features 100% Corticosteroid reduction n = 7 Corticosteroid discontinuation n = 4 Relapses (non-lymphoma) n = 4 Time to relapse 8 months (median)

Adverse events

Flu-like syndrome and mild herpetic eruption n = 1 Fever, arthralgia and pupuric lesion n = 1 Fever, arthralgia and and urticaria n = 1

Sjögren’s Syndrome: Rituximab

Trial

Improvement of Sjögren’s syndrome after two infusions of Rituximab (anti-CD20)

Substance

375 mg/m2 Rituximab infusions (100 mg/hour) weeks 0, 1 No concomitant corticosteroids No cytotoxic drugs £ 4 months

Result

Low-dose Rituximab infusions were well tolerated and improved clinical signs and symptoms of primary Sjögren’s syndrome

Patients

16 patients with primary Sjögren’s syndrome >2 out of: Global disease >50 (VAS; 100 mm) Global pain >50 (VAS; 100 mm) Global fatigue >50 (VAS; 100 mm) Global dryness >50 (VAS; 100 mm)

Authors

Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roué IQ, Cochener B, Youinou P, Saraux A

Publication

Arthritis Rheum. 2007;57(2):310–317

Follow up

36 weeks

Note

Change of (week 36): Global disease (VAS, mm) –16.9 Pain (VAS, mm) –27.4 Fatigue (VAS, mm) –19.3 Dryness (VAS, mm) +44.6 Tender point count –2.5 Tender joint count –3.3 Swollen joint count –1.0 Salivary flow rate (ml/min) +0.02 Schirmer test (mm) +0.6 Focus score –0.2 (after 12 weeks) Anti-SSA –9.5 ESR (mm/hour) –1.1 Latex test –3.1 IgA-RF (IU) –0.1 IgA (mg/l) +0.2 IgG (mg/l) +4.3 IgM (mg/l) –0.31

Adverse events

Only very moderate hypersensitivity reactions were noted in another 8 patients Transient headache or fatigue n = 2 Arthritis n = 4

581

582

Sjögren’s Syndrome: Rituximab

Trial

Reduction of fatigue in Sjögren syndrome with Rituximab: results of a randomised, double-blind, placebo-controlled pilot study

Substance

2 infusions of Rituximab 1 g (n = 8) days 0, 15 Placebo (n = 9) Pre-medication: 100 mg methylprednisolone 60 mg oral prednisolone/day days 2–14 30 mg days oral prednisolone/day days 8–14 Continue with concurrent medication No changing or adding of DMARDs

Result

Rituximab was effective in reducing disease activity of primary Sjögren syndrome

Patients

17 patients with primary Sjögren’s syndrome Fatigue score (VAS 0–100) >50 Positive for anti-Ro and/or anti-La antibody

Autors

Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, Richards A, Rauz S, Emery P

Publication

Ann Rheum Dis. 2008;67(11):1541–1544. Epub 2008 Feb 14

Follow up

26 weeks

Note

20% improvement in fatigue VAS 87.5% (RTX), 55.6% (placebo) No significant changes in the Schimer test

Adverse events

Headache, urticarial rash, fever and meningism n = 3 (RTX) Infusion reactions n = 2 (RTX) Abdominal pain, eventually diagnosed as gastroenteritis n = 1 (RTX)

Takayasu Arteritis

Methotrexate Trial

Treatment of Glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate

Substance

Weekly low-dose 0.3 mg/kg/week methotrexate (max starting dose 15 mg/week) Dose was increased by 2.5 mg/week to max 25 mg/week Gradual reduction of MTX dosage if no sign of active vasculitis Discontinuation approximately 1 year after remission MTX + corticosteroids could be resumed in case of reoccurring activity Concomitant medication: In case of resistance to glucocorticoids (GC) at study entry Increase of dosage to 1 mg/kg/day After remission at the end of first month: Glucocorticoids were tapered by 5 mg every 4 days, on alternate days Further reduction from 20 mg prednisolone/day onward: 2.5 mg every 4 days Previous treatments: GC n = 18 (still on GC at study entry: n = 15) Daily cyclophospamide n = 4 Azathioprine n = 2

Result

Weekly oral low-dose methotrexate was effective in glucocorticoid-resisant Takayasu arteritis

Patients

18 patients with Takayasu arteritis Inclusion criteria: Multifocal angiopathic lesions of the aorta or its branches Failure to respond to glucocorticoid treatment 1 mg/kg/day for ³1 month, or inability to taper glucocorticoid treatment within 5 months Relapse after tapering Glucocorticoid treatment

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_10, © Springer-Verlag London Limited 2011

583

584

Takayasu Arteritis: Methotrexate

Authors

Hoffman GS, Leavitt RY, Kerr GS, Rottem M, Sneller MC, Fauci AS

Publication

Arthritis Rheum. 1994;37(4):578–582

Follow-up

2.6 years (mean)

Note

Remission 81% Relapse following remission 54% (re-treatment with second remission 43%) Sustained remission 50% (mean 18 months, of them: 50% without GC) Remission in absence of GC and MTX 25% (mean duration 11.3 months) Progressive disease 19% Stable MTX dosage 17.1 mg (mean)

Adverse events

Pneumocystis carinii pneumonia n = 1 Dose reductions of MTX due to elevation of liver function n = 5 Recurrent oral ulcers with MTX >10 mg n = 1

Takayasu Arteritis: Mycophenolate mofetil

Trial

Mycophenolate mofetil reduces disease activity and steroid dosage in Takayasu arteritis

Substance

2 g/day mycophenolate mofetil (MMF) for 23.3 months (mean)

585

Previous medication: Corticosteroids Immunosuppressive drugs: Methotrexate n = 4 Azathioprine n = 2 Chlorambucil n = 1 Result

Mycophenolate mofetil reduced clinical and laboratory parameters of disease activity in Takaysu arteritis patients with resistance to or side effects of glucocorticosteroids

Patients

10 consecutive Takayasu arteritis patients Diagnosed by ³3 ACR criteria Active disease despite of prednisone and/or other immunosuppressive drug Or development of side effects to previous therapy Disease duration before study 57.5 months (mean)

Authors

Shinjo SK, Pereira RM, Tizziani VA, Radu AS, Levy-Neto M

Publication

Clin Rheumatol. 2007;26(11):1871–1875. Epub 2007 Feb 28

Follow up

3 years

Note

Active disease at study entry n = 10, at end of study n = 1 Erythrocyte sedimentation rate 24.7 mm/hour (before MMF), 12.8 mm/hour (after MMF) C-reactive protein 24.0 mg/l (before MMF), 11.2 mg/l (after MMF) Prenisone dose 17.1 mg/day (before MMF), 7.8 mg/day (after MMF, effectively treated patients)

Adverse events

No leucopenia Rüdiger, wo genau soll das hin - und warum überhaupt- ist doch klar ohne No elevation of serum hepatic enzymes

586

Takayasu Arteritis: Infliximab and Etanercept

Trial

Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis

Substance

2 × 25 mg etanercept/week s.c. (ETN, n = 7; later changed to infliximab n = 3) 3–5 mg/kg infliximab at weeks 0, 2 and 6, then every 4–8 weeks (IFX, n = 8) Previous immunosuppressive drugs: Methotrexate n = 13 Cyclophosphamide n = 6 Mycophonolate mofetil n = 3 Azathioprine n = 3 Ciclosporin A n = 2 Tacrolimus n = 2 Pretreatment with ³2 of these agents n = 8 Concomitant medication: Azathioprine n = 1 Methotrexate n = 5 Mycophonolate mofetil n = 1 Cyclophosphamide n = 1 Effective glucocorticoid dose before study 20 mg (median)

Result

Anti-TNF therapy resulted in improvement in 14 of 15 Takayasu arteritis patients, with the majority of patients achieving sustained remissions without glucocorticoids

Patients

15 patients with active, relapsing disease Takayasu arteritis Diagnosed by the ACR-criteria and fulfilling all of the following: Previous clinical and imaging (invasive angiography and MRI) Required toxic doses of Glucocorticoids to maintain remission Experienced multiple relapses Previous negative screening for tuberculosis by skin test and chest roentgenogram No former complete remission inspite of glucocortidoid treatment n = 3 Disease duration before study 6.5 years (mean)

Authors

Hoffman GS, Merkel PA, Brasington RD, Lenschow DJ, Liang P

Publication

Arthritis Rheum. 2004;50(7):2296–2304

Follow-up

21.7 months (mean and median)

Note

Improvement 93% Glucocorticoid-free, sustained remission 67% Partial remission 27% Median glucocorticoid dose 20 mg (study entry) Median glucocorticoid dose 0 mg (12 months) Off additional immunosupprisve drugs at end of study n = 8

Adverse events

Infusion reaction to Infliximab n = 1 (IFX) Disseminated histoplasmosis after n = 1 (IFX) Herpes zoster n = 1 (ETN)

Takayasu Arteritis: Anti-TNF

Trial

Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up

Substance

2 × 25 mg s.c etanercept (ETN, n = 9 later changed to infliximab n = 5) 3–5 mg/kg infliximab at weeks 0, 2 ETN, and 6, then every 4–8 weeks (IFX, n = 21) median stable dose 5 mg 6 weekly

587

Concomitant medication: Immunosuppressive drugs continued during trial n = 18 Previous immunosuppressive drugs: Methotrexate n = 22 Cyclophosphamide n = 10 Azathioprine n = 5 Mycophonolate mofetil n = 3 Ciclosporin A n = 2 Tacrolimus n = 2 Result

In this retrospective study of patients with Takaysu arteritis refractory to treatment with glucocorticoids, Etanercept and Infliximab were effective in inducing clinical remission in a majority of cases and reduction or discontinuation of additional glucocorticoids and immunosuppressive drugs

Patients

25 patients with refractory Takayasu arteritis Fulfilling the ACR-criteria Refractory defined as stable remission not being achieved despite: Prednisone £10 mg/day ³1 additional immunosuppressive drug All patients with prior treatment with glucocorticoid (median dose 19 mg) and 2 (mean) immunosuppressive drugs No prior remission n = 13 Median disease duration 9.6 years

Authors

Molloy ES, Langford CA, Clark TM, Gota CE, Hoffman GS

Publication

Ann Rheum Dis. 2008;67(11):1567–9. Epub 2008 Aug 3

Follow up

28 months (median)

Note

Remission and prednisone discontinuation (ETN + IFX) 60% Remission and taper of prednisone to <10 mg/day (ETN + IFX) 28% Discontinuation of additional immunosuppressive drug 50% Remission ETN 66.6%, IFX 85% Relapses after initial remission: ETN 50%, IFX 66.6%

Adverse events

Opportunistic infections n = 1 Breast cancer n = 1

Giant Cell Arteritis

Corticosteroids

Trial

Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: comparison in a prospective study

Substance

All groups: 20 mg prednisone every 8 h for 5 days, then group A: 15 mg of prednisone every 8 h (n = 20) group B: 45 mg of prednisone every morning (n = 20) group C: 90 mg of prednisone every other morning (n = 20) Taper of prednisone after end of study (4 weeks) Previous medication: No adrenocorticosteroids

Result

Patients Authors Publication Follow up Note

Adverse events

Daily doses, but not an alternate day regimen, of corticosteroid suppressed symptoms of temporal arteritis effectively. They were associated with a higher rate of hypercortisolism in this short-term trial 60 patients with giant cell arteritis Proven by biopsy of temporal artery, without prior steroid therapy Hunder GG, Sheps SG, Allen GL, Joyce JW Ann Intern Med. 1975;82(5):613–618 4 weeks Arteritis clinically completely suppressed (after 4 weeks) n = 18 (group A), n = 16 (group B), n = 6 (group C) ESR (after 4 weeks, mm/h) –82 (group A) –71 (group B), –41 (group C) Adverse reactions to prednisone frequently noted in groups A and B but rarely in group C Mild hypercortisolism (after 4 weeks) n = 9 (group A), n = 7 (group B), n = 0 (group C) Cushing syndrome later during the course of the disease n = 12 (group A), n = 0 (group B), n = 0 (group C) Mild diabetes n = 0 (group A), n = 1 (group B), n = 0 (group C) Insomnia/mild depression (after 4 weeks) n = 1 (group A) n = 0 (group B), n = 0 (group C) Lumbar vertebral compression fractures n = 0 (group A) n = 2 (group B), n = 0 (group C)

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_11, © Springer-Verlag London Limited 2011

589

590

Giant Cell Arteritis: Corticosteroids

Trial

Efficacy and adverse effects of different corticosteroid dose regimens in temporal arteritis: a retrospective study

Substance

30–40 mg/day prednisone (group A, n = 23) 40–60 mg/day prednisone (group B, n = 45) >60 mg/day prednisone (group C, n = 9) Continuous taper according to clinical activity in all groups

Result

The lowest starting dose of 30–40 mg/day was as effective, less toxic and allowed for equally fast tapering of prednisone, compared to two regimen with higher starting doses in this retrospective analysis of patients with giant cell arteritis, with dosages based on physician’s expert opinion

Patients

77 patients with temporal arteritis Meeting the ACR-criteria Positive biopsies group A 91%, group B 89%, group C 89%

Authors

Nesher G, Rubinow A, Sonnenblick M

Publication

Clin Exp Rheumatol. 1997;15(3):303–306

Follow up

3 years

Note

Mean starting prednisone dose: Month 0 (mg) 37 (group A), 59 (group B), 92 (group C) Month 2 (mg) 21 (group A), 33 (group B), 43 (group C) Month 6 (mg) 10 (group A), 18 (group B), 22 (group C) Month 12 (mg) 7 (group A), 10 (group B), 14 (group C) Mean prednisone dose: 7 mg (group A), 10 mg (group B), 14 mg (group C) Disease exacerbations First year 26% (group A), 20% (group B), 11% (group C) Second year 5% (group A), 14% (group B), 14% (group C) Third year 5% (group A), 4% (group B), 17% (group C) Cumulative cure rate: First year 13% (group A), 13% (group B), 11% (group C) Second year 35% (group A), 31% (group B), 29% (group C) Third year 50% (group A), 48% (group B), 50% (group C)

Adverse events

All adverse events 36% (group A), 78% (group B), 88% (group C) Life threatening adverse events 14% (group A), 33% (group B), 38% (group C) Other major adverse events 9% (group A), 27% (group B), 37% (group C)

Giant Cell Arteritis: Corticosteroids

Trial

A randomized, multicenter, controlled trial using intravenous pulses of Methylprednisolone in the initial treatment of simple forms of giant cell arteritis: a 1 year follow-up study of 164 patients

Substance

Group A (n = 61) 240 mg i.v. pulse of methylprednisolone Followed by 0.7 mg/kg/day oral prednisone

591

Group B (n = 53) 0.7 mg/kg/day oral prednisone only Group C (n = 50) 240 mg i.v. pulse of methylprednisolone Followed by 0.5 mg/kg prednisone/day Administration of oral prednisone b.i.d. in all groups Corticosteroid dosage was tapered after normalization of inflammatory variables, with the goal to reach half the initial dose within 1 month for Groups A and B, and 20 mg/week for Group C Taper thereafter of 1 mg every month, not beginning before month 6 of treatment Concomitant therapy: Anticoagulant therapy: nadroparin or dalteparin during initial study phase 1 g Calcium 8,000 IU ergocalciferol/week for osteoprosis prevention Result

Methylprednisolone pulses had no corticosteroid sparing effects in addition to oral prednisone in patients with giant cell arteritis

Patients

164 patients with giant cell arteritis Either proven by biopsy of the temporal artery or by the ACR-criteria Important exclusion criteria: Age >85 years Ocular or other vascular event within last month

Authors

Chevalet P, Barrier JH, Pottier P, Magadur-Joly G, Pottier MA, Hamidou M, Planchon B, El Kouri D, Connan L, Dupond JL, De Wazieres B, Dien G, Duhamel E, Grosbois B, Jego P, Le Strat A, Capdeville J, Letellier P, Agron L

Publication

J Rheumatol. 2000;27(6):1484–1491

Follow-up

1 year

592

Note

Giant Cell Arteritis: Corticosteroids

Time (mean) to normalisation of: Clinical signs 3.07 days (group A), 2.47 days (group B), 3.3 days (group C) CRP 7.39 days (group A), 7.77 days (group B), 7.69 days (group C) Time (mean) before: Obtaining 0.3 mg prednisone/day 104.8 days (group A), 95.0 days (group B), 95.2 days (group C) Obtaining 7 mg/kg prednisone/day 255.7 days (group A), 254.0 days (group B), 237.0 day (group C) Cumulative prednisone dose: After 1 month 1,084 g (group A), 1,146 g (group B), 848 g (group C) After 2 month 1,811 g (group A), 1,916 g (group B), 1,555 g (group C) After 6 month 3,973 g (group A), 4,065 g (group B), 3,530 g (group C) After 12 month 5,777 g (group A), 5,578 g (group B), 5,168 g (group C) Patients taking prednisone after 1 year 85% (group A), 77% (group B), 89% (group C) Corticoid dependence in the first 3 months 27% (group A), 30% (group B), 30% (group C) Corticoid dependence in the first 4 months 28% (group A), 35% (group B), 46% (group C) Corticoid resistance 8% (group A), 17% (group B), 16% (group C) Non-corticoid inflammatory therapy 1% (group A), 2% (group B), 4% (group C)

Adverse events

Infections n = 15 (group A), n = 6 (group B), n = 10 (group C) Cushingoid features n = 7 (group A), n = 6 (group B), n = 5 (group C) Rheumatic n = 9 (group A), n = 7 (group B), n = 2 (group C) Psychiatric n = 6 (group A), n = 2 (group B), n = 5 (group C) Cardiovascular n = 3 (group A), n = 3 (group B), n = 3 (group C) Diabetic n = 2 (group A), n = 3 (group B), n = 2 (group C) Digestive n = 3 (group A), n = 0 (group B), n = 4 (group C) Ophthalmologic n = 3 (group A), n = 0 (group B), n = 0 (group C) Phlebitis n = 0 (group A), n = 2 (group B), n = 2 (group C) Steroid induced myopathy n = 1 (group A), n = 0 (group B), n = 1 (group C)

Giant Cell Arteritis: Corticosteroids

593

Trial

Treatment of giant cell arteritis using induction therapy with high-dose Glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial

Substance

15 mg/kg i.v. methylprednisolone (group A) Placebo saline (group B) for 3 days Parallel prednisone tapering therapy (both groups): 40 mg/day prednisone and followed a tapering schedule to control disease activity Tapered to 30 mg after 2 weeks Tapered by 5 mg/2 weeks until 20 mg Tapered by 2.5 mg/2 weeks until 10 mg/day Below 10 mg/day, further reduction by 1 mg/2 weeks Relapse of disease activity: Increase of prednisone dose of 10 mg If prednisone ³ 25 mg/day increase by 5 mg Tapering was started again after 2 weeks Concomitant therapy: Calcium (1,200–1,500 mg/day) Vitamin D (400–800 IU) Bisphosphonates dependent on bone densitometry measurements

Result

Initial i.v. pulse therapy with methylprednisolone led to a quicker tapering and a higher remission rate, compared to oral prednisone alone, in patients with giant cell arteritis

Patients

77 patients with giant cell arteritis Proven by biopsy and meeting the ACR-criteria Major exclusion criteria: Prednisone doses equivalent to >10 mg/day for >10 days Recent vision problems or transient ischemic attacks

Authors

Mazlumzadeh M, Hunder GG, Easley KA, Calamia KT, Matteson EL, Griffing WL, Younge BR, Weyand CM, Goronzy JJ

Publication

Arthritis Rheum. 2006;54(10):3310–3318

Follow-up

78 weeks

Note

<5 mg/day prednisone at week 36: 10/14 (group A), 2/13 (group B) <5 mg/day prednisone at week 52: 11/14 (group A), 2/13 (group B) <5 mg/day prednisone at week 78: 12/14 (group A), 4/12 (group B) Cumulative steroid dose at week 78: 5,636 mg (group A), 7,860 mg (group B) Total relapses 21/14 patients (1.5/patient, group A), 37/13 patients (2.8/patient, group B)

594

Adverse events

Giant Cell Arteritis: Corticosteroids

Hypertension 21.1% (group A), 23.3% (group B) Hyperlipoproteinemia 21.3% (group A), 23.1% (group B) Coronary artery disease 0% (group A), 7.7% (group B) Tachycardia 0% (group A), 15.4% (group B) Upper GI-bleeding 0% (group A), 0% (group B) Rectal bleeding 0% (group A), 7.1% (group B) Osteoporosis 21.3% (group A), 23.1% (group B) Cushingoid habitus 78.6% (group A), 76.9% (group B) Glucose intolerance 7.1% (group A), 15.4% (group B) Glaucoma 7.1% (group A), 0% (group B) Chorioretinopathy 0% (group A), 7.7% (group B) Subconjunctival hemorrhage 0% (group A), 7.7% (group B) VZV 7.1% (group A), 0% (group B) Upper respiratory tract infection 21.3% (group A), 15.4% (group B) Urinary tract infection 21.3% (group A), 15.4% (group B) Pneumonia 7.1% (group A), 15.4% (group B) Candida Oesophagitis 0% (group A), 7.7% (group B) Depression 0% (group A), 7.7% (group B) Dizziness 21.3% (group A), 0% (group B) Deep venous thrombosis 0% (group A), 7.7% (group B) Colon cancer 7.1% (group A), 0% (group B) Sleep apnoea 7.1% (group A), 0% (group B)

Giant Cell Arteritis: Azathioprine

Trial

Azathioprine in giant cell arteritis/Polymyalgia rheumatica: a double-blind study

Substance

2 × 50 mg azathioprine/d (n = 16) Placebo (n = 15)

595

Concomitant therapy: Previous steroid had been reduced to a minimum sufficient to control symptoms 5 mg metoclopramid in case of nausea Previous medication: Corticosteroids (all patients) Result

The mean prednisolone after 52 weeks was lower in the azathioprine treatment than the placebo treatment group in this mixed study population of patients with giant cell arteritis or polymyalgia rheumatica

Patients

31 patients with Polymyalgia rheumatica (PMR), or giant cell arteritis (GCA) Diagnosed on the basis of the criteria proposed by Jones and Hazelmann Disease duration (azathioprine/placebo group, mean): 2.3/2.5 years) Pre-treatment with steroids in all cases

Authors

De Silva M, Hazleman BL

Publication

Ann Rheum Dis. 1986;45(2):136–138

Follow up

52 weeks

Note

Prednisolone dose: Week 0: 8.1 mg/day (Aza), 7.4 mg/day (placebo) Week 12: 5.1 mg/day (Aza), 4.8 mg/day (placebo) Week 24: 3.6 mg/day (Aza), 3.7 mg/day (placebo) Week 36: 2.8 mg/day (Aza), 3.3 mg/day (placebo) Week 52, at end of study: 1.9 mg/day (Aza), 4.2 mg/day (placebo)

Adverse events

Nausea n = 4 (Aza), n = 2 (placebo) Vomiting n = 2 (Aza), n = 0 (placebo) Diarrhea n = 1 (Aza), n = 1 (placebo) Collapse n = 1 (Aza), n = 1 (placebo)

596

Giant Cell Arteritis: Ciclosporin

Trial

No additional steroid-sparing effect of Cyclosporin A in giant cell arteritis

Substance

Prednisone monotherapy, starting dose 40 mg/day (group A, n = 30) 2 mg CsA/kg/day (dose could be increased to 3.5 mg/kg/day or decreased) + prednisone (group B, n = 30)

Result

In this study of giant cell arteritis, cyclosporine A had no steroid-sparing effect, at least partly due to a high drop-out rate because of side effects

Patients

60 consecutive patients with biopsy-proven giant cell arteritis Meeting the ACR-criteria Major exclusion criteria: >1 month corticosteroid therapy Combination with other immunosuppressive drug Uncontrolled hypertension Signs of threatening vascular ischemia

Authors

Schaufelberger C, Möllby H, Uddhammar A, Bratt J, Nordborg E

Publication

Scand J Rheumatol. 2006;35(4):327–329

Duration

12 months

Note

No steroid spearing effect by addition of CsA Premature termination n = 1 (group A), n = 11 (group B) Termination because of side effects n = 0 (group A), n = 9 (group B)

Giant Cell Arteritis: Methotrexate

Trial

Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis?

Authors

van der Veen MJ, Dinant HJ, van Booma-Frankfort C, van Albada-Kuipers GA, Bijlsma JW

Publication

Ann Rheum Dis. 1996;55(4):218–223

Follow up

2 years

Trial Summary under “Polymyalgia rheumatica”

597

598

Giant Cell Arteritis: Methotrexate

Trial

Combined treatment of giant-cell arteritis with methotrexate and prednisone. A randomized, double-blind, placebo-controlled trial

Substance

10 mg methotrexate/week p.o. for 24 months (Group A, n = 21) Placebo + prednisolone (Group B, n = 21) Prednisone therapy: 20 mg prednisolone t.i.d. (from second week: q.d.) Tapered in steps of 10 mg/week to 40 mg/day Tapered by 5 mg steps to 20 mg Tapered by 2.5 mg every 2 weeks until withdrawal Concomitant therapy: Calcium (1,000 mg/day) Vitamin D3 (600 IU/day) Folic acid (5 mg/day) Isoniazid (600 mg/day for 6 months) when signs for tuberculosis visible on chest radiography Previous medication: No immunosuppressive drugs

Result

Treatment with methotrexate plus prednisolone in patients with giant cell arteritis was safe, more effective and resulted in a reduced cumulative prednisolone dose, in comparison with prednisolone monotherapy

Patients

42 patients with new-onset giant-cell arteritis Diagnosed by biopsy £2 weeks of treatment with high-dose corticosteroid (prednisone >10 mg/day) Major exclusion criteria: Serum creatinine >2 mg/dl Low-dose prednisone equivalent £10 mg/day for >3 months Previous immunosuppressive drugs

Authors

Jover JA, Hernández-García C, Morado IC, Vargas E, Bañares A, Fernández-Gutiérrez B

Publication

Ann Intern Med. 2001;134(2):106–114

Follow-up

24 months

Giant Cell Arteritis: Methotrexate

Note

Relapse rate 45% (group A), 84.2% (group B) Cumulative dose 4,187 mg (group A), 5,489.5 mg (group B) Completion of follow up analysis (n = 39; including drop-outs): Patients without relapse n = 11 (group A), n = 3 (group B) Patients with one relapse n = 7 (group A), n = 7 (group B) Patients with two relapses n = 1 (group A), n = 8 (group B) Patients with three relapses n = 1 (group A), n = 1 (group B) Total patients with relapse n = 9 (group A), n = 16 (group B) Total relapses n = 12 (group A), n = 26 (group B) Patients with cranial relapse n = 2 (group A), n = 7 (group B) Patients with non-cranial relapse n = 7 (group A), n = 9 (group B) Completion of treatment analysis (n = 33): Patients without relapse n = 8 (group A), n = 3 (group B) Patients with one relapse n = 6 (group A), n = 7 (group B) Patients with two relapses n = 1 (group A), n = 7 (group B) Patients with three relapses n = 0 (group A), n = 1 (group B) Total patients with relapse n = 7 (group A), n = 15 (group B) Total relapses n = 8 (group A), n = 24 (group B) Patients with cranial relapse n = 1 (group A), n = 6 (group B) Patients with non-cranial relapse n = 6 (group A), n = 9 (group B)

Adverse events

Fracture 20% (group A), 10.5% (group B) Neuropsychiatric disorder 50% (group A), 42.1% (group B) Cataract 10% (group A), 5.2% (group B) Diabetes 15% (group A), 36.8% (group B) Glucose intolerance 10% (group A), 10.5% (group B) Arterial hypertension 60% (group A), 84.2% (group B) Cushingoid appearance 15% (group A), 31.8% (group B) Weight gain 35% (group A), 47.3% (group B) Myopathy 10% (group A), 5.2% (group B) Hypercholesterinemia 0% (group A), 10.5% (group B) Increase liver enzymes 35% (group A), 31.8% (group B) Nausea and vomiting 0% (group A), 5.2% (group B) Thrombocytopenia 15% (group A), 5.2% (group B) Oral ulcers 0% (group A), 5.2% (group B) Alopecia 5% (group A), 10.5% (group B) Infections 40% (group A), 52.5% (group B) Peptic disease 5% (group A), 15.7% (group B) Diarrhea 5% (group A), 15.7% (group B)

599

600

Giant Cell Arteritis: Methotrexate

Trial

A prospective, double-blind, randomized, placebo-controlled trial of methotrexate in the treatment of giant cell arteritis (GCA)

Substance

Prednisone therapy: Recommended starting dose 1 mg/kg/day or 1 g, but lower doses possible Tapered by 10 mg/week based on the clinical course After reaching 40 mg/day tapering by 5 mg/week until 20 mg Then tapering by 2.5 mg/week until withdrawal Randomized trial: After reaching 30 mg prednisone/day Group A (n = 12): 7.5 mg MTX/week Dosage was increased by 2.5–20 mg/week. Monthly taper to 0 by 2.5 mg every 4 weeks after discontinuation of prednisone Group B (n = 9): Placebo Concomitant therapy: Folic acid 1 mg/day Calcium carbonate (1,500 mg/day), vitamin D3 (800 IU/day) Previous medication: No immunosuppressive therapy

Result

Addition of methotrexate to prednisone, compared to prednisone alone, did not result in a steroid-sparing effect or in faster control of giant cell arteritis in this study

Patients

21 patients with newly diagnosed temporal arteritis Proven by biopsy or one of the following: Ischemic optic neuopathy with WSR >50 mm/h and the presence of polymyalgia rheumatica (PMR) Stenotic disease of the aorta, or cranial symptoms incl. visual loss, together with ESR >50 mm/h ESR >50 mm/h and cranial symptoms or PMR, no evidence of other disease plus fabrable clinical response to high dose steroids Major exclusion critieria: Serum creatinine >2 mg /dl

Authors

Spiera RF, Mitnick HJ, Kupersmith M, Richmond M, Spiera H, Peterson MG, Paget SA

Publication

Clin Exp Rheumatol. 2001;19(5):495–501

Follow-up

³68 weeks (no detailed information provided)

Giant Cell Arteritis: Methotrexate

Note

Corticosteroid dose 6,469 mg (group A), and 5,908 mg (group B) Time to complete steroid treatment 68 weeks (group A), 60 weeks (group B) Time to reach prednisone £10 mg/d 23 weeks (group A), 25 weeks (group B)

Adverse events

Muscoskeletal weakness n = 12 (group A), n = 8 (group B) Back pain n = 5 (group A), n = 3 (group B) Vertebral fracture n = 1 (group A), n = 3 (group B) Mood changes n = 12 (group A), n = 9 (group B) Tired/Insomnia n = 10 (group A), n = 7 (group B) Tremor n = 6 (group A), n = 2 (group B) Loss of balance/dizziness n = 3 (group A), n = 5 (group B) Memory loss n = 3 (group A), n = 0 (group B) Gastrointestinal discomfort n = 10 (group A), n = 6 (group B) Diarrhea n = 1 (group A), n = 0 (group B) Skin fragility n = 4 (group A), n = 1 (group B) Alopecia n = 6 (group A), n = 5 (group B) Hirsutism n = 1 (group A), n = 1 (group B) Rash n = 1 (group A), n = 2 (group B) Acne n = 0 (group A), n = 1 (group B) Cushingoid n = 3 (group A), n = 3 (group B) Hyperglycaemia n = 1 (group A), n = 1 (group B) Cellulitis n = 1 (group A), n = 1 (group B) Herpes zoster n = 2 (group A), n = 1 (group B) Fungal skin infection n = 2 (group A), n = 0 (group B) Urinary tract infection n = 1 (group A), n = 1(group B) Pneumonia n = 0 (group A), n = 1 (group B) Adeno-carcinoma n = 1 (group A), n = 0 (group B) Squamous cell carcinoma n = 0 (group A), n = 1 (group B) Basal cell carcinoma n = 1 (group A), n = 0 (group B)

601

602

Giant Cell Arteritis: Methotrexate

INSSYS-Trial

A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis (GCA) INSSYS: International Network for the Study of Systemic Vasculitides

Substance

Group A (n = 51): 15 mg/kg/week methotrexate /week with Increase to 0,25 mg/kg/week, max.15 mg/week Group B (n = 47): Placebo Parallel corticosteroid therapy: 1 mg/kg/day prednisone (max. 60 mg/day) After 4 weeks prednisone was reduced by 5 mg every 4 days on alternate days reaching 60 mg every other day after 3 months Then reduction by 5 mg/week until discontinuation Total duration of prednisone = 6 months Concomitant therapy: Folic acid 5 mg/week (24 h after MTX) Calcium (1,000 mg/d) and 0.5 mg 1.25 vitamin D twice a week

Result

Methotrexate, added to prednisone, war not superior to prednisone alone in controlling disease activity or decreasing the cumulative dose and toxicity of corticosteroids in this trial of patients with giant cell arteritis

Patients

98 patients Age >50 years ESR ³40 mm/h Onset of giant cell arteritis (GCA) symptoms £6 months + at least one of the following: Positive temporal artery biopsy Unequivocal symptoms of GCA Angiographic abnormalities Symptoms of polymyalgia rheumatica (PMR) plus cranial symptoms Major exclusion criteria: Prednisone initiated >21 days prior to study Serum creatinine ³2 mg/dl Prior diagnosis of GCA or PMR Lack of response to prednisone therapy within 5 days (because suggestive for other form of vasculitis)

Authors

Hoffman GS, Cid MC, Hellmann DB, Guillevin L, Stone JH, Schousboe J, Cohen P, Calabrese LH, Dickler H, Merkel PA, Fortin P, Flynn JA, Locker GA, Easley KA, Schned E, Hunder GG, Sneller MC, Tuggle C, Swanson H, HernándezRodríguez J, Lopez-Soto A, Bork D, Hoffman DB, Kalunian K, Klashman D, Wilke WS, Scheetz RJ, Mandell BF, Fessler BJ, Kosmorsky G, Prayson R, Luqmani RA, Nuki G, McRorie E, Sherrer Y, Baca S, Walsh B, Ferland D, Soubrier M, Choi HK, Gross W, Segal AM, Ludivico C, Puechal X; International Network for the Study of Systemic Vasculitides

Publication

Arthritis Rheum. 2002;46(5):1309–1318

Follow up

12 months

Giant Cell Arteritis: Methotrexate

Note

Treatment failure in 6 months 24.4% (MTX), 35.4% (placebo) First relapse in 6 months 68.9% (MTX), 66.1% (placebo) Treatment failure in 12 months 57.5% (MTX), 77.3% (placebo) First relapse in 12 months 74.8% (MTX), 91.3% (placebo) Total dose of prednisone 5,375 mg (MTX), 5,275 mg (placebo) Median duration of corticosteroid treatment was 5.6 months (placebo), 5.4 months (MTX) (range 1–10 months, IQR 2.1 months) (P = 0.5)

Adverse events

Headache or scalp pain 55.2% (placebo), 48.7% (MTX) Tongue or jaw pain 4.8% (placebo), 20.0% (MTX) Polymyalgia rheumatica 73.7% (placebo), 39.9% (MTX) Vision loss 19.7% (placebo), 10.2% (MTX) Sustained fever 18.1% (placebo), 3.9% (MTX) ESR increase 76.1% (placebo), 61.7% (MTX) Death n = 1 (placebo) n = 2 (MTX) (none attributed to therapy)

603

Giant Cell Arteritis: Etanercept

604

Trial

A double-blind placebo-controlled trial of Etanercept in patients with giant cell arteritis and corticosteroid side effects

Substance

Etanercept 2 x 25 mg/week (n = 8) Placebo (n = 9) After 1 month of stable corticosteroids Corticosteroid therapy: 1 month of stable corticosteroids (no dose depicted): Then tapered by 10 mg/week to 30 mg Then tapered by 5 mg/week to 15 mg Then tapered by 2.5 mg/week until discontinuation Screening for TBC (PPD skin test ± chest X-rays), if suspicious: 300 mg isoniazid/day for 9 months, or 600 mg rifampicin/day for 4 months – in case of toxicity Previous medication: Pre-treatment with corticosteroids 10 months (mean), mean dose 15 mg/day at start of study ³10 mg prednisone during previous 4 weeks

Result

Disease was controlled in more patients treated with etanercept than with placebo, the cumulative corticosteroid dose was lower in the etanercept group

Patients

17 patients with biopsy-proven giant cell arteritis, with side-effects secondary to corticosteroids (at least one): Steroid-induced diabetes mellitus Osteoporosis High blood pressure

Authors

Martinez Taboada VM, Rodríguez-Valverde V, Carreño L, Lopez-Longo J, Figueroa M, Belzunegui J, Martín-Mola E, Bonilla G

Publication

Ann Rheum Dis. 2008;67(5):625–630. Epub 2007 Dec 1

Follow-up

15 months

Note

Controlled disease activity 50% (ETN), 22.2% (placebo) Accumulated dose of prednisone 1.5 g (ETN), 3 g (placebo) Patients with relapses 50% (ETN), 77.8% (placebo)

Adverse events

Infections 50% (ETN), 44% (placebo) Injection-site reaction 12.5% (ETN), 22% (placebo) Cardiac failure 12.5% (ETN), 0% (placebo) Abnormal liver function 25% (ETN), 11% (placebo)

Giant Cell Arteritis: Infliximab

Trial

Infliximab for maintenance of Glucocorticosteroid-induced remission of giant cell arteritis (GCA): a randomized trial

Substance

Infliximab (5 mg/kg, n = 28) Placebo (n = 16) Started after 1 week of 40–60 mg prednisolone

605

Corticosteroid therapy: Glucosteroid starting dose was between 40 and 60 mg/day Tapered in steps of 10 mg/week to 20 mg/day Tapered by 2.5 mg steps to 10 mg every 2 weeks until 10 mg/week Tapered by 1 mg/week until withdrawal after 23 weeks at the latest Previous medication: No methylprednisolone >1,000 mg/day for >3 days No DMARDs No biologic agents Result

Infliximab as maintenance therapy of giant cell arteritis in glucosteroidinduced remission, using a rapidly tapered glucocorticosteorid regimen, did not improve clinical results, i.e., rate of relapses and remissions, in comparison with placebo, and was associated with more infections.

Patients

44 patients with newly diagnosed giant cell arteritis on the basis of the ACR-criteria Diagnosis of giant cell arteritis within 4 weeks of enrollment ESR ³40 mm/h at the time of diagnosis Achieved clinical remission before randomization Prednisone or prednisolone 40–60 mg/day for ³1 week before randomization ESR < 40 mm/h No symptoms or signs of active giant cell arteritis Major exclusion criteria: Diagnosis of GCA or polymyalgia rheumatica >4 weeks before screening No response to glucocorticosteroid therapy within 5 days Prior immunosuppressive therapy or biological agents

Authors

Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone JH, Salvarani C, Xu W, Visvanathan S, Rahman MU; Infliximab-GCA Study Group

Publication

Ann Intern Med. 20071;146(9):621–630

Follow up

390 days

606

Giant Cell Arteritis: Infliximab

Note

Week 22 (study ended after this analysis by steering committee and sponsor): Patients without relapse 50% (placebo), 43% (IFX) <10 mg corticosteroid 75% (placebo), 61% (IFX) Complete remission 44% (placebo), 39% (IFX)

Adverse events

Infection 56% (placebo), 71% (IFX) ³1 adverse event 94% (placebo), 93% (IFX) ³1 serious adverse event 25% (placebo), 29% (IFX) Discontinuation due to an adverse event 13% (placebo), 11% (IFX) All infections n = 23 (placebo), n = 47 (IFX) Patients with ³1 infection 56% (placebo), 71% (IFX) Patients with ³1 infection requiring oral or parenteral antimicrobial treatment 50% (placebo), 57% (IFX) Patients with ³1 serious infections 6% (placebo), 11% (IFX) Infusion reactions 0% (placebo), 5% (IFX) Patients with ³1 infusion reactions 0% (placebo), 21% (IFX) Antinuclear antibodies (newly positive) 33% (placebo), 52% (IFX) Antibodies to double-stranded DNA 0% (placebo), 16% (IFX)

Polymyalgia Rheumatica

Azathioprine

Trial

Azathioprine in giant cell arteritis/Polymyalgia rheumatica: a double-blind study

Authors

De Silva M, Hazleman BL

Publication

Ann Rheum Dis. February 1986;45(2):136–138

Trial summary under “Giant cell arteritis”

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_12, © Springer-Verlag London Limited 2011

607

608

Polymyalgia Rheumatica: Corticosteroids

Trial

Corticosteroid injections in polymyalgia rheumatica: a double-blind, prospective, randomized, placebo-controlled study

Substance

Bilateral shoulder injections of 40 mg of 6-methylprednisolone acetate (group A, n = 10) Placebo injections (n = 10) Responders were treated weekly with the same regimen for a total of four bilateral injections and then followed for 6 months Non-responders withdrawn from the study and received 16 mg/day prednisolone

Result

Shoulder corticosteroid injections were an effective and safe therapy for PMR

Patients

20 consecutive patients with active polymyalgia rheumatica (PMR) fulfilling Healey’s diagnostic criteria for PMR Major exclusion criteria: Previous treatment with corticosteroids Peripheral synovitis Pelvic girdle involvement Signs and/or symptoms of present giant cell arteritis Anticoagulant treatment or bleeding disorder

Authors

Salvarani C, Cantini F, Olivieri I, Barozzi L, Macchioni L, Boiardi L, Niccoli L, Padula A, Pulsatelli L, Meliconi R

Publication

J Rheumatol. June 2000;27(6):1470–1476

Duration/follow up 7/7 months Note

Non-responders 100% (group B) Responders 100% (group A): Morning stiffness (min) –183 (group A) VAS pain (cm) –7.4 (group A) Patient’s global assessment, VAS (cm) –7.0 (group A) Physician’s global assessment, VAS (cm) –6.6 (group A) ESR (mm/h) –69 (group A) CRP (mg/L) –6.1 (group A) IL-6 (pg/dL) –22 (group A) Systemic symptoms and signs –50% Response until 6-month follow-up n = 5 Loss of response after 4 weeks n = 5 MRI showed marked improvement of shoulder lesions 1 week after first injection and an almost complete resolution 1 week after last injection in the responder group

Adverse events

No side effects were recorded

Polymyalgia Rheumatica: Corticosteroids

609

Trial

Deflazacort versus Methylprednisolone in Polymyalgia rheumatica: clinical equivalence and relative anti-inflammatory potency of different treatment regimens

Substance

Group A (n = 16): 24 mg deflazacort/day (n = 8) 48 mg deflazacort every other day (n = 8) Groups were crossed over after 6 weeks Group B (n = 15): 16 mg 6-methylprednisolone daily (n = 8) 32 mg 6-methylprednisolone every other day (n = 7) Groups were switched after 6 weeks Total treatment days: 84 First 2 weeks: fixed dose After week 2: reduced dose according to physician’s expert opinion of disease activity

Result

In this short-term study of polymyalgia rheumatica, neither different dose nor daily or alternate day treatment regimen of deflazacort or 6-methylprednisolone showed differences in clinical efficacy. Deflazacort was less potent than presumed

Patients

31 patients with recent onset polymyalgia rheumatica (PMR) Pain and stiffness in the proximal muscle groups (shoulder and/or pelvic girdle) Disease duration >1 month but <3 months ESR >40 mm/h Major exclusion criteria: Evidence of giant cell arthritis or other inflammatory rheumatic disease Previous glucocorticoids Rheumatoid factor

Authors

Di Munno O, Imbimbo B, Mazzantini M, Milani S, Occhipinti G, Pasero G

Publication

J Rheumatol. August 1995;22(8):1492–1498

Follow up

84 days

Note

Change of (after 42 days, daily regimen): Limb pain (VAS) –4.5 (group A), –6.3 (group B) Morning stiffness (min) –83 (group A), –132 (group B) ESR (mm/h) –45 (group A), –53 (group B) CRP (mg/dL) –1.6 (group A), –1.6 (group B) Change of (after 42 days, every other day regimen): Limb pain (VAS) –4.6 (group A), –6.0 (group B) Morning stiffness (min) –84 (group A), –116 (group B) ESR (mm/h) –50 (group A), –46 (group B) CRP (mg/dL) –1.7 (group A), –1.4 (group B)

Adverse events

Moderate gastric pain n = 1 (group A), n = 3 (group B) Facial edema and weight increase n = 0 (group A), n = 2 (group B)

610

Polymyalgia Rheumatica: Corticosteroids

Trial

An initially double-blind controlled 96 week trial of depot Methylprednisolone against oral prednisolone in the treatment of Polymyalgia rheumatica

Substance

Group A (n = 30): 15 mg oral prednisolone/day for 3 weeks 12.5 mg prednisolone/day for 3 weeks 10 mg prednisolone/day for 6 weeks + placebo i.m. saline every 3 weeks Breakage of code at week 12, no placebo injections from then on After 12 weeks, prednisone 9 mg until week 16 From then 1 mg every 8 weeks Group B (n = 30): Oral placebo + 120 mg 3-weekly i.m. methylprednisolone every 3 weeks Treatment duration 21 months (group A), 20 months (group B) Concomitant medication: No bone modifying treatment No previous steroid therapy

Result

There was no difference in clinical efficacy between i.m. methylprednisolone or oral prednisolone in this trial of patients with polymyalgia rheumatica. I.m. methylprednisolone was associated with fewer fractures and lesser weight gain

Patients

60 PMR patients With shoulder and pelvic girdle muscular pain in the absence of true muscle weakness Morning stiffness >30 min ESR >30 mm/h Absence of rheumatoid or other inflammatory arthritis or malignant disease Major exclusion criteria: Clinical features of giant cell arteritis Previous steroid therapy

Authors

Dasgupta B, Dolan AL, Panayi GS, Fernandes L

Publication

Br J Rheumatol. February 1998;37(2):189–195

Polymyalgia Rheumatica: Corticosteroids

Follow up

96 weeks

Note

Study completed n = 25 (group A), n = 24 (group B)

611

Remission rates: Week 12: 60.0% (group A), 66.6% (group B) Week 48: 58% (group A), 45% (group B) Week 96: 30% (group A), 33% (group B) Lower VAS pain at weeks 3 and 6 (group A), no difference in early morning stiffness, VAS or ESR at weeks 48 and 96 Cumulative mean steroid dose (mg) 3,473 (group A), 1,978 (group B) Weight gain 3.42 kg (group A) 0.82 kg (group B) Adverse events

Only patients on oral prednisolone reported moon face, hypertension, cataracts, back pain and depression, but the numbers were small Fracture n = 8 (oral), n = 1 (i.m.) Bruising 13.3% (oral), 33.3% (i.m.) Dyspepsia 9.9% (oral), 16.7% (i.m.) Chest infections 13.3% (oral), 9.9% (i.m.) Urinary tract infections 3.3% (oral), 0% (i.m.) Ankle edema 9.9% (oral), 9.9% (i.m.) Moon face 9.9% (oral), 0% (i.m.) Tremor 3.3% (oral), 0% (i.m.) Depression 3.3% (oral), 0% (i.m.) Hypertension 6.6% (oral), 0% (i.m.) Back pain 6.6% (oral), 0% (i.m.) Cataract 6.6% (oral), 0% (i.m.) Glaucoma 3.3% (oral), 3.3% (i.m.) Breathlessness 6.6% (oral), 0% (i.m.)

612

Polymyalgia Rheumatica: Methotrexate

Trial

Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis?

Substance

Corticosteroid therapy: 20 mg prednisone/day Tapered by 2.5 mg every 3 weeks if erythrocyte sedimentation rate (ESR) £15 mm/h or CRP £0.6 mg% After reaching 7.5 mg, further tapered by 2.5 mg every 6 weeks Group A (n = 20): + Methotrexate 7.5 mg/week Stop after Prednisone discontinuation Group B (n = 20): Placebo Concomitant therapy: Calcium supplements Stop of NSAIDs at study entry

Result

A low dose and rapidly tapered prednisone regimen was effective in this study population of predominantly polymyalgia rheumatica rather than giant cell arteritis patients. Methotrexate at 7.5 mg/week did not show additional efficacy or result in a lower cumulative dose of prednisone

Patients

40 patients with active, untreated polymyalgia rheumatica (PMR) 6 of whom also had clinical symptoms of giant cell arteritis (GCA) Positive temporal artery biopsies PMR n = 3 GCA n = 3 Inclusion criteria PMR: Age ³50 years ESR ³40 mm/h Pain/stiffness shoulders ± hips Inclusion criteria GCA: New onset temporal headache, jaw claudication, temporal artery tenderness on palpation or decreased pulsation, abnormal temporal artery biopsy specimen Age ³50 years, ESR ³50 mm/h Major exclusion criteria PMR and GCA: Signs (clinical or laboratory) of polyarthritis, polymyositis, Parkinson’s disease AST or ALT >twice normal value, serum creatinine >150 mmol/L

Authors

van der Veen MJ, Dinant HJ, van Booma-Frankfort C, van Albada-Kuipers GA, Bijlsma JW

Publication

Ann Rheum Dis. April 1996;55(4):218–223

Follow up

2 years

Polymyalgia Rheumatica: Methotrexate

Note

Remissions n = 11 (group A), n = 9 (group B) Median duration of remission 7 weeks (group A), 35 weeks (group B) Median cumulative prednisone dose (mg) after 2 years 2,400 (group A), 2,947 (group B) Number of relapses n = 18 (group A), n = 15 (group B) Median time to reach remission + stop of Prednisone 48 weeks (group A), 45 weeks (group B)

Adverse events

Gastrointestinal disorder n = 5 (group A), n = 5 (group B) Hair loss n = 1 (group A), n = 0 (group B) Oral ulcerations n = 3 (group A), n = 3 (group B) Rash n = 0 (group A), n = 1 (group B) Increased blood pressure n = 11 (group A), n = 8 (group B) Hypertension n = 9 (group A), n = 5 (group B) Increase in body weight n = 14 (group A), n = 11 (group B) Cardiac insufficiency n = 2 (group A), n = 1 (group B) Osteoporotic fractures n = 1 (group A), n = 2 (group B) Infections n = 5 (group A), n = 2 (group B) Thrombocytopenia n = 0 (group A), n = 1 (group B) Increase AST/ALT n = 15 (group A), n = 8 (group B) Increase in serum creatinine n = 7 (group A), n = 10 (group B) Hyperglycemia n = 5 (group A), n = 7 (group B)

613

614

Polymyalgia Rheumatica: Methotrexate

Trial

Methotrexate in Polymyalgia rheumatica: preliminary results of an open, randomized study

Substance

Group A (n = 12): 15 mg prednisone (Pdn)/day every week for 3 months Tapered to 10 mg Pdn/day for the 4 months Tapered to 5 mg Pdn/day for the 5 months Finally tapered to 2.5 mg Pdn/day for the 6 months or Group B (n = 12): Methotrexate 10 mg/week + 25 mg Pdn/day for 4 weeks 12.5 mg Pdn/day for the 2 months 10 mg Pdn/day for the 3 months 6.25 mg Pdn/day for the 4 months 5 mg Pdn/day for the 5 months Finally 2.5 mg Pdn/dayfor the 6 months Previous medication: No calcium supplements No calcitonin, other bone mass afftect in medications

Result

Additional methotrexate treatment of PMR reduced the cumulative prednisone dose and prevented loss of bone mass over 1 year, in comparison with prednisone alone

Patients

24 patients with recent onset PMR Diagnosed on the basis of the Goodwin-criteria as detailed in the publication Failed treatment with NSAIDs Major exclusion criteria: RA SLE Duration of symptoms (mean) 2.3 months (group A), 1.8 months (group B)

Authors

Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E

Publication

J Rheumatol. April 1996;23(4):624–628

Follow up

12 months

Note

Remissions at months 12: n = 12 (group A), n = 12 (group B) No longer taking Pdn at month 12: n = 0 (group A), n = 6 (group B) ESR –60 mm/hL (group A), –56 mm/h (group B) CRP –85 mg/L (group A), –70 mg/L (group B) Total prednisone dose 3.2 g (group A), 1.84 g (group B) Bone mineral density –4.78 (group A), –2.12 (group B) OH-Pro/creatinine +32.8 (group A), –18 mg/L (group B) Alkaline phosphatase –0.9 (group A), –14 mg/L (group B) Ca/creatinine +2.9 (group A), –3.9 mg/L (group B)

Adverse events

Abnormal liver function tests n = 0 (group A), n = 4 (group B) Vertebral fracture n = 1 (group A), n = 0 (group B) Hypertension n = 2 (group A), n = 0 (group B) Hyperglycemia n = 2 (group A), n = 0 (group B) Cataract n = 2 (group A), n = 0 (group B) Nausea n = 0 (group A), n = 2 (group B)

Polymyalgia Rheumatica: Methotrexate

Trial

Prednisone plus methotrexate for Polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial

Substance

Corticosteroid therapy: 25 mg prednisone (Pdn) Pdn/d tapered to 17.5 mg after 4 weeks Then for 4 weeks each: 12.5, 7.5, 5, and 2.5 mg Then discontinuation Clinical trial: +10 mg/week methotrexate p.o. (MTX, group A, n = 36) +Placebo (group B, n = 36) Both groups for 48 weeks Concomitant medication: 7.5 mg folinic acid (single dose), 24 h after MTX or placebo Oral calcium (1 g/day) Vitamin D3 (800 IU/day)

Result

Addition of methotrexate to standard treatment with prednisone, as compared to placebo, was associated with shorter prednisone treatment, fewer relapses and had a steroid sparing effect

Patients

72 patients with newly diagnosed polymyalgia rheumatica (PMR) Inclusion criteria: Age ³50 years, ESR ³40 mm/h Aching and stiffness at shoulder, hip girdle, or both for more than 1 month Major exclusion criteria: Other musculoskeletal or connective tissue diseases Chronic liver disease, AST > normal value No elevated serum creatinine kinase Osteoporotic fractures Steroid medication within the last month Previous methotrexate or other immunosuppressive agent Concomitant analgesic medications Duration of symptoms (months, mean): 3.2 (group A) 2.6 (group B)

Authors

Caporali R, Cimmino MA, Ferraccioli G, Gerli R, Klersy C, Salvarani C, Montecucco C; Systemic Vasculitis Study group of the Italian Society for Rheumatology

Publication

Ann Intern Med. October 5, 2004;141(7):493–500

Follow up

76 weeks

615

616

Note

Polymyalgia Rheumatica: Methotrexate

Weeks 0–24: Patients no longer taking prednisone n = 16 (group A), n = 15 (group B) Relapses n = 8 (group A), n = 8 (group B) Recurrences n = 0 (group A), n = 0 (group B) Patients with ³1 relapse or recurrence n = 7 (group A), n = 8 (group B) Weeks 24–48: Patients no longer taking prednisone n = 26 (group A), n = 14 (group B) Relapses n = 12 (group A), n = 18 (group B) Recurrences n = 3 (group A), n = 11 (group B) Patients with ³1 relapse or recurrence n = 10 (group A), n = 19 (group B) Week 48–76: Patients no longer taking prednisone n = 28 (group A), n = 16 (group B) Relapses n = 0 (group A), n = 7 (group B) Recurrences n = 4 (group A), n = 6 (group B) Patients with ³1 relapse or recurrence n = 4 (group A), n = 10 (group B) Duration of prednisone therapy, weeks 5.1 (group A), 14.4 (group B) Median duration of prednisone therapy, weeks 0 (group A), 18 (group B) Total prednisone dose 0.19 g (group A), 0.62 g (group B) Median prednisone dose (1st–3rd quartiles) 0 g (group A), 0.56 g (group B)

Adverse events

Weight gain 11.2% (group A) 5.6% (group B) Urinary tract infection 19.6% (group A) 16.8% (group B) Hypertension 14% (group A) 8.4% (group B) Tachycardia 0% (group A) 5.6% (group B) Fracture 5.6% (group A) 2.8% (group B) Neuropathic disorder 8.4% (group A) 14% (group B) Dyspepsia 16.7% (group A) 5.6% (group B) Nausea 2.8% (group A) 2.8% (group B) Diarrhea 5.6% (group A) 0% (group B) Stomatitis 2.8% (group A) 0% (group B) Alopecia 2.8% (group A) 0% (group B) Diabetes 0% (group A) 5.6% (group B) Cataract 0% (group A) 5.6% (group B)

Polymyalgia Rheumatica: Etanercept

Trial

Treatment of refractory Polymyalgia rheumatica with Etanercept: an open pilot study

Substance

Etanercept 2 × 25 mg/week for 24 weeks Corticosteroid therapy: Prednisone 12.5 mg/day Tapered to 10 mg after 1 month of remission Further reduction by 2.5 mg every 4 weeks until lowest effective dose Discontinuation after 24 weeks in case of complete remission, otherwise kept at 2.5 mg/day

Result

Etanercept was safe and effective. The cumulative dose of prednisone reached during the study was lower than in the same period of time before it’s start

Patients

Six patients with polymyalgia rheumatica (PMR), diagnosed according to the Healey criteria Inclusion criteria: Relapsing PMR Inability to reduce prednisone dosage below 7.5–10 mg/day Presence of corticosteroid adverse events Major exclusion criteria: Evidence of giant cell arteritis Fulfilment of the ACR-criteria for RA Presence of latent tuberculosis Disease duration 45 months (mean) Previous relapses n = 3.33 (mean) Corticosteroid adverse events: one n = 6, two n = 5

Authors

Catanoso MG, Macchioni P, Boiardi L, Pipitone N, Salvarani C

Publication

Arthritis Rheum. December 15, 2007;57(8):1514–1519

Follow up

9 months

Note

Sustained EULAR-PMR response ³70% n = 4 Sustained EULAR-PMR response ³50% n = 2 Leeb-DAS Score <7 n = 5 Change of Leeb-DAS Score –6.6 mg/day Decrease of prednisone dose from 8.75 mg/day to 2.5 mg/day (median) Cumulative prednisone dose during 9 months before study start 1,767 mg Cumulative prednisone dose 9 months after start of study 730 mg (means) Improvements at month 6 in ultrasounds of the shoulders n = 6 ESR –0.83 mm/h CRP –0.34 mg/dL

Adverse events

Flu n = 1 Bacterial cystitis n = 2

617

618

Polymyalgia Rheumatica: Infliximab

Trial

Infliximab plus prednisone or placebo plus prednisone for the initial treatment of Polymyalgia rheumatica: a randomized trial

Substance

Infliximab, 3 mg/kg (group A, n = 23) or placebo infusions (group B, n = 28) at weeks 0, 2, 6, 14 and 22 Corticosteroit therapy: 15 mg/day prednisone Tapered in 4 week periods to 10, 5, and 2.5 mg Then discontinued (after 16 weeks) if possible Previous medication: No steroids No biological agents No immunosuppressive agents

Result

Infliximab was not superior to placebo in this trial of early diagnosed polymyalgia rheumatica. There was a high rate of relapses on the background of a low dose and rapidly tapered regimen of prednisone

Patients

51 patients with newly diagnosed polymyalgia rheumatica (PMR) according to the Healey-criteria Inclusion criteria: >50 years of age ESR >40 mm/h Persistent pain (³1 month) Involving two of three areas (neck, shoulders, or pelvic girdle) Morning stiffness lasting >1 h Rapid response to prednisone, 20 mg/day or less Major exclusion criteria: Clinical or histologic evidence of giant cell arteritis RA, signs and symptoms of SLE or other connective tissue disease, myositis, latent or active tuberculosis Duration of symptoms (months, mean): 11 (group A) 10 (group B)

Authors

Salvarani C, Macchioni P, Manzini C, Paolazzi G, Trotta A, Manganelli P, Cimmino M, Gerli R, Catanoso MG, Boiardi L, Cantini F, Klersy C, Hunder GG

Publication

Ann Intern Med. May 1, 2007;146(9):631–639

Follow up

52 weeks

Note

Patients without relapse or recurrence 30% (group A), 37% (group B) Patients not receiving prednisone 50% (group A), 54% (group B) Total Relapses and recurrences, n = 22 (group A), n = 32 (group B) Patients off Prednisone 50% (group A), 54% (group B) Median cumulative dose of Prednisone (week 52) 17.1 g (group A), 12.2 g (group B)

Adverse events

Diabetes mellitus n = 1 (group A), n = 0 (group B) Infusion reaction n = 4 (group A), n = 0 (group B) System. Infection n = 1 (group A), n = 0 (group B) Pancreatitis n = 1 (group A), n = 0 (group B) Cataract n = 0 (group A), n = 1 (group B) Dyspepsia n = 0 (group A), n = 1 (group B) Hypertension n = 0 (group A), n = 2 (group B) Bladder cancer n = 0 (group A), n = 1 (group B)

ANCA-Associated Vasculitis, Churg Strauss syndrome, Polyarteritis Nodosa, and other vasculitic entities

Azathioprine

Trial

Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of 72 patients

Substance

Corticosteroid therapy: I.v. pulse methylprednisolone (15 mg/kg, n = 72) Followed by oral prednisone (1 mg/kg/day) for 3 weeks Tapered by 5 mg every 10 days to 0.5 mg/kg/day Then by 2.5 mg every 10 days to a dosage of 15 mg/day Finally by 1 mg every 10 days to the minimal effective dosage or withdrawal Patients in whom Prednisone doses could not be tapered below 20 mg: Azathioprine arm (n = 10): 6 months of oral 2 mg/kg/day azathioprine Cyclophosphamide arm (n = 9): 6 i.v. pulses of 600 mg/m2 cyclophosphamide (CYC) every 2 weeks for 1 month Then every 4 weeks thereafter Concomitant medication: Uromitexan together with CYC Compulsory: Potassium Calcium Vitamin D3 Bisphosphonates 400 mg trimethoprim/day +80 mg sulfamethoxazole/day (CD4 count < 300/mm3) Previous medication: None for Churg-Strauss syndrome

Result

Remission was achieved by prednisone alone in most patients, with common relapses and requirement of additional immunosuppressive therapy in one-third of them. Azathioprine or pulse cyclophosphamide both had additional effects in a significant proportion of patients with prednisone-resistant disease or major relapse

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_13, © Springer-Verlag London Limited 2011

619

620

Azathioprine

Patients

72 patients with Churg-Strauss syndrome Five Factor Score (FFS) for poor prognostic criteria = 0 FFS: Serum creatinine > 140 mmol/L (1.58 mg/dL) Proteinuria > 1 g/day Presence of severe gastrointestinal tract involvement Cardiomyopathy and/or Central nervous system involvement

Authors

Ribi C, Cohen P, Pagnoux C, Mahr A, Arène JP, Lauque D, Puéchal X, Letellier P, Delaval P, Cordier JF, Guillevin L; French Vasculitis Study Group

Publication

Arthritis Rheum. 2008;58(2):586–594

Follow up

56.2 months

Note

Remission achieved with prednisone therapy alone 93% (all patients) Long term remission 79% (all patients) Patients in remission still taking corticosteroids n = 52 out of 66 Relapse rate 42%, n = 5 (non responders corticosteroids), n = 25 (relapse during tapering) Time to relapse 18.3 months Survival rates in all patients 100% (1 year), 97% (5 years) Randomized patients: Remission n = 5 (Cyc), n = 7 (Aza)

Adverse events

Subclinical osteoporosis n = 10 Infection requiring hospitalization n = 8 Osteoporotic fractures n = 7 Arterial hypertension n = 7 Thromboembolic events n = 7 Diabetes mellitus n = 5 Adrenal insufficiency n = 5 Ophthalmologic complications n = 4 Osteonecrosis of the femoral head n = 3 Cardiovascular damage n = 3 CS-induced myopathy n = 2 Malignancy n = 2 Hepatotoxicity n = 2 Drug eruption n = 2 Tendon rupture n = 2 Sleep apnea syndrome n = 2 Esophageal candidiasis n = 2 Gastrointestinal ulcers n = 1 Hematologic toxicity n = 1 Azoospermia n = 1 Cyclophosphamide-induced cystitis n = 1

621

Co-trimoxazole

Trial

Trimethoprim-sulfamethoxazole (Co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group

Substance

Co-trimoxazole (2 × 800 mg of sulfamethoxazole + 160 mg of trimethoprim, n = 41) Placebo (n = 40) Concomitant medication: Prednisolone n = 23 (co-trimoxazole), n = 19 (placebo) Cyclophosphamide n = 21 (co-trimoxazole), n = 20 (placebo) Allowed previous medication: Cyclophosphamide Prednisolone

Result

There was a difference in the incidence of relapses between placebo and Co-trimoxazole, favouring Co-trimoxazole, in patients in remission in this trial of patients with Wegener’s granulomatosis under or after treatment with cyclophosphamide

Patients

81 patients with Wegener’s granulomatosis in complete remission Further inclusion criteria: Biopsy-proven glomerulonephritis, or Biopsy-proven airway involvement, or Fulfilling the ACR-criteria and positive for ANCA Major exclusion criteria: No history of adverse reaction to co-trimoxazole No impaired renal function (24-h creatinine clearance of £30 mL/min) Longterm therapy with antibiotics or co-trimoxazole Disease duration 30 months (median) ANCA-positive n = 52

Authors

Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG

Publication

N Engl J Med. 1996;335(1):16–20

Follow up

24 months

622

Co-trimoxazole

Note

Patients in Remission at 24 months n = 31 (co-trimoxazole), n = 23 (placebo) Fewer respiratory tract infections and n on-respiratory tract infections in the co-trimoxazole group Relapses n = 7 (co-trimoxazole), n = 16 (placebo) Progressive Glomerulonephritis n = 4 (co-trimoxazole), n = 7 (placebo) Pulmonary lesions n = 3 (co-trimoxazole), n = 2 (placebo) Nasal/upper airway lesions n = 1 (co-trimoxazole), n = 11 (placebo) Scleritis n = 1 (co-trimoxazole), n = 4 (placebo) Mononeuritis multiplex n = 2 (co-trimoxazole), n = 0 (placebo) Dermal granulomatous vasculitis n = 2 (co-trimoxazole), n = 4 (placebo)

Adverse events

Respiratory tract infections n = 0 (co-trimoxazole), n = 1 (placebo) Anorexia and nausea n = 4 (co-trimoxazole), n = 0 (placebo) Rash n = 2 (co-trimoxazole), n = 0 (placebo) Presumed interstitial nephritis with fever and eosinophilia n = 4 (co-trimoxazole), n = 0 (placebo) Asymptomatic hepatotoxic effects n = 4 (co-trimoxazole), n = 0 (placebo) Macrocytic anaemia n = 1 (co-trimoxazole), n = 0 (placebo) Recurrent urinary tract infections n = 0 (co-trimoxazole), n = 1 (placebo) Myocardial infarction and Death n = 0 (co-trimoxazole), n = 1 (placebo) Herpes zoster n = 3 (co-trimoxazole), n = 2 (placebo) Cytomegalovirus n = 0 (co-trimoxazole), n = 1 (placebo)

Cyclophosphamide

623

Trial

Cyclophosphamide therapy of severe systemic necrotizing vasculitis

Substance

2 mg/kg cyclophosphamide Concomitant medication: Corticosteroids (mean starting dose 62.6 mg, range 50–175 mg) Tapered to alternate-day administration of minimal dose after 2 weeks Azathioprine n = 1 Prednisolone n = 23 (co-trimoxazole), n = 19 (placebo) Cyclophosphamide n = 21 (co-trimoxazole), n = 20 (placebo) Previous medication: Corticosteroids in n = 16 (mean duration 22 months) Azathioprine n = 2

Result

Historic systematic description of the usefulness of cyclophosphamide in the induction of remission after insufficient corticosteroid therapy in a heterogeneous population of patients with necrotizing vasculitis

Patients

17 patients with necrotizing vasculitis With or without skin involvement Proven by organ biopsy (n = 15) and/or by angiogram All progressive despite treatment HB-antigen positive n = 7 Cryoglobulinemia n = 6

Authors

Fauci SF, Patz P, Haynes BF, Wolff SM

Publication

N Engl J Med. 1979;301(5):235–238

Follow up

11 years

Note

Remissions n = 14 (one patient treated with azathioprine instead of CYC) Mean duration of remission 22 months

Adverse events

Deaths n = 3, due to vasculitis n = 2, unknown cause n = 1

624

Cyclophosphamide

Trial

Long-term follow-up after treatment of polyarteritis nodosa and ChurgStrauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa

Substance

Group A: 13 plasma exchanges (60 mL/kg/session, 3 × in the first week, 2 ×/second week, then after 10,15, 21, and 30 days and for another 4 months, 1/month, n = 39) Group B: 13 plasma exchanges 2 mg/kg/day cyclophosphamide (n = 32) Concomitant medication: Replacement fluids for plasma exchange: 500 mL fluid gelatine, 4% albumin, fresh frozen plasma 1 mg/kg prednisone/day for 2 months Tapered by 2.5 mg every 10 days to half of the initial level Maintained for 3 weeks Then tapered by 2.5 mg every week to 20 mg/day Further tapered by 1 mg every week to 10 mg/day Maintained at 10 mg for 3 weeks, finally tapered to 5 mg/day by 1 mg Previous medication: No previous high dose corticosteroids Low dose corticosteroid pre-described for asthma £10 mg/day were permitted

Result

Reduced incidence of relapses by prednisone and plasma exchanges plus cyclophosphamide, without additional effect on long term survival or increased treatment-associated mortality, as compared to prednisone and plasma exchange alone

Patients

71 patients with vasculitis of the polyarteritis nodosa (PAN) type (Fauci classification): PAN and Churg-Strauss angiitis Clinical, histological and/or arteriographic evidence of vasculitis Sufficient disease activity to justify immunosuppressive treatment

Authors

Guillevin L, Jarrousse B, Lok C, Lhote F, Jais JP, Le Thi Huong Du D, Bussel A

Publication

J Rheumatol. 1991;18(4):567–574

Follow up

10 years

625

Cyclophosphamide

Note

Treatment stopped because of ineffectiveness: n = 9 (group A), n = 1 (group B) Relapses: 38.5% (group A), 9.4% (group B) Introduction of CYC/reinstallation of plasma exchange for active disease n = 4/3 Control of disease activity after 6 months: 90% (group A), 93.5% (group B) 10 year cumulative survival rates: 72% (group A), 75% (group B)

Adverse events

Treatment was stopped because of side effects n = 9 (group A), n = 1 (group B) Death related to vasculitis: Total n = 3 (group A), n = 2 (group B) Bowel perforation n = 2 (group A), n = 0 (group B) Cardiac insufficiency n = 1 (group A), n = 0 (group B) Multivisceral involvement n = 0 (group A), n = 2 (group B) Infectious adverse events of treatment: Total n = 3 (group A), n = 2 (group B) Bacterial pneumonia/septicaemia n = 3 (group A), n = 1 (group B) Tuberculosis n = 0 (group A), n = 1 (group B) Death not related to systemic vasculitis Total n = 5 (group A), n = 4 (group B) Sudden death n = 2 (group A), n = 0 (group B) Suicide n = 0 (group A), n = 1 (group B) Traffic accident n = 1 (group A), n = 0 (group B) Cancer n = 1 (group A), n = 1 (group B) Liver cirrhosis (post HBV) n = 0 (group A), n = 2 (group B) Pulmonary embolism n = 1 (group A), n = 0 (group B)

626

Cyclophosphamide

Trial

Corticosteroids plus pulse cyclophosphamide and plasma exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome patients with factors predicting poor prognosis. A prospective, randomized trial in 62 patients

Substance

Both groups: 15 mg/kg methylprednisone/day for 3 days Prednisone 1 mg/kg/day for 1 month Tapered to 0 during the follow up + 0.6 g/m2 cyclophosphamide (i.v. bolus every 4 weeks over 12 months) Group A (n = 28): Prednisone + Cyc (i.v. bolus) Group B: Prednisone + Cyc (i.v. bolus) + Plasma exchanges (60 mL/kg, 9 × during 3 weeks, n = 34) Replacement fluids for plasma exchange: 500 mL fluid gelatine, 4% albumin, fresh frozen plasma Concomitant medication: 5–10 mg Prednisone/day (CSS patients with asthma) CD4 count <300/mm3 ³1 Tbl. Co-trimoxazole/day

Result

Treatment with prednisone, cyclophosphamide and plasma exchanges was not superior over treatment with prednisone and cyclophosphamide alone

Patients

62 patients with severe polyarteritis nodosa Polyarteritis nodosa (PAN, n = 48), Churg-Strauss syndrome (n = 14) Inclusion criteria: Systemic PAN diagnosed by the presence of multiple system involvement ³1 criteria for poor prognosis according to Five Factor Score Histologic evidence of vascular lesion If no histologic evidence: arteriographic evidence Or: Fulfillment or the ACR criteria for PAN Or: Fulfillment or the ACR criteria for CSS Major exclusion criterion: HBsAG/HBeAG-positivity Cutaneous or other limited forms of PAN or other systemic vasculitides Typical biopsies n = 42 Positive angiograms n = 30

Authors

Guillevin L, Lhote F, Cohen P, Jarrousse B, Lortholary O, Généreau T, Léon A, Bussel A

Publication

Arthritis Rheum. 1995;38(11):1638–1645

Follow up

5 years

627

Cyclophosphamide

Note

Relapse n = 4 (group A), n = 3 (group B) Remission n = 16 (group A), n = 22 (group B) Remission without treatment n = 3 (group A), n = 2 (group B) Clinical remission requiring a maintenance of low-dose corticosteroids n = 2 (group A), n = 2 (group B)

Adverse events

Death n = 7 (group A), n = 4 (group B) Due to vasculitis n = 2 (group A), n = 2 (group B) Due to septicemia n = 1 (group A), n = 0 (group B) Unknown n = 3 (group A), n = 0 (group B) Shock n = 1 (group A), n = 1 (group B) Lymphoma n = 0 (group A), n = 1 (group B) Pulmonary tuberculosis n = 0 (group A), n = 3 (group B) Pneumonia n = 0 (group A), n = 3 (group B) Sigmoiditis n = 0 (group A), n = 1 (group B) Septicemia n = 0 (group A), n = 2 (group B) Osteoporosis n = 5 (both groups) Vertebral fractures n = 2 (both groups) Cataract n = 1 (both groups) Diabetes n = 2 (both groups) Nervous breakdown n = 1 (both groups)

Cyclophosphamide

628

Trial

Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis

Substance

PCYP arm (n = 24): Pulse i.v. cyclophosphamide and prednisolone After remission increasing oral pulse intervals CCAZP arm (n = 30): Continuous oral Cyclophosphamide + Prednisolone Followed by azathioprine at 3 months Escalation of treatment: Additional plasma exchange n = 8 (PCYP), n = 1 (CCAZP) I.v. prednisolone n = 12 (PCYP), n = 8 (CCAZP) I.v. immunoglobulins n = 8 (PCYP), n = 3 (CCAZP) Continuous oral prednisolone n = 13 (PCYP), n = 0 (CCAZP)

Result

No difference was observed in the frequency of remissions, relapses or treatment failures between the two treatment arms. There was a tendency toward increased toxicity in patients treated with the continuous oral cyclophosphamide regimen

Patients

54 patients with systemic vasculitis Classical polyarteritis n = 8 Microscopic polyarteritis n = 17 Wegener’s granulomatosis n = 29 all diagnosed according to categories resembling the CHC-definitions plus histologic or arteriographic evidence

Authors

Adu D, Pall A, Luqmani RA, Richards NT, Howie AJ, Emery P, Michael J, Savage CO, Bacon PA

Publication

QJM. 1997;90(6):401–409

Follow up

40.4 months (median)

Note

Partial remission n = 12 (PCYP), n = 19 (CCAZP) Complete remission n = 8 (PCYP), n = 7 (CCAZP) Treatment failure n = 4 (PCYP), n = 4 (CCAZP) Dead n = 5 (PCYP), n = 4 (CCAZP) Relapse n = 7 (PCYP), n = 8 (CCAZP) Chronic dialysis n = 2 (PCYP), n = 3 (CCAZP)

Adverse events

Leukopenia n = 7 (PCYP), n = 13 (CCAZP) Infective episodes 1.7/pat (PCYP), 1.66/pat. (CCAZP) Chest infection n = 9 (PCYP), 9 (CCAZP) Ear–Nose Throat infection n = 6 (PCYP), n = 3 (CCAZP) Conjunctivitis n = 1 (PCYP), n = 2 (CCAZP) Urine n = 8 (PCYP), n = 10 (CCAZP) Septicaemia n = 3 (PCYP), n = 2 (CCAZP) Cellulitis n = 2 (PCYP), n = 4 (CCAZP) Peritonitis n = 1 (PCYP), n = 2 (CCAZP) Herpes zoster n = 0 (PCYP), n = 1 (CCAZP) Herpes simplex n = 1 (PCYP), n = 3 (CCAZP) Gastroenteritis n = 2 (PCYP), n = 1 (CCAZP)

629

Cyclophosphamide

Trial

Treatment of good-prognosis Polyarteritis nodosa and Churg-Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides

Substance

Group oral (n = 12): Oral 2 mg/kg cyclophosphamide/day for 12 months Group i.v. (n = 13): Monthly i.v. 0.6 g/m2 cyclophosphamide pulses Flair: Increase of prednisone dose Concomitant medication: 1 mg/kg prednisone/day Daily dose was tapered by 2.5 mg every week until 10 mg/day Daily dose was tapered by 1 mg every week until withdrawal Prophylactic anti-emetic treatment was not systematically prescribed 500 mg calcium/day was recommended 800 IU vitamin D/day was recommended Previous medication: Low dose corticosteroids to control asthma No cytotoxic agents

Result

No difference of efficacy were observed between the two regimens; more toxicity in patients treated with oral cyclophosphamide

Patients

25 patients suffering from systemic vasculitis with recent onset of symptoms Churg-Strauss vasculitis (n = 8) Polyarteriitis nodosa (n = 17), all fulfilling the ACR-criteria Inclusion criteria: Systemic PAN or CSS diagnosed by the presence of multiple system involvement Absence of ³1 criteria for poor prognosis according to Five Factor Score Histologic evidence of vascular lesion If no histologic evidence: arteriographic evidence

Authors

Gayraud M, Guillevin L, Cohen P, Lhote F, Cacoub P, Deblois P, Godeau B, Ruel M, Vidal E, Piontud M, Ducroix JP, Lassoued S, Christoforov B, Babinet P

Publication

Br J Rheumatol. 1997;36(12):1290–1297

Follow up

60.8 months

Cyclophosphamide

630

Note

Complete Recovery n = 9 (oral), n = 10 (i.v.) Relapse n = 2 (oral), n = 2 (i.v.) Treatment failure n = 1 (oral), n = 1 (i.v.)

Adverse events

Group A: 27 toxic side effects in ten patients Group B: 14 toxic side effects in eight patients Osteopenia 33% (oral), 0% (i.v.) Cushing’s syndrome 17% (oral), 23% (i.v.) Amenorrhea 25% (oral), 15% (i.v.) Weight gain 8% (oral), 15% (i.v.) Malaise during infusion 0% (oral), 23% (i.v.) Alopecia 17% (oral), 0% (i.v.) Hemorrhagic cystitis 17% (oral), 0% (i.v.) Neutropenia 17% (oral), 0% (i.v.) Hypertension 17% (oral), 0% (i.v.) Skin folliculitis 17% (oral), 0% (i.v.) Urinary tract infection 0% (oral), 8% (i.v.) Hepatitis 8% (oral), 0% (i.v.) Herpes keratis 8% (oral), 0% (i.v.) Osteonecrosis 8% (oral), 0% (i.v.) Cataract 8% (oral), 0% (i.v.) Digestive candidiasis 8% (oral), 0% (i.v.) Sinusitis 8% (oral), 0% (i.v.) Gastric ulcers 8% (oral), 0% (i.v.) Pulmonary infections 0% (oral), 8% (i.v.) Infectious bronchitis 0% (oral), 8% (i.v.) Acne 0% (oral), 8% (i.v.)

631

Cyclophosphamide

Trial

A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis

Substance

Initial regimen: 15 mg/kg methylprednisolone/day i.v. for 3 days Followed by oral 1 mg/kg prednisone/day Tapering every 10 days by 2.5 mg until the half the initial dose Dose maintained stable for 3 weeks Tapered every 10 days by 2.5 mg to 20 mg/day Then tapered every 2 weeks by 1 mg until discontinuation On the day after the third methylprednisolone: 1 pulse 0.7-g/m2 pulse of cyclophosphamide (CYC) Randomization phase: Group A (i.v., n = 27): 0.7-g/m2 pulse of CYC, every 3 weeks until complete remission and 1 year thereafter Intervals between pulse treatments were then increased to 4 weeks for a 4-month period, then to 5 weeks for another 4-month period, and finally, to 6 weeks until discontinuation after 2 years After 2 years of treatment Group B (p.o., n = 23): Oral 2 mg/kg CYC/day starting day 10 until complete remission and 1 year thereafter Concomitant medication: 400 mg trimethoprimi-sulfamethoxazole/day

Result

Pulse and oral cyclophosphamide were equally effective in achieving initial remission, with fewer side effects for pulse cyclophosphamide. In the long term, pulse cyclophosphamide was inferior with respect to maintenance of remission or prevention of relapses, but was associated with higher survival

Patients

50 patients with systemic Wegener’s granulomatosis (WG) Inclusion criteria: Systemic WG diagnosed by multi-organ or severe monovisceral involvement Characteristic histology Positive immunofluorescence for ANCA n = 42

Authors

Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I, Lesavre P, Jacquot C, Bindi P, Bielefeld P, Desson JF, Détrée F, Dubois A, Hachulla E, Hoen B, Jacomy D, Seigneuric C, Lauque D, Stern M, Longy-Boursier M

Publication

Arthritis Rheum. 1997;40(12):2187–2198

Follow up

60 months

632

Note

Cyclophosphamide

At 6 months: Remission at 88.9% (i.v.), 78.3% (p.o.) Complete remission at 59.3% (i.v.), 65.2% (p.o.) Partial remission at 29.6% (i.v.), 13.0% (p.o.) Treatment failure 11.1% (i.v.), 21.7% (p.o.) Death 14.8% (i.v.), 26.1% (p.o.) Long term outcome: Sustained remission 47.8% (i.v.), 70.6% (p.o.) Relapse 52.2% (i.v.), 17.6% (p.o.) Death 21.7% (i.v.), 23.5% (p.o.) Final outcome: Remission 66.7% (i.v.), 56.5% (p.o.) Survival rate 66.7% (i.v.), 56.5% (p.o.) Death rate 33.3% (i.v.), 43.5% (p.o.) Survived without relapse 37% (i.v.) 48% (p.o.) Relapse rate 59.2% (i.v.), 13% (p.o.)

Adverse events

Infectious side effects 40.7% (i.v.), 69.6% (p.o.) Pneumocystis carinii pneumonia 30.4% (p.o.), 11.1% (i.v.) Esophageal candidiasis 4.3% (p.o.), 3.7% (i.v.) Bacterial pneumonia 8.7% (p.o.), 3.7% (i.v.) Septicemia (other) 4.3% (p.o.), 3.7% (i.v.) Septicemia linked to dialysis catheter 0% (p.o.), 3.7% (i.v.) Septic arthritis 0% (p.o.), 3.7% (i.v.) Herpes zoster/CMV Pneumonia 4.3% (p.o.), 3.7% (i.v.) Herpes zoster/CMV Retinitis 4.3% (p.o.), 0% (i.v.) Papovavirus multifocal leukoencephalitis 3.7% (p.o.), 0% (i.v.) Patients with at least one side effect 69.6% (p.o.), 66.7% (i.v.) No. of side effects n = 23 (p.o.), n = 21 (i.v.) Death related to treatment side effects 26.1% (p.o.), 11.1% (i.v.) Hemorrhagic cystitis 8.7% (p.o.), 3.7% (i.v.) Transient aplasia 7.4% (p.o.), 4.3% (i.v.) Amenorrhea 20% (p.o.), 50% (i.v.) Nausea 3.7% (p.o.), 0% (i.v.) Dysmyelopoesis 0% (p.o.), 4.3% (i.v.) CS-related side effects 8.7% (p.o.), 7.4% (i.v.) Diabetes 4.3% (p.o.), 3.7% (i.v.) Glaucoma 0% (p.o.), 3.7% (i.v.) Osteoporosis with fractures 4.3% (p.o.), 0% (i.v.) Infections 69.6% (p.o.), 40.7% (i.v.) Psychiatric disorders 0% (p.o.), 3.7% (i.v.) Atherosclerosis 0% (p.o.), 3.7% (i.v.)

633

Cyclophosphamide

Trial

Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic a ntibodyassociated vasculitis and renal involvement: a prospective, randomized study

Substance

Group A (n = 22): 0.75 g/m2 cyclophosphamide (CYC) i.v. every 4 weeks for 1 year Group B (n = 25): Oral 2 mg/kg CYC/day for 1 year Concomitant medication: I.v. methylprednisolone 0.5 g on days 1–3 p.o. 1 mg/kg prednisolone day 4–day 14 Tapered by 10 mg/week to 30 mg/day Tapered by 5 mg/week to 15 mg/day Tapered by 2.5 mg/week to 30 mg/day Stop of treatment after 1 year Treatment continued if remission not achieved for at least 6 months and ANCA titers not below 1:64 Concomitant medication (only i.v. Cyc): Antiemetic drugs; alizapride or ondansetron 3 L of fluid was administered on the day of CYC treatment No prophylaxis for infectious complications such as pneumocystis carinii pneumonia, tuberculosis, or fungal infections

Result

I.v. and oral cyclophosphamide administration were equally effective, i.v. CYC with lower toxicity concerning rate of leukopenia, severe infections and gonadal function

Patients

47 patients with systemic vasculitis with first manifestations of: Wegener’s disease (WG, n = 22) Microscopic Polyangiitis (MPA, n = 25) Diagnosed by the ACR-criteria for WG or the presence of nectrotizing pauci-immune vasculitis or glomerulonephritis without granuloma for MPA Further inclusion criteria: Renal involvement (proteinuria, erythrocyturia) Positive cANCA (WG) Positive c- or pANCA (MPA) Granulomatous inflammation evident on histology (WG) Major exclusion criterion: Creatinine > 200 µmol/L

Authors

Haubitz M, Schellong S, Göbel U, Schurek HJ, Schaumann D, Koch KM, Brunkhorst R

Publication

Arthritis Rheum. 1998;41(10):1835–1844

Follow up

12 months

634

Note

Cyclophosphamide

Prednisolone dose not different between the two groups after 3–6–9–12 months Remission n = 21 (p.o.), n = 22 (i.v.) Time to remission 1.5–12 months (p.o.), 2–9 months (i.v.) Improvement of renal function 64% (p.o.), 59% (i.v.) Renal survival after 2–3 years 64% (p.o.), 59% (i.v.) Gonadal toxicity, leukopenia and severe infections significantly reduced in the i.v. group compared with the p.o. treated group Relapse during CYC, n = 3 (p.o.), n = 5 (i.v.) Organ manifestation: Kidney n = 3 (p.o.), n = 4 (i.v.) Eye n = 1 (p.o.), n = 1 (i.v.) Arthralgia n = 1 (p.o.), n = 1 (i.v.) Ear–nose throat n = 1 (p.o.), n = 0 (i.v.) B symptoms n = 2 (p.o.), n = 3 (i.v.) Outcome complete remission n = 3 (p.o.), n = 4 (i.v.) Partial remission n = 1 (p.o.), n = 0 (i.v.) Oral prednisolone dose at 12 months 3 mg/day (p.o.), 4 mg/day (i.v.)

Adverse events

Nausea, partly with vomiting n = 5 (p.o.), n = 11 (i.v.) FSH + 29 IU/L (p.o.), + 14.6 IU/L (i.v.) Death n = 3 (p.o.), n = 0 (i.v.) Leukopenia 60% (p.o.), 18% (i.v.) Lymphopenia 86% (p.o.), 47% (i.v.) Nausea n = 5 (p.o.), n = 11 (i.v.)

635

Cyclophosphamide

CHUSPAN-Trial Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: A prospective trial comparing glucocorticoids and 6 or 12 i.v. cyclophosphamide pulses in 65 patients CHUSPAN: Churg Strauss and Polyarterritis nodosa Substance

All patients: Glucocorticoids 15 mg/kg for 3 days Then 1 mg/kg/day glucocorticoids orally for 3 weeks Glucocorticoids tapered by 5 mg every 10 days until 0.5 mg/kg Then tapered by 2.5 mg every 10 days until 15 mg/day Glucocorticoids <10 mg, reduced by 1 mg every 10 days until being definitively stopped Cyclophosphamide: 3 × 0.6 g/m2 cyclophosphamide every 2 weeks, subsequently administered monthly Six pulses (n = 31) 12 pulses (n = 34) Concomitant medication: CD4 <300/mm3 ³ cotrimoxazole Uromitexan Bisphosphonates for osteoporosis

Result

A lower relapse probability and higher event-free survival for the 12-, versus the 6-Cyclophosphamide pulse group was demonstrated

Patients

65 patients with Polyarteritis nodosa (PAN, n = 18) Microscopic polyangiitis (MPA, n = 47) Histologically proven or Meeting the ACR classification criteria and the CHC nomenclature for MPA Inclusion with ≥1 criteria of poor prognosis according to Five Factor Score Serum creatinine > 1.58 mg/dL Proteinuria > 1 g/day Presence of severe gastrointestinal tract involvement Cardiomyopathy and/or Central nervous system involvement ANCA-positive n = 37

Authors

Guillevin L, Cohen P, Mahr A, Arène JP, Mouthon L, Puéchal X, Pertuiset E, Gilson B, Hamidou M, Lanoux P, Bruet A, Ruivard M, Vanhille P, Cordier JF

Publication

Arthritis Rheum. 2003;49(1):93–100

Follow up

36 months

636

Cyclophosphamide

Note

Complete remission 86% (MPA, 12 pulses), 100% (PAN, 12 pulses), 74% (MPA, 6 pulses), 100% (PAN, 6 pulses) Death 21% (MPA, 12 pulses), 0% (PAN, 12 pulses), 26% (MPA, 6 pulses), 17% (PAN, 6 pulses) Relapses 21% (MPA, 12 pulses), 17% (PAN, 12 pulses), 37% (MPA, 6 pulses), 50% (PAN, 6 pulses) Events (relapse and/or death) 39% (MPA, 12 pulses), 17% (PAN, 12 pulses), 68% (MPA, 6 pulses), 58% (PAN, 6 pulses) Event occurring after the end of CYC 22% (MPA, 12 pulses), 17% (PAN, 12 pulses), 67% (MPA, 6 pulses), 58% (PAN, 6 pulses)

Adverse events

Non insulin-dependent diabetes n = 1 (6 pulses), n = 2 (12 pulses) Insulin-dependent diabetes n = 1 (6 pulses), n = 0 (12 pulses) Femoral osteonecrosis n = 3 (6 pulses), n = 1 (12 pulses) Vertebral fracture n = 3 (6 pulses), n = 1 (12 pulses) Cushing’s syndrome n = 1 (6 pulses), n = 3 (12 pulses) Obesity n = 1 (6 pulses), n = 2 (12 pulses) Cataract n = 1 (6 pulses), n = 0 (12 pulses) Oesophagitis n = 1 (6 pulses), n = 1 (12 pulses) Myopathy n = 2 (6 pulses), n = 0 (12 pulses) Arterial hypertension n = 0 (6 pulses), n = 1 (12 pulses) Amenorrhea n = 0 (6 pulses), n = 1 (12 pulses) Leukopenia n = 0 (6 pulses), n = 1 (12 pulses) Cardiomyopathy n = 0 (6 pulses), n = 1 (12 pulses) Skin allergy to Mesna n = 0 (6 pulses), n = 1 (12 pulses) Adrenal insufficiency n = 0 (6 pulses), n = 1 (12 pulses) Mild thrombocytopenia n = 1 (6 pulses), n = 0 (12 pulses) Abdominal abscess (Staph. aureus) n = 0 (6 pulses), n = 1 (12 pulses) Cellulitis (hand) n = 1 (6 pulses), n = 0 (12 pulses) Bacterial sacroiliitis n = 1 (6 pulses), n = 0 (12 pulses) Cytomegalovirus pancreatitis n = 0 (6 pulses), n = 1 (12 pulses) Herpes zoster, n = 1 (6 pulses), n = 3 (12 pulses) Septicaemia on indwelling catheter 0 (6 pulses), 1 (12 pulses) Bacterial pneumonia n = 1 (6 pulses), n = 0 (12 pulses) Fungal infection n = 1 (died, 6 pulses), n = 0 (12 pulses) Pneumonia n = 1 (6 pulses), n = 0 (12 pulses) Sinusitis n = 1 (6 pulses), n = 0 (6 pulses) Methotrexate pneumonia n = 1 (6 pulses), n = 0 (12 pulses) Skin allergy to i.v. Immunoglobulins n = 1 (6 pulses), 0 (12 pulses) Lymphoma n = 1 (death, 6 curses), n = 0 (12 pulses) Prostate cancer n = 1 (death, 6 pulses), n = 0 (12 pulses) Malabsorption (small bowel resection) n = 3 (6 pulses), n = 1 (12 pulses) Pulmonary embolism n = 1 (6 pulses), n = 0 (12 pulses) Thrombosis n = 1 (6 pulses), n = 0 (12 pulses)

637

Cyclophosphamide

CYCAZAREMTrial

A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic auto-antibodies CYCAZAREM: Cyclophosphamide versus Azathioprine as Remission Maintenance Therapy for ANCA-Associated Vasculitis Study

Substance

Induction of remission: 3 months of 2 mg/kg cyclophosphamide/day p.o. +1 mg/kg prednisolone/day Tapered to 0.25 mg/kg/day by 12 weeks Maintenance therapy (after begin of remission): 1.5 mg/kg cyclophosphamide/day (CYC, n = 71) Or 2 mg/kg azathioprine/day (AZA, n = 73) After 12 months (both groups): 1.5 mg/kg azathioprine/day +7.5 mg prednisolone/day Concomitant medication: 10 mg prednisolone/day Prophylaxis against corticosteroid-induced gastritis, fungal infection, and Pneumocystis carinii pneumonia was recommended but not mandatory Previous medication: No cytotoxic drug within previous year

Result

In patients with generalized vasculitis the substitution of cyclophosphamide by azathioprine after remission was clinically equivalent to the continuation with cyclophosphamide and did not increase the rate of relapse

Patients

Patients with a new diagnosis of generalized vasculitis Wegener’s granulomatosis n = 95 Microscopic polyangiitis n = 60 According to CHC-definitions modified earlier by the authors Renal involvement and/or threatened loss of function of other vital organ Presence of ANCA Serum creatinine £5.7 mg/dL Patients without ANCA only in case of histologically proven vasculitis (n = 10) DEI/BVAS at study start: 6.1/18.9 (means)

Authors

Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C; European Vasculitis Study Group

Publication

N Engl J Med. 2003;349(1):36–44

Follow up

18 months

Note

Relapse rate 15.5% (AZA), 13.7% (CYC) Increase of glomerular filtration rate 7.5 mL/min (AZA), 23.5 mL/min (CYC)

638

Adverse events

Cyclophosphamide

Leukopenia mild 30% (Induction), 21% (AZA), 32% (CYC) Severe 7% (Induction), 1% (AZA), 3% (CYC) Anaemia mild 0% (Induction), 2% (AZA), 1% (CYC) Anaemia severe 0% (Induction), 0% (AZA), 0% (CYC) Diabetes mild 3% (Induction), 2% (AZA), 2% (CYC) Diabetes severe 2% (Induction), 1% (AZA), 0% (CYC) Infection mild 3% (Induction), 9% (AZA), 10% (CYC) Infection severe 4% (Induction), 4% (AZA), 3% (CYC) Bone fracture mild 0% (Induction), 0% (AZA), 0% (CYC) Severe 0% (Induction), 2% (AZA), 2% (CYC) Gastrointestinal events mild 3% (Induction), 3% (AZA), 2% (CYC) Gastrointestinal severe 0% (Induction), 0% (AZA), 3% (CYC) Cardiovascular events mild 0% (Induction), 1% (AZA), 1% (CYC) Cardiovascular events severe 4% (Induction), 2% (AZA), 2% (CYC) Cystitis mild 0% (Induction), 1% (AZA), 3% (CYC) Cystitis severe 0% (Induction), 0% (AZA), 0% (CYC) Allergy mild 3% (Induction), 4% (AZA), 2% (CYC) Allergy severe 0% (Induction), 1% (AZA), 0% (CYC) Amenorrhea mild 0% (Induction), 0% (AZA), 0% (CYC) Amenorrhea severe 0% (Induction), 1% (AZA), 2% (CYC) Alopecia, mild 3% (Induction), 0% (AZA), 2% (CYC) Alopecia severe 0% (Induction), 0% (AZA), 0% (CYC) Psychiatric events 3% (Induction), 0% (AZA), 0% (CYC)

Cyclophosphamide

639

NORAM Trial

Randomized trial of Cyclophosphamide versus Methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis NORAM: Treatment of Non-Renal Wagener’s granulomatosis

Substance

Group A (n = 51): 15 mg methotrexate/week p.o. Escalating to a maximum of 20–25 mg/week by 12 weeks Month 10: tapered and discontinued by month 12 Group B (n = 49): 2 mg/kg cyclophosphamide/day p.o. (CYC, max. 150 mg/day) until remission (minimum 3, maximum 6 months) Then reduction to 1.5 mg/kg/day Concomitant medication: 1 mg/kg prednisone Tapered to 7.5 mg by 6 months Discontinued after 12 months Antimicrobial prophylaxis optional

Result

Methotrexate was as effective as cyclophosphamide in the induction of remission of early ANCA associated vasculitis, but less effective in patients with extensive disease and pulmonary involvement. More relapses observed with methotrexate than with the cyclophosphamide after termination of treatment. High relapse rates in both treatment arms after end of treatment at 12 months

Patients

100 patients with newly diagnosed ANCA associated vasculitis Wegener’s granulomatosis (n = 89) or microscopic polyangiitis (n = 6), according to the CHC-definitions Involvement of one or more organ systems Serum creatinine levels <150 µmol/L Additional inclusion criteria: ESR > 45 mm/h and/or CRP > 2 × the upper limit of normal values, or ANCA positivity Histologic confirmation of WG or MPA n = 51 c- or p-ANCA positive n = 86 PR3- or MPO-ANCA positive n = 82 DEI (median) 11 BVAS (median) 15 VDI (median) 0

Authors

De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, Gross WL, Luqmani R, Jayne DR

Publication

Arthritis Rheum. 2005;52(8):2461–2469

Follow up

18 months

Cyclophosphamide

640

Note

Remission at 6 months 89.8% (MTX), 93.5% (CYC) MTX median remission delayed in patients with entry disease extent index (DEI) above median of 10 and lower respiratory tract involvement Relapse rate/18 months 69.5% (MTX), 46.5% (CYC) Time remission-relapse 13 months (MTX), 15 months (CYC) Death n = 2 (MTX), n = 2 months (CYC)

Adverse events

Allergy n = 1 (MTX), n = 0 (CYC) Thrombocytopenia n = 0 (MTX), n = 1 (CYC) Mild infections n = 5 (MTX), n = 5 (CYC) Severe infections n = 4 (MTX), n = 4 (CYC) Leukopenia n = 3 (MTX), n = 14 (CYC) Multiple leukopenia n = 0 (MTX), n = 6 (CYC) Alopecia n = 0 (MTX), n = 1 (CYC) Cataract n = 0 (MTX), n = 1 (CYC) Osteoporosis n = 0 (MTX), n = 1 (CYC) Avascular necrosis n = 1 (MTX), n = 0 (CYC) Diabetes n = 0 (MTX), n = 3 (CYC) Infertility n = 1 (MTX), n = 0 (CYC) Hypertension n = 3 (MTX), n = 1 (CYC) Liver dysfunction n = 7 (MTX), n = 1 (CYC) Nausea n = 1 (MTX), n = 0 (CYC) Hypersensitivity n = 0 (MTX), n = 1 (CYC)

641

Cyclophosphamide

CYCLOPS-Trial Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody–associated vasculitis Substance

Pulse cyclphosphamide (n = 76): Three pulses at 15 mg/kg cyclphosphamide (CYC) i.v. given 2 weeks apart After that, pulses in 3 weeks intervals at 15 mg/kg i.v. or 5 mg/orally on 3 consecutive days, until remission Then for another 3 months Maximum CYC dose 1.2 g/pulse Or Daily oral cyclphosphamide group (n = 73): 2 mg/kg cyclphosphamide/day, until remission Then 1.5 mg/kg/day for another 3 months. Maximum daily oral dose 200 mg. Age- and leukocyte nadir-adapted reductions applied Both groups: CYC continuation for 3 months after remission, then change to azathioprine, 2 mg/kg/day, maximum daily dose 200 mg Concomitant therapy: 1 mg/kg/day prednisolone Tapered to 12.5 mg at the end of month 3 Tapered to 5 mg at the end of 18 months Pneumocystis jiroveci prophylaxis recommended for all patients calcium and vitamin D supplementation for patients >50 years

Result

There was no difference in the pulse or oral cyclophosphamide therapy groups with respect to induced remissions in this trial of ANCA-associated vasculitis. Pulse therapy resulted in a lower cumulative cyclophosphamide dose and showed a lower incidence of leucopenia, with no difference in other adverse events during the observation period

Patients

149 patients with systemic vasculitis diagnosed according to the CHCdefinitions, modified earlier by the authors Wegener’s granulomatosis (n = 56) Microscopic polyangiitis (n = 71) Renal limited vasculitis (n = 22) Renal involvement of active vasculitis with at least one of the following: Serum creatinine 1.7–5.7 mg/dL Biospy of necrotizing glomerulonephritis Erythrocyte castas Hematuria Proteinuria + confirmatory histology or ANCA ANCA-negative n = 3 Confirmatory biopsy n = 117 BVAS at study start: 20 (i.v.), 21 (oral) DEI at study start: 2.2 (i.v.), 2.2 (oral)

Authors

de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO; EUVAS (European Vasculitis Study Group)

Publication

Ann Intern Med. 2009;150(10):670–680

Cyclophosphamide

642

Follow up

18 months (median)

Note

Patients with achieved remission n = 131 Remission: at 3 months: n = 49 (i.v.), n = 43 (oral) at 6 months: n = 61 (i.v.), n = 55 (oral) at 9 months: n = 61 (i.v.), n = 58 (oral) at 12 months: n = 61 (i.v.), n = 55 (oral) at 15 months: n = 61 (i.v.), n = 54 (oral) at 18 months: n = 61 (i.v.), n = 54 (oral) End stage renal disease: at 3 months: n = 1 (i.v.), n = 0 (oral) at 6 months: n = 4 (i.v.), n = 0 (oral) at 9 months: n = 4 (i.v.) n = 0 (oral) at 12 months: n = 4 (i.v.), n = 1 (oral) at 15 months: n = 4 (i.v.), n = 1 (oral) at 18 months: n = 5 (i.v.), n = 1 (oral) Time to remission (median, both groups): 3 months Time to remission: no difference between groups, hazard ratio 1.098 Major relapses within 9 months n = 7 (i.v.), n = 3 (oral) Minor relapses within 9 months n = 6 (i.v.), n = 3 (oral) Improvement of glomerular filtration rate (median, estimated): 32 => 45 mL/min per 1.73 m2 (i.v.), 29 => 45 mL/min per 1.73 m2 (oral) Prompt and sustained reduction of BVAS to 1–2 (estimated according to Figure 4, no detailed numbers provided) in both groups Absolute CYC-dose (median) 15.9 (i.v.), 8.2 (oral)

Adverse events

Any adverse events: n = 58 (i.v.), n = 56 (oral) Mild or moderate episodes n = 77 (i.v.), n = 101 (oral) Severe or life-threatening n = 19 (i.v.), n = 31 (oral) Death (total) n = 5 (i.v.), n = 6 (oral) Death associated to active vasculitis n = 3 (i.v.), n = 7 (oral) Leukopenia n = 20 (i.v.), n = 33 (oral) Patients with ³2 episodes n = 4 (i.v.), n = 15 (oral) Episodes (total) n = 28 (i.v.), n = 59 (oral) Infection: n = 20 (i.v.), n = 21 (oral) Mild or moderate n = 15 (i.v.), n = 19 (oral) Severe or life-threatening n = 7 (i.v.), n = 10 (oral) New or worsening diabetes n = 8 (i.v.), n = 4 (oral) Liver dysfunction n = 2 (i.v.), n = 3 (oral) Alopecia n = 0 (i.v.), n = 2 (oral) Hypersensitivity reaction to azathioprine n = 10 (i.v.), n = 5 (oral) Osteoporosis n = 2 (i.v.), n = 0 (oral) Cancer n = 1 (i.v.), n = 0 (oral) Hemorrhagic cystitis n = 2 (i.v.), n = 1 (oral) Amenorrea n = 1 (i.v.), n = 0 (oral) Cataract n = 0 (i.v.), n = 3 (oral) Hypertension n = 0 (i.v.), n = 2 (oral) Cardiovascular events n = 3 (i.v.), n = 2 (oral) Pulmonary embolism or deep venous thrombosis n = 2 (i.v.), n = 4 (oral) Other n = 15 (i.v.), n = 18 (oral)

643

Cyclophosphamide

Trial

Churg-Strauss syndrome with poor-prognosis factors: A prospective multicenter trial comparing glucocorticoids and 6 or 12 cyclophosphamide pulses in 48 patients

Substance

Initial Corticosteroid therapy: Three consecutive i.v. pulses 15 mg/kg methylprednisolone on days 1–3 Then oral prednisone (1 mg/kg/day) for 3 weeks Tapered by 5 mg every 10 days to 0.5 mg/kg/day Then further tapered by 2.5 mg every 10 days to 15 mg/day Finally tapered by 1 mg every 10 days to the minimal effective dose 1 g calcium/day Ater randomization: Six pulses 0.6 g CYC/m2 (n = 23) Or 12 pulses 0.6 g CYC/m2 (n = 25) Pulses every 2 weeks for 1 month Then CYC pulses (0.6 g/m2) every 4 weeks Concomitant medication: 400 IU vitamin D3 Oral daily or weekly bisphosphonates Mesna at the same dose as CYC Cotrimoxazole (400/80 mg) was strongly recommended if CD4 count £300/mm3

Result

12 cyclophosphamide pulses resulted in fewer relapses in severe CSS than a 6-pulse regimen

Patients

48 patients with recently diagnosed, untreated Churg-Strauss syndrome, satisfying the CHC-definitions Biopsy-proven necrotizing vasculitis Eosinophilia >1,500/mm3 or, >10% Asthma, and clinical manifestations of systemic vasculitis Fulfilled ³4 ACR-criteria: n = 38 At least one factor associated with poor outcome according to Five Factor Score: Creatinine >140 mmol/L (1.58 mg/dL) Proteinuria >1 g/day; or Central nervous system or Gastrointestinal, or myocardial involvement

Authors

Cohen P, Pagnoux C, Mahr A, Arène JP, Mouthon L, Le Guern V, André MH, Gayraud M, Jayne D, Blöckmans D, Cordier JF, Guillevin L; French Vasculitis Study Group

Publication

Arthritis Rheum. 2007;57(4):686–693

Follow up

36 months

644

Cyclophosphamide

Note

Clinical remission 91.3% (6 pulses), 84% (12 pulses) Failure 8.7% (6 pulses), 16% (12 pulses) Patients who relapsed 78.2% (6 pulses), 52% (12 pulses) Major relapses 55.5% (6 pulses), 61.5% (12 pulses) Minor relapses 77.7% (6 pulses), 46.1% (12 pulses) Patients with severe side effect 47.8% (6 pulses), 52% (12 pulses) Death 8.7% (6 pulses), 8% (12 pulses)

Adverse events

Infections n = 11 (Group A), n = 10 (12 pulses) GC-induced osteoporotic fractures n = 3 (6 pulses), n = 5 (12 pulses) GC-induced diabetes mellitus n = 2 (6 pulses), n = 1 (12 pulses) Venous thromboembolism n = 1 (6 pulses), n = 1 (12 pulses) GC-induced osteonecrosis n = 1 (6 pulses), n = 1 (12 pulses) Amenorrhea n = 1 (6 pulses), n = 2 (12 pulses) Glaucoma n = 1 (6 pulses), n = 1 (12 pulses) GC-induced cataract n = 1 (6 pulses), n = 1 (12 pulses) Neutropenia <1,000/mm3 n = 1 (6 pulses), n = 1 (12 pulses) Miscellaneous n = 1 (6 pulses), n = 6 (12 pulses)

645

Methotrexate

Trial

The treatment of Wegener’s granulomatosis with glucocorticoids and methotrexate

Substance

Followed by 0.3 mg/kg/week MTX therapy (max. 15 mg, increased to max. 25 mg/week) Increased every 1–2 week to max. 25 mg/week Concomitant medication: Oral prednisolone 1 mg/kg/day Tapered down in case of significant improvement, after 1 month, eventually to alternate day schedule Previous medication: Various medical therapies Cyclophosphamide n = 2

Result

Weekly low-dose MTX was an effective alternative to cyclophosphamide in patients without immediately life-threatening disease or with ineffective or seriously toxic prior cyclophosphamide treatment

Patients

29 patients with Wegener’s granulomatosis With current of past evidence of upper and/or lower airway disease And/or other organ involvement Without immediately life-threatening disease

Authors

Hoffman GS, Leavitt RY, Kerr GS, Fauci AS

Publication

Arthritis Rheum. 1992;35(11):1322–1329

Follow up

25 months

Note

Remission in 69% n = 20 Marked improvement in 76% n = 22 Disease progression n = 5 Sustained remission after discontinuation of Prednisolone n = 13 Relapse after discontinuation of Prednisolone n = 2

Adverse events

Abnormal liver function tests 10% Pneumocystis carinii pneumonia 10% MTX pneumonitis 7% Oral ulcers and rash 3%

Methotrexate

646

Trial

An analysis of 42 Wegener’s granulomatosis patients treated with methotrexate and Prednisone

Substance

Low-dose 0.3 mg/kg methotrexate/(MTX) week (max. 15 mg at start, increased to 20–25 mg/week) Maintained at this dose for 1 year in the case of remission Then taper of 2.5 mg/month until discontinuation, if possible + approximately 1 mg/kg prednisone/day Begin of taper after 4 weeks, to 0, if possible Previous medication: No increase in immunosuppressive drugs £4 weeks No therapy 16% Prednisone alone 33% Prednisone + trimetroprim/sulfamethoxazole 10% Prednisone + cyclophosphamide 10% Azathioprine 10%

Result

Weekly low-dose methotrexate was an effective alternative in patients with Wegener’s granulomatosis without immediately life-threatening disease or with prior serious cyclophosphamide-associated toxicity

Patients

42 patients with biopsy proven active Wegener’s granulomatosis (i.e., necrotizing vasculitis, granulomatous inflammation) No immediately life-threatening disease Patients with ineffective pre-treatment 62% (n = 26) Patients without therapy for more or more weeks before study 38% (n = 16) No renal failure/insufficiency

Authors

Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS, Hallahan CW, Fauci AS

Publication

Arthritis Rheum. 1995;38(5):608–613

Follow up

38 months

Note

Patients surviving 93% Remission of disease 71% Relapses after achieving remission 36% Median time to remission 4.2 months Median time to relapse in patients achieving remission 29 months Induced remission after second course of MTX plus prednisone 75% Discontinuation of prednisolone 7 months

Adverse events

Elevated transaminase levels 24% Leukopenia 7% Opportunistic infections 9.5% MTX pneumonitis 7% Stomatitis 2%

647

Methotrexate

Trial

Therapy for the maintenance of remission in 65 patients with generalized Wegener’s granulomatosis. Methotrexate versus trimethoprim/ sulfamethoxazole

Substance

Induction of remission: 2 mg/kg cyclophosphamide p.o./day or I.v. 650 mg/m2 cyclophosphamide pulse + 1 mg/kg prednisone/day Until Maintenance of remission (after beginning of complete or partial remission): 0.3 mg/kg methotrexate/week i.v., alone (group A; n = 22) Trimethoprim/sulfamethoxazole, 160/800 mg, alone (group B; n = 24) Methotrexate plus concomitant prednisone (median dose 3 mg/day, group C; n = 11) Trimethoprim/sulfamethoxazole + prednisone (median dose 10 mg/day, group D; n = 8)

Result

Low-dose methotrexate, with or without concomitant prednisone, was effective in most patients and more effective than trimethoprim/ sulfamethoxazole for the maintenance of remission in patients with generalized WG after induction of remission with cyclophosphamide

Patients

65 patients with generalized Wegener’s granulomatosis Diagnosis according to ACR criteria and CHC definitions Histologically proven disease n = 58 Serum creatinine £150 mmol/L cANCA positivity in n = 61; in all seven patients without histologic prove of disease

Authors

de Groot K, Reinhold-Keller E, Tatsis E, Paulsen J, Heller M, Nölle B, Gross WL

Publication

Arthritis Rheum. 1996;39(12):2052–2061

Follow up

33 months

Note

Partial or complete remission: Group A: 86% (n = 19), DEI decrease (median) 2; median time of remission 16 months (6–30) Group B: 58% (n = 14), DEI (0 at start) change 0; median time of remission 36.5 months (6–73) Group C: 91% (n = 10), DEI decrease 1.5; median time of remission 22 months (5–34) Group D: 0% (n = 8)

Adverse events

Nausea n = 6 (Groups A + C), n = 0 (Groups B + D) Leukopenia n = 5 (Groups A + C), n = 5 (Groups B + D) Rise in transaminase levels n = 2 (Groups A + C), n = 0 (Groups B + D) Mucositis n = 1 (Groups A + C), n = 0 (Groups B + D) Rise in creatinine levels n = 0 (Groups A + C), n = 4 (Groups B + D) MTX pneumopathy n = 0 (Groups A + C), n = 4 (Groups B + D) Additional folinic acids n = 11 (Groups A + C), n = 0 (Groups B + D) Opportunistic infections n = 0 (Groups A + C), n = 0 (Groups B + D) Dosage reduction due to adverse events n = 6 (Groups A + C), n = 0 (Groups B + D) Withdraw. due to adverse events n = 2 (Groups A + C), n = 3 (Groups B + D)

Methotrexate

648

Trial

Induction of remission in Wegener’s granulomatosis with low dose methotrexate

Substance

0.3 mg/kg methotrexate/weekly i.v. + low dose prednisone 10 mg/day Previous medication: Previous untreated disease n = 11 Oral cyclophosphamide + prednisone n = 4 Azathioprine + prednisone n = 1 Dapsone + prednisone n = 1

Result

Weekly low dose methotrexate in combination with low dose corticosteroids lead to remission in almost 60% without significant side effects

Patients

17 patients with non life threatening, generalized Wegener’s granulomatosis Serum creatinine £150 mmol/L

Authors

de Groot K, Mühler M, Reinhold-Keller E, Paulsen J, Gross WL

Publication

J Rheumatol. 1998;25(3):492–495

Follow up

24.5 months (median)

Note

Complete remission n = 6 (median 24.5 months) Partial remission n = 4 Minor relapse n = 2 Major relapse n = 0 Non responders n = 7 Median Prednisone dose 1.75 mg/day (7.5 mg in non-responders; high concomitant Prednisone a general higher risk for non-response) Median time to discontinuation of Prednisone 7.5 months Median DEI at study start 5.5, at study end 0 (responders) De novo glomerulonephritis in five of the seven non-responders (high likelihood in patients with need for higher concomitant Prednisone) Relapse after initial response n = 2 (need for higher concomitant Prednisone at risk for non-response) Progressive disease despite MTX treatment n = 5

Adverse events

Nausea n = 1 Oral mucositis n = 1

Methotrexate

649

Trial

A staged approach to the treatment of Wegener’s granulomatosis: induction of remission with glucocorticoid and daily cyclophosphamide switching to methotrexate for remission maintenance

Substance

Induction of remission: 2 mg/kg cyclophosphamide/day + 1 mg/kg prednisone/day Maintenance of remission (after achieving remission): Prednisone tapered by 5 mg every other day in 1-week intervals until 60 mg every other day Then tapered by 2.5–5 mg/week until discontinuation Cyclophosphamide was discontinued at remission 3 mg/kg methotrexate/week (max. 15 mg/week and increased to 25 mg/week)

Result

Methotrexate-mediated maintenance of remission after cyclophosphamideand glucocorticoid-induced remission was effective in WG patients

Patients

31 Wegener’s granulomatosis patients 28 patients with biopsy-proven Wegener’s granulomatosis (necrotizing vasculitis, granulomatous inflammation) Three Wegener’s granulomatosis patients without biopsy-proven disease, diagnosed by all of: pos. cANCA, upper airways disease, active glomerulonephritis, ³1 other major organ system, after exclusion of infection All patients ANCA positive n = 27 cANCA, n = 4 pANCA/MPO No evidence of chronic renal insufficiency (serum creatinine >2.5 mg/dL at remission)

Authors

Langford CA, Talar-Williams C, Barron KS, Sneller MC

Publication

Arthritis Rheum. 1999;42(12):2666–2673

Follow up

16 months (median)

Note

Deaths, n = 0 Drop out because of toxicity, n = 2 Number surviving 100% Number achieving remission 100% Number with relapse after achieving remission 16% Median months to remission 3 Median months to taper to alternate-day Prednisone 4 Median months to discontinuation of Prednisone 8 Median months from remission to relapse for five patients 13 Median months Prednisone discontinued before relapse for five patients 8

Adverse events

Leukopenia requiring dosage reduction of Cyclophosphamide 10% Leukopenia requiring dosage reduction of Methotrexate 13% Methotrexate pneumonitis 6% Cystitis 6% Avascular necrosis 3% Cataracts 3% Diabetes mellitus 3% Cutaneous herpes zoster 13% Bacterial pneumonia 6%

Methotrexate

650

Trial

Use of methotrexate and glucocorticoids in the treatment of Wegener’s granulomatosis Long-term renal outcome in patients with glomerulonephritis

Substance

Low-dose 0.3 mg/kg methotrexate/week (max. 15 mg at start, increased to 20–25 mg/week) Maintained at this dose for 1 year in the case of remission Then taper of 2.5 mg/month until discontinuation, if possible, + 1 mg/kg prednisone/day Tapered after 4 weeks to 0, if possible

Result

The combination of methotrexate and prednisone was effective as initial therapy for patients with Wegener’s Granulomatosis and active glomerulonephritis

Patients

42 patients with Wegener’s Granulomatosis, fulfilling the ACR-criteria 21 with active glomerulonephritis All 42 patients with biopsy-proven WG With necrotizing vasculitis Granulomatous inflammatory changes Or both in a typical organ system All with active disease requiring therapy Important exclusion criteria: Life-threatening disease: Acute renal failure with serum creatinine <2.5 mg/dL Acute pulmonary haemorrhage with an arterial PO2 <70 mm Hgand/or DLCO <70% of predicted Presence of chronic liver disease Recent increase in immunosuppressive medication

Authors

Langford CA, Talar-Williams C, Sneller MC

Publication

Arthritis Rheum. 2000;43(8):1836–1840

Follow up

76 months (median)

Note

Renal remission n = 20 of 21 patients with glomerulonephritis Stable or improved creatinine levels at 1 and 6 months after study entry Stable (n = 6) or improved (>0.2 mg/dL; n = 12) creatinine levels in 18 patients Death n = 1 (week 14, of opportunistic infection) Relapse n = 11; remission in seven after retreatment with MTX Long-term decline of renal function n = 2

Methotrexate

651

Trial

High rate of renal relapse in 71 patients with Wegener’s granulomatosis under maintenance of remission with low-dose methotrexate

Substance

Induction of remission: 2 mg/kg/day cyclophosphamide (CYC) p.o. With equivalent dose of uromitexan, in three to four doses per day + 1 mg/kg glucocorticosteroid/day Tapered weekly by 10–20 mg Tapered further by 2.5 mg/3 weeks to 5 mg/day In stable remission, further reduction by 1 mg/month until discontinuation Maintenance of remission: At £7.5 mg glucocorticosteroid and persistent complete or partial remission for ³3 months 7.5 mg methotrexate (MTX)/week i.v. with escalation to 0.3 mg/kg/week (mean dosage of 22.5 mg) Seven patients with glucocorticosteroid dose of ³7.5 included because of persistent leukopenia under CYC MTX tapered by 2.5 mg/month in case of persistent complete remission for 6 months and no glucocorticosteroids

Result

Efficacy of methotrexate in the long-term maintenance of remission was limited by relapses during ongoing treatment in 36.6% of patients. No additive protective effect with regard to maintenance of remission of glucocorticosteroids was observed

Patients

71 patients, fulfilling the ACR-criteria for Wegener’s granulomatosis (WG) Biopsy: necrotizing vasculitis, granuloma, or both n = 58 In the patients with no histologic confirmation, the diagnosis was made on the basis of the typical history, characteristic clinical findings, and a positive cANCA on immunofluorescence, with anti-PR3-specifity Positive c/PR3-ANCA n = 69 Enrollment within first WG episode n = 53 Enrollment after relapse already n = 18 Mean DEI at diagnosis/start of study 10.1/2.1

Authors

Reinhold-Keller E, Fink CO, Herlyn K, Gross WL, De Groot K

Publication

Arthritis Rheum. 2002;47(3):326–332

Follow up

77 months

Note

Media duration of prior CYC 10 months n = 70 out of 71 patients with concomitant glucocorticosteroid therapy during induction therapy with CYC, n = 55 (mean dose of 5.9 mg/day) at study start Relapse 36.6% (n = 26) after a mean of 19.4 months, within mean observation period of 25.2 months 18 of these relapses classified as major, 16 of them with switch to CYC 65.4% (n = 17) of these patients had terminated glucocorticosteroid therapy at the time of relapse Relapses mainly in the initially involved organ systems: 18/26 with initial manifestation in the ear, nose, throat tract 16/26 with initial manifestation in the kidney In 15/26 significant increase in ANCA titer prior or parallel to relapse MTX cessation because of persistent leukopenia n = 2

652

Methotrexate

Trial

Churg-Strauss syndrome – successful induction of remission with methotrexate and unexpected high cardiac and pulmonary relapse ratio during maintenance treatment

Substance

Induction of remission: With 0.3 mg/kg methotrexate (MTX)/week i.v., and concomitant folinic acid given on the next day (induction, n = 11) Maintenance of remission: (maintenance) n = 25, including the n = 8 of the n = 11 with successful MTX induction therapy With p.o. cyclophosphamide (CYC), n = 11 With pulse CYC, n = 3 With azathioprine, n = 1 With prednisolone alone, n = 2 Initial MTX dosage 7.5 mg/week Increased by 2.5 mg every week to 0.3 mg/kg/day Plus individual doses of prednisolone, increased to 1 mg/kg/day in cases of BVAS ³10 or DEI ³6 Taper: −10 mg every 3 days until 20 mg/day Then −2.5 mg/week until 5 mg, then 1 mg/month Prednisolone (median) at start: 10 mg/day (induction) 8 (maintenance)

Result

Methotrexate was safe and effective for the induction of remission in non-life-threatening Churg-Strauss syndrome. Limited efficacy of methotrexate to prevent cardiac and pulmonary relapses within the observation period

Patients

28 consecutive patients with Churg-Strauss syndrome Diagnosed according to the ACR-criteria and the CHC-definition Major exclusion criteria: Life threatening disease Serum creatinine >1.5 mg/dL Leucopenia <4,000 mL Thrombocytopenia <100,000 mL Hemoglobin <10 g/dL Biospy proven patients (n, positive/negative): 7/4 (induction), 16/7 (maintenance) ANCA-positive patients (n, positive/negative): 0/11 (induction), 4/19 (maintenance) Median DEI/BVAS/FFS at start of study 7/6/0

Authors

Metzler C, Hellmich B, Gause A, Gross WL, de Groot K

Publication

Clin Exp Rheumatol. 2004;22(6 Suppl 36):S52–S61

Follow up

48 months (median)

653

Methotrexate

Note

Induction of remission after MTX treatment n = 8 (n = 6 complete remission) Median time to remission 5 months Remission maintained n = 12 Eight patients with major (six cardiac, five pulmonary events) and three with minor relapses Cumulative prednisone dose 6.2 g (during MTX induction), reduced by 53% (during MTX maintenance)

Adverse events

Pneumonitis n = 1 Upper respiratory tract infections n = 2 Urinary tract infection n = 1

654

Methotrexate

Trial

Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener’s granulomatosis

Substance

Induction of remission: 2 mg/kg cyclophosphamide p.o. + 1 mg/kg prednisone/day for 6 months Prednisone tapered by 10 mg every 3 days until 20 mg/day Followed by a 2.5 mg reduction/week until 5 mg/day and then of 1 mg/ month Maintenance of remission: LEF: After complete or stable partial remission ³3 months 20 mg leflunomide/day (100 mg for the first 3 days) until week 4 Then 30 mg leflunomide/day 4, n = 26 Or MTX: 7.5 mg methotrexate/week p.o. for 4 weeks 15 mg methotrexate/week p.o. for 4 weeks 20 mg methotrexate/week p.o. (n = 28) Concomitant medication: Folic acid once weekly at 10 mg, 24 h after MTX Concomitant prednisone £10 mg/day Tapered by 2.5 mg/month until 5 mg Then tapered by 1 mg/month Calcium 1 g/day and vitamin D 1,000 i.E./day

Result

Leflunomide 30 mg/day decreased the relapse rate in patients with Wegener’s granulomatosis. It was associated with an increased frequency of adverse events. Higher incidence of major relapses in the methotrexate group

Patients

44 patients with Wegener’s granulomatosis Diagnosed according to the ACR-criteria and CHC definitions Major exclusion criteria: Leucopenia <4,000/mL, haemoglobin <10 d/dL, thrombocytopenia <100,000/mL, serum creatinine >1.3 mg/dL Confirmative biopsy (positive/negative): 18/8 in the LEF, 18/10 in the MTX group ANCA (positive/negative): 23/3 in the LEF, 25/3 in the MTX group Median DEI at randomization: 0 in both groups

Authors

Metzler C, Miehle N, Manger K, Iking-Konert C, de Groot K, Hellmich B, Gross WL, Reinhold-Keller E; German Network of Rheumatic Diseases

Publication

Rheumatology (Oxford). 2007;46(7):1087–1091. Epub May 22, 2007

Follow up

25 months

655

Methotrexate

Note

Withdrawal LEF n = 6, MTX n = 2 Relapse rate LEF n = 6 (major n = 1), MTX n = 13 (major n = 7) Time point of relapse 7 months (LEF), 6 months (MTX) Premature termination of study because of higher incidence of major relapses in MTX-group

Adverse events

CNS granuloma n = 0 (LEF), n = 1 (MTX) Cold/fever 12% (LEF), 7% (MTX) Cough/bronchitis 8% (LEF), 0% (MTX) Chronic obstructive pulmonary disease 4% (LEF), 15% (MTX) Gastroenteritis/diarrhoea/abdominal pain 4% (LEF), 4% (MTX) Urinary tract infection 4% (LEF), 7% (MTX) Sinusitis 4% (LEF), 4% (MTX) Pneumonia 4% (LEF), 0 (MTX) Herpes zoster 4% (LEF), 0% (MTX) Erysipel 4% (LEF), 0% (MTX) Lumbalgia/disc-protrusion 4% (LEF), 1% (MTX) Arthralgia/myalgia 15% (LEF), 4% (MTX) Oedema 4% (LEF), 1% (MTX) Cardiac insufficiency 4% (LEF), 0% (MTX) Tachycardia 4% (LEF), 0% (MTX) Weakness/nausea 4% (LEF), 0% (MTX) Dry skin 0% (LEF), 4% (MTX) Thrombophlebitis 4% (LEF), 0% (MTX) Hypertension 8% (LEF), 0% (MTX) Leukopenia 8% (LEF), 0% (MTX) Cholecystectomy 0% (LEF), 4% (MTX) Removal of osteosynthetic material 4% (LEF), 0% (MTX) Peripheral neuropathy 4% (LEF), 0% (MTX) Leiomyosarcoma 4% (LEF), 0% (MTX)

656

Methotrexate

Trial

Azathioprine or methotrexate maintenance for ANCA-associated vasculitis

Substance

Induction of remission: 15 mg/kg methylprednisolone for 3 days Followed by oral 1 mg/kg prednisone for 3 weeks Tapered to a daily dose of 12.5 mg at 6 months and 5 mg/day at 18 months Complete discontinuation after the 24th month Three pulses of 0.6 g/m2 cyclophosphamide every 2 weeks Then every 3 weeks 0.7 g/m2 cyclophosphamide until remission Followed by three additional consolidation pulses 0.7 g/m2 cyclophosphamide (n = 201) Concomitant medication: Mesna and trimethoprim-sulfamethoxazol 80/400 or 160/800 mg, or (in case of intolerance) aerosolized pentamidine (300 mg every 3–4 weeks) Maintenance of remission (after achieving remission): Azathioprine (AZA, 2.0 mg/kg/day, n = 63) Or 0.3 mg/kg methotrexate (MTX)/day p.o. (increased every week by 2.5 mg, to 25 mg per week, n = 63) Starting 2–3 weeks after the last pulse 12 months of maintenance therapy Then withdrawal of MTX or AZA over a period of 3 months

Result

The primary hypothesis that methotrexate is less toxic than azathioprine was not supported. Both agents had similar efficacy and safety in patients with Wegener’s granulomatosis and microscopic polyangiitis after initial remission

Patients

159 eligible patients with active Wegener’s granulomatosis (WG) or microscopic Polyangiitis (MPA) Patients with WG meeting either ACR-criteria or CHC-definition and renal disease Involvement ³2 organs or 1 organ + general symptoms e.g. fever >38°C Patients with mPA meeting the CHC-definition and at least one item of the FFS Remission after induction therapy and subsequent randomization n = 126 Biopsy-proven WG with necrotizing vasculitis, granulomatous inflammation Important exclusion criterion: Use of corticosteroids for >1 month before induction therapy

Authors

Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, Kyndt X, Lifermann F, Papo T, Lambert M, Le Noach J, Khellaf M, Merrien D, Puéchal X, Vinzio S, Cohen P, Mouthon L, Cordier JF, Guillevin L; French Vasculitis Study Group

Publication

N Engl J Med. 2008;359(26):2790–2803

Follow up

36 months

Methotrexate

657

Note

Primary hypothesis: MTX less toxic than AZA (see also “Adverse Events”) Relapse rate AZA n = 23, MTX n = 21 73% of these patients with relapse after discontinuation of study drug 24 month event free survival 69.9% (Aza), 60.8% (MTX) Death: MTX n = 1, AZA n = 0

Adverse events

Adverse events (total): AZA n = 29, MTX n = 35 Severe (grade 3 and 4) adverse events: AZA n = 5, MTX n = 11 Adverse event requiring study-drug withdrawal or causing death n = 7 (AZA), n = 12 (MTX) Cutaneous eruption any n = 1 (AZA), n = 1 (MTX), severe n = 0 (AZA), n = 0 (MTX) Anaemia any n = 2 (AZA), n = 2 (MTX), severe n = 0 (AZA), n = 1 (MTX) Lymphopenia any n = 10 (AZA), n = 14 (MTX), severe n = 1 (AZA), n = 3 (MTX) Neutropenia any n = 2 (AZA), n = 3 (MTX), severe n = 0 (AZA), n = 3 (MTX) Thrombocytopenia any n = 1 (AZA), n = 3 (MTX), severe n = 0 (AZA), n = 1 (MTX) Mucosal toxicity any 0 (AZA), n = 7 (MTX), severe n = 0 (AZA), n = 4 (MTX) Gastrointestinal event any n = 8 (AZA), n = 11 (MTX), severe n = 0 (AZA), n = 0 (MTX) Liver toxicity any n = 4 (AZA), n = 4 (MTX), severe n = 4 (AZA), n = 2 (MTX) Infection any n = 12 (AZA), n = 15 (MTX), severe n = 1 (AZA), n = 5 (MTX) Cumulative no. of infections n = 19 (AZA), n = 25 (MTX) Respiratory event any n = 1 (AZA), n = 3 (MTX), severe n = 0 (AZA), n = 2 (MTX) Bone fracture any n = 1 (AZA), n = 3 (MTX), severe n = 0 (AZA), n = 0 (MTX) Cystitis any n = 0 (AZA), n = 0 (MTX) Psychiatric event any n = 1 (AZA), n = 2 (MTX) Severe n = 0 (AZA), n = 0 (MTX) Cancer n = 2 (AZA), n = 1 (MTX) Venous thrombotic event n = 1 (AZA), n = 2 (MTX)

Mycophenolate mofetil

658

Trial

Mycophenolate mofetil for maintenance therapy of Wegener’s granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement

Substance

Induction of remission: 2 mg/kg/day of cyclophosphamide (CYC) plus oral corticosteroids 1 mg/kg/day for at least 3 months or longer until remission was achieved Maintenance of remission: 2 g mycophenolate mofetil/day Taper of oral corticosteroids to £7.5 mg/day at the end of the study

Result

Mycophenolate mofetil in combination with low-dose corticosteroids was safe and effective for the maintenance of remission in patients with Wegener’s granulomatosis and microscopic polyangiitis

Patients

Newly detected or untreated patients with Wegener’s granulomatosis (WG, n = 9, all c-ANCA/PR3-positive) Diagnosed based on clinical presentation, serology, and/or histology Renal involvement and/or severe involvement of other organs required Microscopic polyangiitis n = 2 (all p-ANCA/MPO-positive) BVAS2 of 5 = grumbling disease still present at start of maintenance therapy

Authors

Nowack R, Göbel U, Klooker P, Hergesell O, Andrassy K, van der Woude FJ

Publication

J Am Soc Nephrol. 1999;10(9):1965–1971

Follow up

15 months

Note

Relapse n = 1 (WG) All but one patient remained in stable remission at the end of the study BVAS2 negative in 6 of 11 patients Oral Glucocorticoids could be reduced to a median daily dose of 5 mg and discontinued in three patients No further decline of renal function during maintenance therapy Reduction of proteinuria from at median 0.5 g/day to a median of 0.2 g/day in all patients

Adverse events

Abdominal pain n = 3 Diarrhea n = 2 Respiratory infection n = 2 Leukopenia (<3,000/mL) n = 2

Mycophenolate mofetil

659

Trial

Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis

Substance

Induction of remission: 2 mg/kg cyclophosphamide/day + 1 mg/kg prednisone/day Tapering after 1 month Change to alternate day regime and subsequent discontinuation (during therapy for maintenance), if clinically possible Maintenance of remission: 2 g mycophenolate mofetil/day (initiated 1–2 days after the last application of CYC) Concomitant trimetoprim/sulfamethoxazole (160/800 mg; one tablet three times weekly) and either calcium carbonate/calcitriol or calcium carbonate/ etidronate

Result

Mycophenolate mofetil plus prednisone for maintenance of remission was safe, with limited efficacy with regard to the frequency of relapses

Patients

14 patients with active Wegener’s granulomatosis 13 with biopsy-proven Wegener’s granulomatosis with necrotizing vasculitis, granulomatous inflammation or both in a typical organ system One patient diagnosed on the basis of upper airway and lower airway disease – where infection had been ruled out- and by the presence of PR3-ANCA 13 patients with cANCA, 1 with p/MPO-ANCA

Authors

Langford CA, Talar-Williams C, Sneller MC

Publication

Arthritis Rheum. 2004;51(2):278–283

Follow up

18 months (median)

Note

Deaths n = 0 Remission n = 14 Time to remission, 3 months (median) Relapse after achieving remission n = 6 Time from remission to relapse, 10 months (median) Discontinuation of prednisone n = 12 Time to tapering to alternate-day prednisone, 4 months (median) Time discontinuation of prednisone, 8 months (median) Time from remission to relapse in six patients, 10 months (median) Time off prednisone before relapse in six patients, 5 months (median)

Adverse events

Bone marrow toxicity requiring dosage reduction: Cyclophosphamide n = 2 Mycophenolate mofetil n = 2 Cataracts n = 1 Diabetes mellitus n = 2 Dermatomal cutaneous herpes zoster n = 4 Bacterial pneumonia n = 2 Pneumocystis carinii pneumonia n = 2

660

Mycophenolate mofetil

Trial

A pilot study using Mycophenolate mofetil in relapsing or resistant ANCA small vessel vasculitis

Substance

2 × 500 mg Mycophenolate mofetil (MMF)/day Then increased to 2 × 1,000–1,500/day, for a maximum of 24 weeks, the decision about continuation of MMF or change to different medication Patients with relapse: Begin of corticosteroids at 1 mg/kg/day for £30 days, then taper by 25% of initial dose per week for 1 month, discontinuation after 3 months Rapid loss of renal function: initial i.v. pulses of mehtylprednisolone Patients with resistance to cyclophosphamide (CYC): no increase of corticosteroids allowed Concomitant therapy: With corticosteroids allowed Vit D and calcium for all patients on corticosteroids

Result

Mycophenolate mofetil was safe and adequately efficient in the treatment of non-life-threatening vasculitis which was either relapsing or resistant to therapy with cyclophopsphamide or showed toxicity to cyclophosphamide or azathioprine

Patients

12 patients with active, either therapy resistant (n = 6) to CYC or relapsing (n = 6) disease Wegener’s granulomatosis n = 7 Microscopic polyangiitis n = 2 Isolated renal vasculitis n = 2 Churg-Strauss syndrome n = 1 Major inclusion criteria: Treatment resistance or relapse plus one of the following: Two prior courses of 6 monthly CYC (intravenous or daily oral); toxicity of CYC or azathioprine; patient’s refusal of further treatment after one course; current disease activity despite a full course of CYC Major exclusion criterion: Glomerulonephritis only, i.e., no extrarenal manifestation of vasculitis, with advanced renal failure Total BVAS at start of study: 9.1 (mean) PR3-ANCA n = 9 MPO-ANCA n = 3

Authors

Joy MS, Hogan SL, Jennette JC, Falk RJ, Nachman PH

Publication

Nephrol Dial Transplant. 2005;20(12):2725–2732

Follow up

52 weeks

661

Mycophenolate mofetil

Note

Total BVAS 9.1 (baseline), 2.8 (24 weeks), 2.8 (week 52) ANCA titers 57 (baseline), 43.3 (24 weeks), 50.7 (week 52) = no difference between time points Prednisone dose 42 mg (baseline), 12.5 mg (24 weeks) One patient with significant increase of activity after initial 24 weeks Two patients with minor increase of activity after initial 24 weeks Two patients withdrawn early because of worsening of vasculitis and/or signs of infection

Adverse events

Upper respiratory tract infection n = 5 Urinary tract infection symptoms n = 1 Herpes Zoster infection n = 1 Diarrhoea/loose stools n = 4 Abdominal cramping n = 3 Nausea/vomiting n = 2 Constipation n = 1 Leukopenia n = 2 Insomnia n = 2 Mid-epigastric pain n = 1 Increased serum amylase n = 1 Adverse events were all transient

Anti-Thymocyte Globulin

662

SOLUTIONTrial

Treatment of refractory Wegener’s granulomatosis with anti-thymocyte globulin (ATG): an open study in 15 patients SOLUTION: Completed name of study, no acronym

Substance

Individual amount of infusions 2.5 mg/kg rabbit anti-human ATG each over 10 days (IMIX SangStat n = 14: mean of 2.2 infusions, mean total dose 300 mg; AQTG-Fresenius n = 1: 5 infusions, total 1,050 mg) Further doses adjusted according lymphocyte count (SOLUTION protocol) Concomitant medication: 100 mg methylprednisolone before the first administration of ATG 2 mg/kg azathioprine throughout ATG-treatment to prevent serum sickness Cotrimoxazol was permitted Amphotericin-B was permitted Previous medication: Glucocorticosteroids (all patients) Oral cyclophosphamide (all patients) Plasma exchange n = 5 Mycophenolate mofetil n = 4 Intravenous immunoglobulins n = 3 Cyclosporine A n = 2 15-deoxyspergualine n = 2

Result

Anti-T-cell-directed treatment with ATG was effective in most treated cases of severe refractory Wegener’s granulomatosis despite limited safety due to bacterial infections and pulmonary hemorrhage

Patients

15 patients with active, severely refractory Wegener’s granulomatosis Histologically proven; all c/PR3-ANCA positive Unresponsive to cyclophosphamide n = 7, intolerant n = 8 Cumulative DEI 8.7 (mean) Number of previous therapeutics 5.2 (mean) Cumulative dose of cyclophosphamide 56.5 g (mean) Disease duration before study entry 63.2 (mean) Number of relapses before study entry 2.8 (mean)

Authors

Schmitt WH, Hagen EC, Neumann I, Nowack R, Flores-Suárez LF, van der Woude FJ; European Vasculitis Study Group

Publication

Kidney Int. 2004;65(4):1440–1448

Follow up

21.8 (range 6–68)

Note

Favorable response n = 13 Partial remission n = 9 Complete remission n = 4 Relapsed after a mean of 8.4 months n = 7 Death n = 2

Adverse events

Fever and chills n = 10 Serum sickness n = 2 Serious bacterial infections n = 5 Death of a pulmonary bacterial infection n = 1 Death of pulmonary haemorrhage n = 1

Etanercept

663

Trial

Etanercept combined with conventional treatment in Wegener’s granulomatosis: a 6-month open-label trial to evaluate safety

Substance

2 × 25 mg etanercept/week s.c. Concomitant medication: Added to standard therapies for Wegener’s granulomatosis (glucocorticoids, methotrexate, cyclophosphamide, azathioprine, ciclosporin) Trimetoprim-sulfamethoxazole, double-strength three times a week one tablet

Result

Etanercept used in combination with standard treatments was well-tolerated in patients with Wegener’s granulomatosis with few adverse events. There were intermittent flares in most cases, severe flares in a minority. Activity was reduced in the majority of patients after 6 months

Patients

20 Patients with Wegener’s granulomatosis Diagnosed clinically and on the basis of ³2 of modified ACR-criteria (1990 criteria + PR3-ANCA) Major inclusion criterion: BVAS ³1 Time since diagnosis: 63.6 months (mean) BVAS/WG at study entry: 3.6 (mean)

Authors

Stone JH, Uhlfelder ML, Hellmann DB, Crook S, Bedocs NM, Hoffman GS

Publication

Arthritis Rheum. 2001;44(5):1149–1154

Follow up

6 months

Note

Still taking etanercept at 6 months n = 19 BVAS/WG –3 Change in BVAS/WG, entry to 6 months –3.0 Change in Physicians global assessment, –25.3 mm Change in mean daily prednisone dose, –11.6 mg BVAS/WG = 0 at 6 months n = 12 Some increase in BVAS/WG within study period: n = 12 (75%) Minor increase n = 10 Major flares n = 3 (n = 1 glomerulonephritis + mesenteric vasculitis, n = 2 recurrent orbital disease)

Adverse events

Injection-site reactions n = 8 Hospitalization needed n = 5 Herpes zoster infection n = 1 Infections n = 2 Elevated liver transaminases n = 1 Cytopenias n = 5 Sleep disturbances n = 1

Etanercept

664

WGET-Trial

Etanercept plus Standard Therapy for Wegener’s Granulomatosis WGET: Wegener’s Granulomatosis Etanercept Trial

Substance

Additional immunosuppressive therapy (begin before randomization): Severe disease: 2 mg/kg cycloposphamide/day for at least 3–6 months, exchanged for methotrexate at remission or when reclassified as limited disease – or azathioprine, if serum creatinine >2 mg/dL- + glucocorticoids Limited disease: 0.25 mg/kg methotrexate/week (for 12 months after remission, increased to max. 25 mg/week) + glucocorticoids Randomized phase: 2 × 25 mg Etanercept (ETN)/week (group A, n = 89) Or Placebo (group B, n = 92) Both groups: Glucocorticoids at start with i.v. pulse methylprednisolone 1 g for 3 days or 0.5–1 mg/kg/day (max. 80 mg), taper with aim to reach 20 mg/day after 2 months and to discontinue within 6 months Concomitant therapy: All patients trimethoprim/sulfamethoxazole (80/400 mg) Folic acid (1 mg/day, MTX treated patients) Prophylactic treatment for pneumocystis infection and for osteoporosis More details on therapy regimen in: Control Clin Trials. 2002;23;450–468

Result

Etanercept was not effective for the maintenance of remission in patients with severe or limited Wegener’s granulomatosis, respectively. There was a high rate of treatment-related complications with all six solid cancers occurring in the etanercept group

Patients

180 patients with severe Wegener’s granulomatosis Diagnosed clinically and on the basis of ³2 of modified ACR-criteria (1990 criteria plus PR3-ANCA) Both patients with a new diagnosis or with flares of previously quiescent existing disease Biopsy results: Granulomatous inflammation 54.9% Vasculitis/glomerulonephritis 63.4% Inclusion criteria: Without immediate threat to either the patient’s life or vital organ function Serum creatinine £1.4 mg/dL + no change to patient’s baseline over 25% No more than circumscribed pulmonary involvement Active for the previous 28 days, either under first course of treatment or with flare BVAS/WG ³3 Further details on inclusion/exclusion and baseline cohort data in: Control Clin Trials. 2002;23:450–468 and Arthritis Rheum. 2003;48(8):2299–2309 Severe disease n = 128, limited disease n = 52 BVAS/WG (mean) 6.5 (group A), 7.5 (group B) ANCA-IF positive (%): 87.1 PR3/MPO positive (%): 72.6/11.9

Etanercept

665

Authors

Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group

Publication

N Engl J Med. 2005;352(4):351–361

Follow up

25 months (group A), 19 months (Group B; means)

Note

Completed study (%) 60.7 (Group A), 63.0 (Group B) Sustained remission 69.7% (Group A), 75.3% (Group B) No difference between group A and group B with respect to time to sustained remission Remission at any time during trial 89.9 (Group A), 92.3 (Group B) Remained in remission 49.4% (both groups) Sustained low level of disease activity 86.5% (Group A), 90.6% (Group B) All disease flares (%) 66.3 (Group A), 74.1 (Group B) Severe disease flares (%) 14.9 (Group A), 12.8 (Group B) Overall also no difference in severe and limited or new and existing disease in all outcome parameters No details on previous immunosuppressive therapies provided in all three publications

Adverse events

At least 1 event of: Grade 3 (severe events), grade 4 (life-threatening events) or grade 5 (death) 56.2% (Group A), 57.1 (Group B) Grade 5 events: n = 4 (Group A: one cholangiocarcinoma, one sepsis, two cardiac arrest); n = 2 (Group B: one cardiac arrest, one sepsis) Cancers during trial period: Group A: n = 11 (one prostate cancer, two mucinous colon adenocarcinoma, one cholangiosarcoma, one breast carcinoma, one liposarcoma, three cutaneous basal-cell or squamous-cell carcinoma) Group B: n = 4 (four cutaneous basal-cell or squamous-cell carcinoma)

666

Immunoglobulins

Trial

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin

Substance

I.v. polyspeccific 7S-immunoglobulin (IVIG), 30 g/day for 5 days Concomitant medication: Trimethoprim/sulphamethoxazole n = 4 2.5–30 mg prednisone/day at stable dose n = 5 Cyclophosphamide at stable dose n = 9 Previous medication: Cyclophosphamide n = 10 Trimethoprim/sulphamethoxazole n = 4

Result

Intravenous immunoglobulin were partially effective in ANCA associated vasculitis, particularly in the skin, ear–nose–throat and arthritis, with some influence on PR3-ANCA levels

Patients

15 patients with ANCA-associated systemic vasculitis Fullfilling the ACR criteria Wegener’s granulomatosis (WG) and the CHC-definitions, with PR-3 ANCA, 1 with MPO-ANCA positive limited systemic vasculitis n = 14 Histologic confirmation of diagnosis n = 13 Generalized disease n = 13, initial disease n = 2 Pre-treatment with different regimens, among others: CYC n = 9 (stopped before IVIG because of toxicity n = 2), with T/S n = 4, IVIG as first treatment of WG n = 1 Concomitant therapy with prednisone n = 5

Authors

Richter C, Schnabel A, Csernok E, De Groot K, Reinhold-Keller E, Gross WL

Publication

Clin Exp Immunol. 1995;101(1):2–7

Follow up

4 weeks

Note

Clinically significant benefit (skin, ear–nose–throat findings) n = 6 Improvement of conjunctivitis and scleritis, pericarditis or nephritis n = 0 Complete remission n = 0 Repeated courses were no more effective than single courses Decrease of CRP levels n = 7 (n = 3 >50%) Decrease of ANCA levels (4×) n = 5 DEI drop from 4 to 3 (median)

Adverse events

None

667

Immunoglobulins

Trial

Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome

Substance

1 mg/kg Prednisone/day for 1 month Then slowly tapered to 10 mg/day by month 6 (all patients) + 2 mg/kg cyclophosphamide/day for 6 months in severe cases + synchronized cycles with plasmapheresis Randomization: And i.v. immunoglobulin (IVIG, 2 g/kg/month) for 6 months and every other month for a further three cycles (group A, n = 9) No plasmapheresis (group B, n = 9)

Result

Treatment with intravenous immunoglobulin in conjunction with plasmapheresis led to complete and long term remissions with few side effects in all patients with Churg-Strauss syndrome

Patients

18 subjects with new onset Churg-Strauss syndrome Fulfilling the ACR-criteria and the CHC-definitions for Churg Strauss syndrome Treatment group with plasmapheresis/IVIG n = 9 Control group with standard therapy without plasmapheresis/IVIG n = 9 Anti-leukotriene therapy in both groups n = 0 Major exclusion criteria: Serious infections in the past 6 months Other concomitant severe or uncontrolled disease

Authors

Danieli MG, Cappelli M, Malcangi G, Logullo F, Salvi A, Danieli G

Publication

Ann Rheum Dis. 2004;63(12):1649–1654

Follow up

44 months (median)

Note

Remission at 12 months: n = 9 (group A), n = 4 (group B) Treatment free remission n = 6 (group A), n = 7 (group B) Relapses n = 1 (group A), n = 4 (group B) BVAS (median) 4 (group A), 7 (group B) Systemic Necrotising Vasculitis Damage Index 3.78 (group A), 5.56 (group B) Modified Rodnan skin score 1.11 (group A), 1.78 (group B) Significant lower CRP levels in the treatment group from month 6 until last evaluation

Adverse events

Steroid related osteoporosis n = 3 (group A), n = 8 (group B) Diabetes n = 2 (group A), n = 3 (group B) Arterial hypertension n = 2 (group A), n = 4 (group B) Myopathy n = 1 (group A), n = 2 (group B) Cushingoid habitus n = 1 (group A), n = 1 (group B) Hypogammaglobulinaemia n = 0 (group A), n = 2 (group B) Permanent lymphopenia n = 1 (group A), n = 1 (group B) Bacterial pneumonia n = 1 (group A), n = 2 (group B)

668

Infliximab

Trial

Prospective study of TNF alpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis

Substance

Infliximab (5 mg/kg), at 0, 2, 6, and 10 weeks Additive therapy study I: Oral 2 mg/kg cyclophosphamide/day for 14 weeks until remission Then switch to 2 mg/kg azathioprine/day unless inefficient Then mycophenolate and prednisolone Additive therapy study II: Continuation of established therapy, with prednisolone tapered according to clinical status Concomitant therapy: Sulfamthoxazole/trimethoprim 480 mg three times a week and antifungals continued for 14 weeks in patients on cyclophosphamide

Result

Infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction of steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares

Patients

32 patients with ANCA-associated small vessel vasculitis Wegener’s granulomatosis or microscopic polyangiitis fulfilling the CHC definitions; histologic confirmation n = 32 ANCA immunofluorescence positive n = 31 Study I (as adjuvant therapy for induction of remission, n = 16): Patients with acute flares that were not immediately life-threatening BVAS ³10, either initial disease presentation or relapse Study II (as additional therapy in persistent disease, n = 16): Patients with active AASV despite ³3 months of combination therapy with Prednisolone + cyclophosphamide, azathioprine or methotrexate BVAS ³4 Major exclusion criteria: Immediately life-threatening pulmonary vasculitis Untreated infection or previous tuberculosis Cardiac failure

Authors

Booth A, Harper L, Hammad T, Bacon P, Griffith M, Levy J, Savage C, Pusey C, Jayne D

Publication

J Am Soc Nephrol. 2004;15(3):717–721

Follow up

52 weeks

Infliximab

669

Note

Change during follow up: Remission 88% (n =14 in both studies), of these patients n = 5 (16%, study I) n = 3 (21%, study II) with relapses BVAS decreased –10 CRP –22.4 Mean prednisolone dose –15 mg/day Relapse after a mean of 27 weeks 18% Two treatment failures in both studies, respectively

Adverse events

Death (pulmonary haemorrhage, n = 1, bronchopneumonia, n = 4) Bronchopneumonia (n = 1) Urinary tract sepsis, klebsiella (n = 1) Leg abscess, surgical drainage required (n = 1) Endophthalmitis, evisceration of the eye (n = 1) Skin ulcer/urinary tract infection (n = 1) Diarrheal illness (n = 1) B cell lymphoma, chemotherapy (n = 1) Pulmonary embolus (n = 1) Axillary vein thrombosis (n = 1)

670

Rituximab

Trial

Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with Rituximab

Substance

4 × 500 mg or 375 mg/m2 RTX, every 4 weeks n = 6 500 mg, once weeks, for 2 weeks n = 3 Concomitant medication: Mycophenoloate mofetil n = 5 Azathioprine n = 1 Cyclophosphamide 5 or 7 weeks, respectively, n = 2 Prednisolone n = 9 Concomitant medication: Cyclophosphamide n = 9 Anthithymocyte globulin n = 1 Intravenous immunoglobulins n = 3 Sirolimus n = 2 Azathioprine n = 5 Leflunomide n = 1 Cyclosporin n = 2 Methotrexate n = 2 Mycophenolate mofetil n = 4 Plasma exchange n = 1

Result

Rituximab was effective and safe in ANCA-positive vasculitis, in addition to other immunomodulatory therapy

Patients

Nine patients with ANCA pos vasculitis PR-3 ANCA n = 7 with a diagnosis of Wegener’s granulomatosis MPO-ANCA n = 2 with a diagnosis of microscopic polyangiitis Involvement of of organs 4 (median), BVAS 6 (median) All patients resistant to prior immunosuppressants and prednisolone

Authors

Eriksson P

Publication

J Intern Med. 2005;257(6):540–548

Follow up

6 months, duration 6–24 months

Note

Complete remission n = 8 with BVAS 0, at 6 months Minor relapses n = 2 cases, at 12 and 13 months, respectively Improvement of chest X-rays n = 4 Stop progression of gangrene n = 1 Remission of neuropathy n = 1 Remission of renal vasculitis n = 2 Improvement of muscosceletal pain n = 1 CRP −18 mg/L ESR −31 mm/h No effect on PR-3 ANCA-levels MPO-ANCA not present at study start

Adverse events

No serious adverse events occurred Respiratory tract infections n = 2 Cutaneous Herpes infection n = 1

671

Rituximab

Trial

Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial

Substance

3 × 1 g/day of methylpredniolone allowed alternatively as start dosis Oral prednisone/day (1 mg/kg, maximum 80 mg/day) Prednisone was tapered and discontinued over 5 months, if no relapse Four weekly infusions of 375 mg/m2 rituximab (RTX) Retreatment in case of relapse (with prednisone) or significant rise of ANCA (without prednisone) and parallel return of B lymphocytes Concomitant medication: Discontinuation of immunosuppressive therapies at study start (no washout) 650 mg of acetaminophen p.o. before RTX application 50 mg of diphenhydramine p.o. before RTX application Previous medication: Cyclophosphamide n = 10 Corticosteroids n = 10 Azathioprine n = 3 Mycophenolate mofetil n = 1 Etanercept n = 1

Result

Rituximab was effective and safe as the sole remission induction agent for severe refractory Wegener’s granulomatosis

Patients

Ten patients with active severe ANCA-associated vasculitis Biopsy-proven or fulfilling the ACR-criteria and CHC-definitions for Wegener’s granulomatosis or microscopic polyangiitis Wegener’s granulomatosis n = 10, PR-3 ANCA n = 10 BVAS/WG: 6 (median) Major additional inclusion criteria: PR-3 or MPO-ANCA positive at time of enrollment Active severe (life- or organ-threatening) disease Resistance to (n = 3) or intolerance of (n = 7), cyclophosphamide BVAS ³3 or refractory disease Major exclusion criteria: Active infection, HIV, NYHA III/IV

Authors

Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U

Publication

J Respir Crit Care Med. 2006;173(2):180–187

Follow up

12 months

672

Rituximab

Note

Complete clinical remission (activity score, 0) n = 10 after 3 months Complete remission at end of trial n = 9 Tapered off glucocorticoids by 6 months n = 10 Significant drop or disappearance of ANCA n = 10 CRP/BSR/serum creatinine in parallel decline to inflammatory disease Recurring/rising ANCA titer n = 5 Relapse n = 1, at 9 months Effect on quality of life: improvement in all domains of the SF-36

Adverse events

Rigors and chills n = 1 (first infusion) Herpes zoster eruptions followed by post-herpetic neuropathy n = 2 Influenza n = 1 Upper respiratory tract infections n = 13 in five patients (rhinitis, sinusitis, cough with yellow and green nasal discharge, and phlegm production, with or without fevers)

Rituximab

673

Trial

Lack of efficacy of rituximab in Wegener’s granulomatosis with refractory granulomatous manifestations

Substance

4 × Rituximab (RTX) 375 mg/m2, every fourth week Concomitant medication: 2 mg/kg cylcophosphamide/day p.o. 15–20 mg/kg cylcophosphamide i.v. every 18–21 days 0.3 mg/kg methotrexate/week Previous medication: Cylcophosphamide n = 5 Prednisone n = 8 Infliximab n = 6 Methotrexate n = 1 Leflunomide n = 1 Etanercept n = 2 Mycophenolate mofetil n = 1

Result

No change or progression of granulomatous disease manifestations in the majority of patients with rituximab and additional cyclophosphamide therapy, additional clinical efffect in a minority

Patients

Eight consecutive patients Fulfilling the CHC-definitions for Wegener’s granulomatosis and PR-3ANCA positive, biopsy-proven Active disease ³3 months despite of therapy with cyclophosphamide/ predisolone and TNF-inhibitors All patients with granulomatous manifestations: Retro-orbital granulomata n = 5 Lung nodules n = 1 Subglottic stenosis n = 2 BVAS 1: 7.5 (mean) DEI 4 (mean)

Authors

Aries PM, Hellmich B, Voswinkel J, Both M, Nölle B, Holl-Ulrich K, Lamprecht P, Gross WL

Publication

Ann Rheum Dis. 2006;65:853–858

Follow up

18 months (median)

Note

Reduction of disease activity n = 3 Complete remission n = 2 No change in disease activity n = 3 Progression of disease n = 2 No change in ANCA titers n = 8 Change of: BVAS 1 after RTX: 6.25 (mean) DEI after RTX: 3.5 CRP − 24 mg/L ESR – 28 mm/h

Adverse events

None reported

Rituximab

674

Trial

Rituximab for treatment-resistant extensive Wegener’s granulomatosis – additive effects of a maintenance treatment with Leflunomide

Substance

4 × 375 mg/m2 rituximab (RTX) in weekly intervals Maintenance treatment: 20 mg leflunomide/day (n = 5) after the last RTX-dose Stop of previous ineffective medication (n = 4) Concomitant medication: Increase of prednisolone to 1 mg/kd/day Previous medication: Cyclophosphamide n = 6 Corticosteroids n = 6 Infliximab n = 2

Result

Rituximab, along with leflunomide, was an effective and safe remissoninducing agent for patients with Wegener’s granulomatosis

Patients

patients with Wegener’s granulomatosis Fulfilling the ACR-criteria for Wegener’s granulomatosis c-/PR-3-ANCA positive n = 6 Progressive disease despite: Cyclophosphamide-pulse n = 6 Cyclophosphamide oral n = 4 TNF-Antagonists n = 2 Corticosteroids n = 6 Pulmonary involvement n = 6 Renal involvement n = 3 Granulomatosis inflammation of the ear, nose, throat tract n = 5 Biopsy-proven, meningeal granulomatous inflammation n = 1 BVAS/WG (mean): 5

Authors

Henes JC, Fritz J, Koch S, Klein R, Horger M, Risler T, Kanz L, Koetter I

Publication

Clin Rheumatol. 2007;26(10):1711–1715. Epub May 15, 2007

Follow up

16 months (mean)

Note

Complete remission at 6 months n = 5 Persistant sinusitis n = 1 Mild disease activity at 3 months n = 2 Major relapse n = 1 Glucosteroids tapered –49.9 mg PR3-ANCA (mean; start/end of study) 36.8 U/mL/21.4 U/mL RTX infusions were well tolerated

675

Rituximab

Trial

Efficacy of Rituximab in Limited Wegener’s Granulomatosis with Refractory Granulomatous Manifestations

Substance

4 × 375 mg/m2 rituximab (RTX), weekly Other therapies: Methotrexate n = 7 Cyclophosphamide n = 6 Chlorambucil n = 2 Mycophenolate mofetil n = 1 Etancercept n = 2 Infliximab n = 1 Adalimumab n = 2 Azathioprine n = 1

Result

Rituximab was safe and effective in limited granulomatous Wegener’s granulomatosis

Patients

Eight patients with limited, i.e., non-life or vital organ threatening, Wegener’s granulomatosis Fulfilling the ACR-criteria Failed three immunosuppressive agents (mean): cyclophosphamide n = 6, methotrexate n = 8 All patients with predominantly necrotizing granulomatous disease manifestations ANCA-negative at time of first RTX n = 5

Authors

Seo P, Specks U, Keogh KA

Publication

J Rheumatol. 2008;35(10):2017–2023

Follow up

Minimum 4 months, maximum 3 years

Note

Remission n = 7 Relapse n = 5, 3 with successful retreatment with RTX Time to relapse 14 months (mean) and 5 months after B-cell repopulation

Adverse events

Deaths n = 1 (adenoviral pneumonitis after two courses of RTX and additional therapy with adalimumab for resistant orbital pseudotumor 2 months after last RTX)

Rituximab

676

Trial

Rituximab is effective in the treatment of refractory ophthalmic Wegener’s granulomatosis

Substance

2 × 1 g rituximab 2 weeks apart Continuation of standard immunosuppressive and corticosteroids Second line agents post RTX: Mycophenolate mofetil n = 3 (6 months), n = 1 (12 months) Azathioprine n = 2 (6 months), n = 2 (12 months) Cyclophosphamide n = 1 (6 months), n = 0 (12 months) Methotrexate n = 2 (6 months), n = 1 (12 months) None n = 2 (6 months), n = 6 (12 months) Previous medication: Anti TNF n = 4 Immunoglobulins n = 1 Azathioprine n = 10 Methotrexate n = 6 Mycophenolate mofetil n = 9 Corticosteroids n = 10

Result

Rituximab was effective in patients with ophthalmic Wegener’s granulomatosis refractory to standard immunosuppressive therapy including cyclophosphamide, high-dose corticosteroids and in some cases TNFantagonists

Patients

Retrospective analysis of ten consecutive patients with refractory ophthalmic Wegener’s granulomatosis Fulfilling the ACR-criteria and the CHC-definitions Either biopsy-proven or characteristic disease manifestations of retro-orbital granulomas/necrotizing scleritis Refractory scleritis n = 3 Orbital granulomas causing optic nerve compromise n = 4 Or a combination of both conditions n = 3 All ³3 previous immunosuppressive agents, including cyclophosphamide and high-dose corticosteroids Previous treatment with TNF alpha blockade n = 5 All PR3 ANCA pos.

Authors

Taylor SR, Salama AD, Joshi L, Pusey CD, Lightman SL

Publication

Arthritis Rheum. 2009;60(5):1540–1547

Follow up

36 months

Note

Beneficial response n = 10 Clinical remission n = 10, within 7 months Clinical remission sustained for 6.5 months (median) n = 10, for >12 months n = 4 DEI = 0 (mean ~3 at start of study) at 24 and 36 months in all patients N = 1 with 1 more RTX infusion for rise in ANCA within 6 months Relapses n = 0 Daily prednisolone at almost 0 at 36 months in all patients Positive trend toward decreased ANCA-levels No adverse events reported

677

Rituximab

Trial

A multicenter survey of Rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis

Substance

Retrospectively analyzed without randomization: 2 × 1 g rituximab (RTX) 2 weeks apart (n = 32) 4 × 375 mg/m2 rituximab 1 weeks apart (n = 26) Other dosing regimens for RTX (n = 7) Second course of RTX n = 38 ³3 courses of RTX (up to 6) n = 20 No immunosuppressive therapy in addition to RTX n = 22 Concomitant medication: Mycophenolate mofetil n = 28; 2 g/day (average dose) Azathioprine n = 7; av. 75 mg/day IV pulse cyclophosphamide (CYC) n = 6 Oral CYC n = 5; 150 mg/day (average dose) Deoxyspergualin n = 4 Methotrexate n = 3; 20 mg/day (average dose) Plasma exchange n = 1 Enteric coated mycophenolate sodium n = 1; av. 2.16 g/day Alemtuzumab n = 1; 11 months before RTX Combination of 2 or 3 therapies n = 4 None n = 5 Oral corticosteroid 12.5 mg/day (average dose) I.v. corticosteroids/5 days followed by 1 mg/kg/day p.o. n = 17 Previous medication: Anti-TNF n = 24 Immunoglobulins n = 17 Azathioprine n = 49 Methotrexate 10 n = 18 Mycophenolate mofetil n = 47 Other n = 25 Total no. of previous therapies/patient n = 4

Result

Rituximab was effective and safe in the induction of remission of refractory ANCA-associated vasculitis in this retrospective analysis, without difference in efficacy between the two main treatment regimens. Re-treatment was effective and safe after relapses

Patients

Retrospective analysis of 65 sequential patients with refractory ANCAassociated vasculitis Wegener’s granulomatosis 71% Microscopic polyangiitis Churg Strauss Syndrome Diagnosis according to the CHC-definitions All patients with active disease at time of first RTX Median DEI n = 4 (new disease), 2 (persistant disease), at first RTX ANCA (PR3 or MPO) positive n = 33 Age 7–77 years Major exclusion criteria: RTX as first line therapy, follow-up after first RTX-infusion £6 months

678

Rituximab

Authors

Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, Jayne DR

Publication

Arthritis Rheum. 2009;60(7):2156–2168

Follow up

21 months (median)

Note

Complete remission 75%, time to remission 2 months (median) DEI 0 (median) at 6 and 12 months Partial remission 23% No response 2% Prednisolone dose (median) from 12.5 to 9.0 mg/day (6 months), to 7.5 mg (12 months) Withdrawal of immunosuppressives 62% Relapse after remission 57%, 48% of them before B-cell repopulation Remission after second RTX course 84%, time to remission 1.5 months (median) Decrease in ANCA No difference in patients with or without additional immunosuppressives with regard to rate of relapses No differences between the 2 RTX-treatment protocols were detected

Adverse events

Endo-bronchial disease 7.5% Asthma 3.0% Peripheral neuropathy 1.5% ENT disease 3.0% Pulmonary fibrosis, respiratory failure, and death 1.5% Retro-orbital granuloma 1.5% Pneumonia (organism not specified) 11.0% Aspergillus lung infection 1.5% Pseudomonas lung infection 1.5% Line sepsis 1.5% Sepsis 3.0% Cellulitis 1.5% Pulmonary embolism 1.5% Sudden unexplained death 1.5% Addisonian crisis 3.0% Hip surgery 1.5% Aseptic meningitis post-IVIG therapy 1.5% Aortic valve replacement 1.5% Neutropenia 3.0% Failure of B cells to deplete 1.5% Ankle surgery 1.5% Eye surgery 1.5%

Plasma Exchange

679

Trial

Complications of plasma exchange in the treatment of polyarteritis nodosa and Churg-Strauss angiitis and the contribution of adjuvant immunosuppressive therapy: a randomized trial in 72 patients

Substance

Corticosteroid (1 mg/kg/day) for 2 months Tapered by 2.5 mg every 10 days for a month Tapered by 2.5 mg every week until half the initial dose was reached Maintenance of this dose for 3 weeks Further reduction by 1 mg/day every week when under 20 mg/day with a 3 week plateau at 10 and 5 mg Randomization: 2 mg/kg cyclophosphamide/day during 1 year (n = 35) Without cycophosphamide (CYC, n = 35) Both groups with plasma exchange: Centrifugation was used in 678 plasma exchange sessions (83.4%) Filtration was used in 128 (15.7%) Every patient with 13 exchanges in 6 months Replacement fluid: 4% albumin (n = 698 sessions) fresh-frozen plasma (n = 68 sessions) both (n = 47 sessions) Replacement fluid in 745 sessions was 4% albumin and in 115 was fresh-frozen plasma

Result

Plasma exchange was relatively safe in this study of plasmapheresis and corticosterois in patients with newly diagnosed polyarteritis nodosa or Churg-Straus syndrome. Additional cyclophosphamide probably contributed to increased mortality by severe infections while corticosteroids alone resulted in more death due to activity of vasculitis

Patients

72 patients with polyarteritis nodosa or Churg-Strauss angiitis Newly diagnosed based on histologic or angiographic data and without previous treatment

Authors

Lhote F, Guillevin L, Leon A, Bussel A, Lok C, Sobel A, Simon P

Publication

Artif Organs. 1988;12(1):27–33

Follow up

36 months

680

Plasma Exchange

Note

251 complications in 60 patients during 206 (25.3%), of the 813 completed exchanges; 47 sessions (5.8%), were temporarily stopped as a result of complications Data not available in two patients

Adverse events

Death n = 6 (CYC), all attributed to the vasculitis, n = 6 (no CYC), four of which due to severe infections (three times related to leukopenia) Hypotension n = 26 (CYC), n = 26 (no CYC) Allergic reactions n = 23 (CYC), n = 28 (no CYC) Malaise or vasovagal reactions n = 8 (CYC), n = 12 (no CYC) Reactions to citrate n = 6 (CYC), n = 5 (no CYC) Abdominal pain, nausea, vomiting n = 7 (CYC), n = 4 (no CYC) Hypoglycaemia n = 3 (CYC), n = 3 (no CYC) Cardiac arrhythmia n = 2 (CYC), n = 2 (no CYC) Fever n = 1 (CYC), n = 1 (no CYC) Voluminous hematoma n = 0 (CYC), n = 1 (no CYC) Hypertension n = 1 (CYC), n = 0 (no CYC) Viral hepatitis B n = 0 (CYC), n = 1 (no CYC) Phlebothrombosis n = 0 (CYC), n = 1 (no CYC)

681

Plasma Exchange

Trial

Lack of superiority of steroids plus plasma exchange to steroids alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome. A prospective, randomized trial in 78 patients

Substance

Prednisone and plasma exchange (Group A, n = 36) Prednisone alone (Group B, n = 42) No information on type of disease within groups Treatment failure: 2 mg/kg cyclophospamide (CYC)/day n = 9 (Group A), n = 5 (Group B) Prednisone 1 mg/kg/day for 1 month Tapered after evidence of improvement by 2.5 mg/week until half starting dose Maintained for 3 weeks Then reduction of 2.5 mg/week, to approximately 20 mg/day Further tapered in 1 mg/week steps to final 5 mg/day Plasma exchange: 12 treatments during first 2 weeks 2 treatments in week 3 The other four treatments spread over period to 30 days after last treatment in week 3 Plasma per session 60 mL/kg Concomitant medication: Corticosteroids <10 mg/day for asthma No high dose corticosteroids

Result

Combined treatment of polyarteritis and Churg-Strauss syndrome with prednisone and plasma exchange was not superior to treatment with prednisone alone

Patients

78 patients with polyarteritis nodosa (PAN) or Churg-Strauss syndrome Multiple system involvement Major inclusion criteria: Histological or arteriographic evidence of vasculitis, multiple system involvement, activity sufficient for corticosteroid use Major exclusion criterion: HBV-related PAN

Authors

Guillevin L, Fain O, Lhote F, Jarrousse B, Le Thi Huong D, Bussel A, Leon A

Publication

Arthritis Rheum. 1992;35(2):208–215

Follow up

7 years

682

Plasma Exchange

Note

Completely recovered n = 27 (group A), n = 29 (group B) Prednisolone dose after 1 year 10 mg/day (group A), 13.7 mg/day (group B) Additional treatment needed n = 10 (group A), n = 6 (group B) Relapses n = 10 (group A), n = 8 (group B) Disease activity not controlled n = 14 (group A), n = 12 (group B) Steroid dose increased n = 4 (group A), n = 6 (group B) CYC was able to control the disease in the 14 patients treated (no further details provided)

Adverse events

Osteoporosis n = 2 Aseptic necrosis of femoral head n = 2 Duodenal ulcers n = 2 Pneumonia n = 1 Deaths n = 6 (Group A), n = 5 (Group B) 7-year cumulative survival rates 83% (Group A), 79% (Group B) Death n = 5 Cause of death (none attributed to additional use of CYC): Bowel infarction n = 1 (Group A), n = 1 (Group B) Hematoperitoneum n = 0 (Group A), n = 1 (Group B) Stroke n = 2 (Group A), n = 0 (Group B) Respiratory failure n = 0 (Group A), n = 1 (Group B) Cardiac failure n = 1 (Group A), n = 2 (Group B) Infections n = 0 (Group A), n = 1 (Group B) Septicaemia n = 0 (Group A), n = 1 (Group B) Pulmonary embolism n = 0 (Group A), n = 1 (Group B) Unknown n = 1 (Group A), n = 1 (Group B) Cancer n = 1 (Group A), n = 1 (Group B)

Plasma Exchange

683

MEPEX-Trial

Randomized trial of plasma exchange or high-dosage Methylprednisolone as adjunctive therapy for severe renal vasculitis

Substance

Seven Plasma exchanges (Group A, n = 70) 3,000 mg of intravenous methylprednisolone (Group B, n = 67) Both groups: Oral 2.5 mg/kg cyclophosphamide/day (reduced to 1.5 mg/kg/day after 3 months) Oral 1 mg/kg prednisolone/day Taper to 0.25 mg/kg/day by week 10 10 mg total/day from months 5 to 12 Concomitant medication: Prophylaxsis against fungal infection and Pneumocystis jirovecii pneumonia suggested

Result

Plasma exchange, in comparison to intravenous methylprednisolone, increased the rate of renal recovery in Wegener’s granulomatosis and microscopic polyangiitis presenting with renal failure on a background of oral cyclophosphamide and prednisolone. Patient survival and severe adverse event rates were similar in both groups

Patients

137 patients with a new diagnosis of vasculitis Wegener’s granulomatosis (n = 42) Microscopic polyangiitis (n = 95) Biopsy-proven pauci-immune, necrotizing and/or crescentic glomerulonephritis (GN) Serum creatinine 500 mmol/L (5.8 mg/dL) Major exclusion criteria: Antibodies to glomerular basal membrane Life-threatening other organ manifestation Dialysis for >2 weeks before entry Creatinine >200 mmol/L ³1 year before entry Previous necrotizing and/or crescentic GN Previous major or longer immunosuppressive medication ANCA-negative n = 3 BVAS 21 (median), Vasculitis damage index 0 (median)

Authors

Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, Mirapeix E, Savage CO, Sinico RA, Stegeman CA, Westman KW, van der Woude FJ, de Lind van Wijngaarden RA, Pusey CD; European Vasculitis Study Group

Publication

J Am Soc Nephrol. 2007;18(7):2180–2188. Epub June 20, 2007

Follow-up

12 months

684

Plasma Exchange

Note

Alive and independent of dialysis at month 3: 69% (Group A), 49% (Group B) Patient survival at month 12: 76% (Group A), 48% (Group B) Treatment in Group A was associated with a reduction in risk for progression to end stage renal disease of 24%, as compared to Group B (from 43% to 19%) at month 12

Adverse events

Leukopenia mild 52% (Group B), 10% (Group A) Severe 10% (Group B), 11% (Group A) Recurrent Leukopenia mild 19% (Group B), 3% (Group A) Severe 16% (Group B), 6% (Group A) Infection mild 19% (Group B), 24% (Group A) Infection severe 25% (Group B), 15% (Group A) Thrombopenia mild 3% (Group B), 0% (Group A) Thrombopenia severe 4% (Group B), 7% (Group A) Allergy mild 6% (Group B), 0% (Group A) Allergy severe 8% (Group B), 0% (Group A) Cardiovascular mild 3% (Group B), 4% (Group A) Cardiovascular severe 1% (Group B), 4% (Group A) Diabetes mild 4% (Group B), 3% (Group A) Diabetes severe 3% (Group B), 1% (Group A) Gastrointestinal mild 0% (Group B), 1% (Group A) Gastrointestinal severe 4% (Group B), 3% (Group A) Bone fracture mild 0% (Group B), 3% (Group A) Bone fracture severe 1% (Group B), 3% (Group A) Thrombosis mild 1% (Group B), 0% (Group A) Thrombosis severe 1% (Group B), 4% (Group A) Haemorrhage mild 1% (Group B), 1% (Group A) Haemorrhage severe 10% (Group B), 11% (Group A) Alopecia mild 0% (Group B), 0% (Group A) Alopecia severe 3% (Group B), 0% (Group A) Vascular access complications mild 0% (Group B), 1% (Group A) Vascular access complications severe 1% (Group B), 11% (Group A)

Purpura Schoenlein Henoch

Corticosteroids

Trial

Early prednisone therapy in Henoch-Schönlein purpura: a randomized, double-blind, placebo-controlled trial

Substance

Prednisone/day at 1 mg/kg b.i.d, for 14 day (max. 50 mg) Tapered by 0.5 mg/kg/day for 1 week To 0.5 mg/kg/day on alternate days (n = 84) or Placebo tablets in equal administration pattern (n = 87) Concomitant medication: Analgetics (paracetamol was permitted)

Result

Some patients with Henoch-Schönlein purpura benefitted from early prednisone treatment. It reduced extra-renal symptoms and positively influenced (but did not prevent) the course of renal involvement, especially in children older than 6 years

Patients

171 patients <16 years of age Clinical diagnosis of Henoch-Schönlein purpura Typically distributed purpura or petechiae With or without gastrointestinal and/or joint pain Major exclusion criteria: Thrombocytopenia Systemic vasculitis Established nephritis

Authors

Ronkainen J, Koskimies O, Ala-Houhala M, Antikainen M, Merenmies J, Rajantie J, Ormälä T, Turtinen J, Nuutinen M

Publication

J Pediatr. 2006;149(2):241–247

Follow-up

6 months

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_14, © Springer-Verlag London Limited 2011

685

686

Note

Purpura Schoenlein Henoch: Corticosteroids

Difference in the improvement of renal symptoms: Prednisone compared to placebo: –27% (month 1), –21% (month 3), –23% (month 6) Free of renal symptoms at study end (patients ≥6 years only): 63% (prednisone), 15% (placebo) Systolic blood pressure (mmHg) 109 (prednisone), 106 (placebo) Diastolic blood pressure (mmHg) 64 (prednisone), 61 (placebo) Need for analgesic (days) 2.2 (prednisone), 2.7 (placebo) Change of: Increase in weight (kg) +1.4 (prednisone), +0.4 (placebo) Abdominal pain score Severity 2.5 (prednisone), 4.8 (placebo) Duration 1.5 (prednisone), 2.7 (placebo) Joint pain score Severity 4.6 (prednisone), 7.3 (placebo) Duration 3.1 (prednisone), 4.4 (placebo)

Adverse events

Improved appetite 31% (prednisone), 0% (placebo) Increased liveliness 8% (prednisone), 0% (placebo)

Purpura Schoenlein Henoch: Corticosteroids

Trial

A randomized, placebo-controlled trial of prednisone in early Henoch Schönlein Purpura [ISRCTN85109383]

Substance

Oral prednisone, 2 mg/kg/day (n = 21) Tapered over 1 week to 25% of starting dose, then discontinuation Or Placebo (n = 19)

Result

40 children with Henoch Schönlein Purpura Age 2–15 years ³6 days of disease onset

687

± 1 of the following: Arthritis Renal involvement (defined as haematuria on urine microscopy ³5 red blood cells per high powered field, proteinuria ³0.3 g/l) Hypertension ³90th percentile for age and gender Gastrointestinal involvement (abdominal pain, gross or occult blood in stool, or a surgical complication, such as intussusception or perforation) Major exclusion criteria: Any corticosteroid treatment within the previous month Life-threatening complication of HSP Renal involvement n = 4 (prednisone) n = 2 (placebo) Gastrointestinal involvement n = 18 (Prednison) n = 11 (placebo) Patients

Early prednisone therapy in Henoch Schönlein Purpura did not reduce the risk of renal involvement at one year or the risk of acute gastrointestinal complications. There were no cases of intussusceptions in the prednisone group

Authors

Huber AM, King J, McLaine P, Klassen T, Pothos M

Publication

BMC Med. 2004;2:7

Follow-up

1 year

Note

Renal involvement n = 3 (prednisone) n = 2 (placebo) at 1 year No difference between groups, also with respect to start of study Rash duration 7 days (prednisone), 11 days (placebo) Joint pain duration 3 days (prednisone), 6 days (placebo) Abdominal pain duration 5.5 days (prednisone), 2 day (placebo)

Adverse events

Gastrointestinal complications n = 2 (prednisone), n = 3 (placebo) Intussusceptions n = 0 (prednisone), n = 2 (placebo)

688

Purpura Schoenlein Henoch: Azathioprine

Trial

Can Azathioprine and steroids alter the progression of severe HenochSchönlein nephritis in children?

Substance

Group A, n = 10: Azathioprine/day, at 2 mg/kg, for 8 months + prednisolone Group B, n = 10: Prednisolone alone Corticosteroid therapy: Oral prednisolone 2 mg/kg/day on alternate days for 4 weeks Tapered to 1.5, 1.0 and 0.5 mg/kg every other day, each for 2 months Initial pulse 30 mg/kg Methylprednisolone for 6 alternate days n = 2 (Group A), n = 0 (Group B) Concomitant therapy: Angiotensin-converting enzyme inhibitors for blood pressure control n = 5 (Group A), n = 7 (Group B)

Result

There was a tendency for superiority of the combination treatment with azathioprine and steroids, in comparison to steroids alone, in improving the clinical course of severe Henoch-Schönlein nephritis

Patients

20 Henoch-Schönlein patients median age 9.3 years nephritis with nephrotic proteinuria Major exclusion criterion: Previous treatment with cytotoxic drugs

Authors

Shin JI, Park JM, Shin YH, Kim JH, Lee JS, Kim PK, Jeong HJ

Publication

Pediatr Nephrol. 2005;20(8):1087–1092. Epub 2005 May 12

Follow up

4.8 years (mean)

Note

Resolution of hematuria n = 6 (Group A), n = 4 (Group B) Resolution of proteinuria n = 8 (Group A), n = 6 (Group B) Favorable clinical response n = 10 (Group A), n = 6 (Group B) Unfavorable clinical response n = 0 (Group A), n = 4 (Group B) Description of histological changes in kidney biopsies (repeat biopsies performed in Group A only)

Purpura Schoenlein Henoch: Ciclosporin

Trial

Cyclosporin A therapy for severe Henoch-Schönlein nephritis with nephrotic syndrome

Substance

Oral prednisolone, n = 5 Initial pulse 30 mg/kg methylprednisolone (6 × on alternate-days i.v. 30 mg/kg; max. 1.0 g/day), then oral prednisolone, n = 2 + ciclosporin A 5 mg/kg/day, mean duration 10.6 months

689

Concomitant therapy: Angiotensin-converting enzyme (ACE) inhibitors for blood pressure control n = 4 (2.5 mg cilazapril once daily) Previous medication: No immunosuppressive therapy Result

Retrospective analysis of a case series without controls, showing a possible beneficial effect of ciclosporin A plus prednisolone treatment in severe Henoch-Schönlein nephritis

Patients

Seven patients with severe Henoch-Schönlein nephritis With nephrotic syndrome Hypoalbuminemia <2.5 g/dl Urinary protein excretion >40 mg/m2/h Mean age 6.5 years

Authors

Shin JI, Park JM, Shin YH, Kim JH, Kim PK, Lee JS, Jeong HJ

Publication

Pediatr Nephrol. 2005;20(8):1093–1097. Epub 2005 Jun 10

Follow up

5.5 years/4.3 years (median) after: disease onset/cessation of ciclosporin A therapy

Note

Proteinuria (g/m2/day) –8.9 No proteinuria at latest observation n = 6 Total protein +2.9 g/dl Albumin (g/dl) +2.5 Creatinine (mg/dl) +0.1 Creatinine clearance (ml/min/1.73 m2) +45 Histopathologic changes (n = 7): Activity index –2.9 Chronicity index +0.1 Tubulointerstitial scores –0.6

690

Purpura Schoenlein Henoch: Cyclophosphamide

Trial

Henoch-Schönlein purpura nephritis: course of disease and efficacy of yclophosphamide

Substance

Cyclophosphamide, 90 mg/m2/day (Group A, n = 28) for 42 days Control (Group B, n = 28) Group C: patients followed concurrently outside trial (n = 23) Concomitant therapy: Diet modifications Diuretics Exchange resins Vitamins

Result

Cyclophosphamide treatment of severe Henoch-Schönlein nephritis did not result in more full recoveries of nephritis than supportive therapy alone

Patients

56 patients with histo-pathologically severe Henoch-Schönlein nephritis Age 12 weeks–16 years Estimated GFR ³35 ml/min/1.73 m2 Inclusion criteria: Age between 12 and 16 years Biopsy-proven HSP nephritis histopathology ³ Grade III With heavy proteinuria for >1 month Estimated glomerular filtration rate >35 ml/min/1.73 m2 Purpura + urticaria, affecting lower limbs and possibly buttocks and elbows + ≥1 of the following: Joint pain and swelling Renal involvement Abdominal pain Intestinal bleeding Major exclusion criteria: Prior immunosuppressive drugs Henoch-Schönlein purpura present for >3 months

Authors

Tarshish P, Bernstein J, Edelmann CM Jr

Publication

Pediatr Nephrol. 2004;19(1):51–56. Epub 2003 Nov 22

Follow up

6.93 years (recoveries), 3.71 years (persistent abnormities)

Note

Fully recovered n = 14 (Group A), n = 13 (Group B), n = 16 (Group C) Persistent mild abnormalities n = 8 (Group A), n = 6 (Group B), n = 0 (Group C) Persistent moderate/severe abnormalities n = 4 (Group A), n = 4 (Group B), n = 0 (Group C) End stage renal disease/death n = 3 (Group A), n = 4 (Group B), n = 1 (Group C)

Purpura Schoenlein Henoch: Cyclophosphamide

691

Trial

Efficacy of methylprednisolone and urokinase pulse therapy combined with or without cyclophosphamide in severe Henoch-Schoenlein nephritis: a clinical and histopathological study

Substance

Retrospectively analyzed without randomization: Group A (n = 20): 30 mg/kg methylprednisolone/day i.v. at on 3 days followed by oral 1 mg/kg prednisolone/day for 6 months Then tapering of prednisolone until discontinuation over 3 months + urokinase at 5,000 units/kg/day i.v. on 7 days Group B (n = 17): 30 mg/kg methylprednisolone/day i.v. at on 3 days followed by oral 1 mg/kg prednisolone/day for 6 months Then tapering of prednisolone until discontinuation over 3 months + urokinase at 5,000 units/kg/day i.v. on 7 days + cyclophosphamide/day at 2.5 mg/kg for 12 weeks Concomitant medication: 1 mg warfarin/day for 24 months. Along with 5 mg/kg dipyridamole/day

Result

Methylprednisolone and urokinase pulse therapy, combined with cyclophosphamide, showed improvement of nephritic symptoms and changes in severe Henoch-Schoenlein nephritis, as compared to methylprednisolone and urokinase pulse therapy alone in this retrospective analysis

Patients

37 patients with Henoch-Schoenlein nephritis grade IVb Inclusion criteria: Age <15 years Diagnosed clinically by pupuric rash and abdominal pain without thrombocytopenia With additional arthritis and nephritis consistent with the diagnosis Major exclusion criterion: Previous treatment with immunosuppressive drugs

Authors

Kawasaki Y, Suzuki J, Suzuki H

Publication

Nephrol Dial Transplant. 2004;19(4):858–864

Follow up

24 months

692

Note

Purpura Schoenlein Henoch: Cyclophosphamide

Urinary protein expretion (mg/m2/h) –140 (Group A), –175 (Group B) Haematuria –15% (Group A), –17% (no haematuria at the end of follow up, Group B) Serum albumine (g/l) +3 (Group A), +14 (Group B) Serum creatinine (µmol/l) –10 (Group A), –23 (Group B) Mean blood pressure (mmHg) –4 (Group A), –11 (Group B) Change of renal biopsy staging: Stage 0: +40% (Group A), +76% (Group B) Stage 1: –40% (Group A), –64% (Group B) Stage 2: 0% (Group A), –12% (Group B) Stage 3: 0% (Group A), 0% (Group B)

Adverse events

Cushingoid changes n = 5 (Group A), n = 5 (Group B) Glaucoma n = 3 (Group A), n = 2 (Group B) Mild growth retardation n = 1 (Group A), n = 1 (Group B) Mild hypertension n = 1 (Group A), n = 0 (Group B) Leukopenia n = 0 (Group A), n = 1 (Group B) Infections n = 1 (Group A), n = 1 (Group B)

Morbus Behçet

Corticosteroids

Trial

A double-blind trial of depot corticosteroids in Behçet’s syndrome

Substance

40 mg methylprednisolone acetate (n = 42) Placebo (n = 44) Every 3 weeks for 27 weeks Concomitant medication: NSAIDs n = 1 (steroid), n = 4 (placebo) Low dose aspirine n = 3 (steroid), n = 3 (placebo) Amitriptyline n = 2 (steroid), n = 4 (placebo) Colchicine n = 18 (steroid), n = 24 (placebo) Previous medication: Corticosteroids <5 mg/day were permitted

Result

Low-dose depot corticosteroids treatment of genital ulcers of patients suffering from Behçet’s syndrome did not have any beneficial effect on genital ulcers. Erythema nodosum lesions improved

Patients

86 Behçet’s syndrome patients Who had active disease with ³1 genital ulcers occurring £6 months No severe organ involvement

Authors

Mat C, Yurdakul S, Uysal S, Gogus F, Ozyazgan Y, Uysal O, Fresko I, Yazici H

Publication

Rheumatology (Oxford). 2006;45(3):348–52. Epub 2005 Nov 1

Follow up

27 weeks

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8_15, © Springer-Verlag London Limited 2011

693

694

Note

Morbus Behçet: Corticosteroids

Treatment period: Genital ulcers 0.3 (Steroid), 0.3 (placebo) Oral ulceration 1.8 (Steroid), 1.8 (placebo) Erythema nodosum 0.1 (Steroid), 0.3 (placebo) Folliculitis 1.1 (Steroid), 1.0 (placebo) Joints with arthritis 0.1 (Steroid), 0.1 (placebo) Post-treatment period: Genital ulcers 0.1 (Steroid), 0.1 (placebo) Oral ulceration 1.9 (Steroid), 2.0 (placebo) Erythema nodosum 0.2 (Steroid), 0.6 (placebo) Folliculitis 1.0 (Steroid), 0.9 (placebo) Joints with arthritis 0.1 (Steroid), 0.1 (placebo) Treatment period (females only): Genital ulcers 0.2 (Steroid), 0.4 (placebo) Oral ulceration 1.8 (Steroid), 1.8 (placebo) Erythema nodosum 0.2 (Steroid), 0.4 (placebo) Folliculitis 0.7 (Steroid), 0.8 (placebo) Joints with arthritis 0.2 (Steroid), 0.1 (placebo) Post-treatment period (females only): Genital ulcers 0.0 (Steroid), 0.2 (placebo) Oral ulceration 1.9 (Steroid), 2.1 (placebo) Erythema nodosum 0.2 (Steroid), 0.8 (placebo) Folliculitis 0.6 (Steroid), 0.8 (placebo) Joints with arthritis 0.2 (Steroid), 0.1 (placebo) Treatment period (males only): Genital ulcers 0.3 (Steroid), 0.3 (placebo) Oral ulceration 1.8 (Steroid), 1.8 (placebo) Erythema nodosum 0.1 (Steroid), 0.2 (placebo) Folliculitis 1.6 (Steroid), 1.3 (placebo) Joints with arthritis 0.0 (Steroid), 0.1 (placebo) Post-treatment period (males only): Genital ulcers 0.1 (Steroid), 0.0 (placebo) Oral ulceration 1.8 (Steroid), 1.8 (placebo) Erythema nodosum 0.2 (Steroid), 0.4 (placebo) Folliculitis 1.4 (Steroid), 1.0 (placebo) Joints with arthritis 0.0 (Steroid), 0.1 (placebo)

Adverse events

Fatigue 42% (Steroid), 67% (placebo) Increased appetite 17% (Steroid), 46% (placebo) Weight gain 47% (Steroid), 51% (placebo) Facial swelling 11% (Steroid), 10% (placebo) Abdominal pain 22% (Steroid), 18% (placebo) Hypertrichosis 6% (Steroid), 0% (placebo)

Morbus Behçet: Azathioprine

Trial

A controlled trial of Azathioprine in Behçet’s syndrome

Substance

2.5 mg/kg azathioprine/d (group 1: n = 12, group 2: n = 13) Placebo (group 1: n = 25, group 2: n = 23) Severe exacerbation: 1,000 mg methylprednisolone on 3 alternate days Or oral corticosteroid Alternative immunosuppressive agents were permitted Concomitant medication: No information provided Previous medication: No immunosuppressive agents

Result

Azathioprine was superior to placebo in preventing ocular manifestations in patients suffering from Behçet’s syndrome

Patients

Turkish men with Behçet’s syndrome fulfilling the O’Duffy criteria for diagnosis No history/evidence of uveitis (group 1: n = 25) With uveitos (group 2: n = 48) Disease duration £24 months Major exclusion criteria: No bilateral eye disease Patients with non-assessable fundi were excluded

Authors

Yazici H, Pazarli H, Barnes CG, Tüzün Y, Ozyazgan Y, Silman A, Serdaroğlu S, Oğuz V, Yurdakul S, Lovatt GE, et al

Publication

N Engl J Med. 1990;322(5):281–285

Follow up

2 years

695

696

Note

Morbus Behçet: Azathioprine

Group 1: Necessitating withdrawal n = 0 (Aza), n = 0 (placebo) New eye disease n = 1 (Aza), n = 8 (placebo) Hypopyon uveitis n = 0 (Aza), n = 0 (placebo) Pulse i.v. corticosteroid n = 0 (Aza), n = 1 (placebo) Oral corticosteroid treatment n = 0 (Aza), n = 0 (placebo) Group 2: Necessitating withdrawal n = 0 (Aza), n = 6 (placebo) Involvemen of previous unaffected eye n = 0 (Aza), n = 5 (placebo) Hypopyon uveitis n = 1 (Aza), n = 7 (placebo) Pulse i.v. corticosteroid n = 6 (Aza), n = 10 (placebo) Oral corticosteroid treatment n = 1 (Aza), n = 4 (placebo) New during drug trial: Oral ulcerations 52% (Aza), 47% (placebo) Genital ulcerations 10% (Aza), 38% (placebo) Erythema nodosum 19% (Aza), 21% (placebo) Papulopustular lesions 79% (Aza), 85% (placebo) Arthritis 3% (Aza), 23% (placebo) Thrombophlebitis 11% (Aza), 26% (placebo) Neurological involvement no change 6% (Aza), 8% (placebo) Present at 24 months: Oral ulcerations 12% (Aza), 35% (placebo) Genital ulcerations 3% (Aza), 13% (placebo) Erythema nodosum 0% (Aza), 0% (placebo) Papulopustular lesions 79% (Aza), 74% (placebo) Arthritis 3% (Aza), 9% (placebo) Thrombophlebitis 29% (Aza), 35% (placebo) Neurological involvement no change 3% (Aza), 4% (placebo)

Adverse events

Low white cell counts n = 11 (Aza), n = 3 (placebo) Gastrointestinal 23% (Aza), 18% (placebo) Abdominal pain 6% (Aza), 3% (placebo) Nausea 6% (Aza), 5% (placebo) Indigestion 5% (Aza), 1% (placebo)

Morbus Behçet: Azathioprine

Trial

Azathioprine in Behcet’s syndrome: effects on long-term prognosis

Substance

2.5 mg/kg azathioprine/day (n = 12, group 1, n = 25 group 2) Placebo (n = 13, group 1, n = 23, group 2) Deterioration: Systemic corticosteroids or Patients were withdrawn from the trial Concomitant medication: No information provided Previous medication: No immunosuppressive agents Post trial period: Ciclosporin A and subsequent cyclophosphamide were added in case of an active disease

Result

Early treatment with azathioprine favourably affected the long-term prognosis of Behçet’s syndrome

Patients

Behcet’s syndrome patients fulfilling the O’Duffy criteria for diagnosis n = 73 Disease duration (<24months) Group 1: Absence of eye involvement n = 25 Group 2: Presence of eye involvement n = 48

Authors

Hamuryudan V, Ozyazgan Y, Hizli N, Mat C, Yurdakul S, Tüzün Y, Senocak M, Yazici H

Publication

Arthritis Rheum. 1997;40(4):769–774

Follow up

80 months

Note

New mild eye involvement (group 1) n = 4 (placebo), n = 0 (Aza) Emergence of a 2-line drop in visual acuity Group 2 right eye n= 6 (placebo), n = 6 (Aza) Emergence of a 2-line drop in visual acuity Group 2 left eye n = 10 (placebo), n = 6 (Aza) Blindness n = 3 (group 2, placebo), n = 1 (group 2, Aza) Deveolped blindness during follow up n = 8 (group 2, placebo), n = 3 (group 2 Aza) Neurologic involvement n = 2 (group 2, placebo), n = 2 (group 2, Aza) Drop in visual acuity of the right eye n = 6 of 10 (group 2), n = 3 of 10 (group 2, Aza), n = 2 of 7 (group 2, placebo), n = 1 of 9 (group 2, Aza)

Adverse events

Pulmonary artery aneurysm n = 1 (group 1 placebo), n = 1 (group 2 placebo) Vena cava superior syndrome n = 1 (group 1 placebo) none (group 1, Aza) Carotid artery aneurysm and secondary amyloidosis n = 1 (group 2 placebo) Death n = 4 (placebo), n = 1 (Aza)

697

698

Morbus Behçet: Ciclosporin vs. Colchicine

Trial

Double-masked trial of Cyclosporin versus Colchicine and long-term open study of Cyclosporin in Behçet’s disease

Substance

10 mg/kg ciclosporin/day (CsA, n = 47) 1 mg colchicine/day (n = 49) When CsA was stoped colchicine was introduced Concomitant medication: No information provided Previous medication: No information provided

Result

Ciclosporin was effective in treating not only the ocular manifestations of Behçet’s disease but also oral aphthous ulcers, dermal lesions, and genital ulcerations. Efficacy remained stable during long-term treatment

Patients

36 patients with compete or incomplete Behçets disease Ocular lesions Visual acuity £20/40 ³3 occular attacks during 16 weeks prior randomization

Authors

Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G

Publication

Lancet. 1989;1(8647):1093–1096

Follow up

80 weeks

Note

Improvement of clinical symptoms 91% (CsA), 33% (colchicine) Dermal leasion improvemen 40% (CsA), 15% (colchicine) Improvement of clinical symptoms 91% (CsA), 33% (colchicine)

Adverse events

Hirsutism n = 23 (CsA), n = 2 (colchicine) Renal dysfunction n = 1 (CsA), n = 2 (colchicine) Hepatic dysfunction n = 0 (CsA), n = 2 (colchicine) Gingival hypertrophy n = 6 (CsA), n = 0 (colchicine)

Morbus Behçet: Ciclosporine

Trial

Cyclosporin in Behçet’s disease: results in 16 patients after 24 months of therapy

Substance

5 mg/kg/day of ciclosporin (serum level 300–900 ng/ml) Concomitant medication: No information provided Previous medication: Previously treated with corticosteroids and/or cytotoxic agents, both stoped ³10 day

Result

Ciclosporin was an effective treatment of ocular and aphtous symptoms of patients suffering from Behçet’s disease

Patients

16 Behçet’s syndrome patients fulfilling the Nussenblatt criteria With all 4 major symptoms: Aphthous stomatitis Genital ulcers Ocular lesions Skin manifestations

Authors

Pacor ML, Biasi D, Lunardi C, Cortina P, Caramaschi P, Girelli D, Botto M, Urbani G, Lombardo G, Bambara LM

Publication

Clin Rheumatol. 1994;13(2):224–227

Follow up

24 months

Note

Clinical remission n = 14 (6–12 months) Change of: Visual acuity +3

Adverse events

Renal dysfunction n = 1 Anaemia n = 1 Increases alanin aminotransferase and alkaline phosphatase n = 0 Hirsutism n = 2 Gastrointestinal discomfort n = 1

699

700

Morbus Behçet: Ciclosporine

Trial

Low dose Cyclosporin-A therapy in Behçet’s disease

Substance

Ciclosporin-A (5 mg/kg/day as initial dose) No improvement (after week 2): + 0.2–0.6 mg/kg/day prednisolone Previous medication: Chlorambucil n = 6 Colchicine n = 2 Cyclophosphamide n = 2 Prednisolone (all)

Result

Ciclosporin-A treatment of Behçet’s disease patients lead to an improvement of ocular disease

Patients

22 morbus Behçet patients With severe ocular involvement HLA B5 pos 50%

Authors

Sajjadi H, Soheilian M, Ahmadieh H, Hassanein K, Parvin M, Azarmina M, Ehyaee V, Amiransari B

Publication

J Ocul Pharmacol. 1994 Fall;10(3):553–560

Follow up

4–32 months

Note

Improvement or stabilization of vision 95% Control of intraocular inflammation 100% Improvement of visual acuity +59%

Adverse events

Rise in creatinine 45% Rise in bilirubin in 27% Hypertrichosis 18% Increase uric acid 14% Hypertension 4.5% Gynecomastia 4.5% Gingivitis 4.5%

Morbus Behçet: Ciclosporin vs. Cyclophosphamide

Trial

Low dose Ciclosporin A versus pulsed Cyclophosphamide in Behçet’s syndrome: a single masked trial

Substance

Ciclosporin A 5 mg/kg/day (CsA, n = 11) Cyclophosphamide 1 g intravenous monthly boluses (CYC, n = 12) Concomitant medication: Corticosteroid together with CYC (1 month)

Result

Cyclosporin was effective in the treatment of uveitis in Behçet’s disease

Patients

23 patients with Behçet’s syndrome With active, bilateral uveitis ³3 ocular disease exacerbations within the preceding 6 months No end stage disease No irreversible damage No blindness

Authors

Ozyazgan Y, Yurdakul S, Yazici H, Tüzün B, Işçimen A, Tüzün Y, Aktunç T, Pazarli H, Hamuryudan V, Müftüoğlu A

Publication

Br J Ophthalmol. 1992;76(4):241–243

Follow up

24 months

Note

Number of ocular attacks (6 months) 0.48 (CsA), 0.62 (CYC) Number of ocular attacks (6 months – unmasking) 0.49 (CsA), 0.60 (CYC) Changes after 6 months: Visual acuity +2.36 (CsA), –0.63 (CYC)

701

702

Morbus Behçet: Colchicine

Trial

A double-blind trial of Colchicine in Behçet’s syndrome

Substance

Colchicine (1–2 mg/day, adjusted to body weight, n = 58) Placebo (n = 58) Concomitant medication: NSAIDs n = 3 (colchicine), n = 3 (placebo) Intraarticular corticosteroids n = 1 (colchicine), n = 1 (placebo) 1 g methylprednisolone for 3 days n = 0 (colchicine), n = 1 (placebo) 100 mg thalidomide for 1 week and 50 mg for 2 weeks n = 0 (colchicine), n = 1 (placebo) Previous medication: No immunosuppressive agents £6 months

Result

Colchicine was useful in treating some of the manifestations of Behçet’s syndrome, especially of women

Patients

116 consecutive patients with Behçet’s syndrome fulfilling the criteria of the International Study Group for Behcet’s Disease (60 male/56 female) Active mucocutaneous disease No eye involvement No major organ involvement Disease duration of £2 years Minimum presence of oral or genital ulceration or erythema nodosum occurring ³3 times within the preceding 6 months 18–35 years of age

Authors

Yurdakul S, Mat C, Tüzün Y, Ozyazgan Y, Hamuryudan V, Uysal O, Senocak M, Yazici H

Publication

Arthritis Rheum. 2001;44(11):2686–2692

Follow up

24 months

Note

Absence of arthritis 91% (colchicine), 64% (placebo) Inflamed joints women 0.3 (colchicine), 2.4 (placebo), men 2.8 (colchicine), 4.4 (placebo) Erythema nodosum women 1.4 (colchicine), 6.0 (placebo), men 0.7 (colchicine), 2.0 (placebo) Free of new attacks of genital ulceration women 89% (colchicine), 46% (placebo), men no difference

Adverse events

Loss of appetite 38% (colchicine), 34% (placebo) Nausea 26% (colchicine), 39% (placebo) Abdominal pain 41% (colchicine), 30% (placebo) Diarrhoea 44% (colchicine), 36% (placebo) Superficial Thrombophlebitis n = 1 (colchicine), n = 5 (placebo)

Morbus Behçet: Cyclophosphamide vs. Colchicine

Trial

Long-term effects of Cyclophosphamide and Colchicine treatment in Behçet’s disease

Substance

100–150 mg cyclophosphamide (CYC, n = 46) 1–1.5 mg colchicine (n = 18) Concomitant medication: 5 mg prednisolone/day Previous medication: No information provided

Result

No statistically significant positive changes in ocular symptoms which might be attributed to the treatment could be shown when compared with the period after treatment

Patients

64 patients with Behcet’s disease With ocular disease

Authors

Kazokoglu H, Saatçi O, Cuhadaroglu H, Eldem B

Publication

Ann Ophthalmol. 1991;23(4):148–151

Follow up

9–156 months

Note

Mean number of attacks during treatment n = 3.4 (CYC), n = 1.94 (colchicine) Mean number of attacks during treatment n = 2.54 (CYC), n = 1.27 (colchicine) Mean total attacks n = 7.32 (CYC), n = 3.22 (colchicine) Mean follow up 84.2 months (CYC), 43.05 months (colchicine) Mean Period post treatment 51.06 months (CYC), 15.33 months (colchicine) Macular pigment epithelial alteration 47.6% (CYC), 46.4% (colchicine) Optic atrophy 44.6% (CYC), 50.0% (colchicine) Perivascular sheating 26.2% (CYC), 7.1% (colchicine) Chorioretinal atrophy 7.6% (CYC), 3.5% (colchicine) Branch vein occlusion 1.5% (CYC), 0% (colchicine) Cystoid macular oedema 1.5% (CYC), 3.5% (colchicine) Univisualized fundi n = 8 (CYC), n = 2 (colchicine) Posterior synechias 28.7% (CYC), 46.6% (colchicine) Complicated cataract 26.0% (CYC), 21.4% (colchicine) Seclusio pupillae 6.8% (CYC), 0% (colchicine) Rubeosis 4.1% (CYC), 3.3% (colchicine) Secondary glaucoma 2.7% (CYC), 0% (colchicine) Phthisis 4.1% (CYC), 0% (colchicine)

Adverse events

Azoospermia 73.3% (CYC), 0% (colchicine) Hemorrhagic cystitis 10.8% (CYC), 0% (colchicine)

703

704

Morbus Behçet: Dapsone

Trial

Dapsone in Behçet’s disease: a double-blind, placebo-controlled, cross-over study

Substance

100 mg dapsone/day (n = 10) Placebo (n = 10) Treatment was crossed over after 3 months Concomitant medication: No information provided

Result

Dapsone was effective in the treatment of mucocutaneous manifestations of Behçet’s disease and possibly in the prophylaxis against systemic manifestations of the disease

Patients

20 patients with Behçet’s disease according to the criteria of the International Study Group Mucocutaneous manifestations Joint involvement Oral aphtae ± 2 symptoms out of: Recurrent genital aphtae Eye lesions Skin lesions Pos. Pathergy test No eye/neurological involvement No anaemia Mo glucose-6-phosphatase dehydrogenase deficiency

Authors

Sharquie KE, Najim RA, Abu-Raghif AR

Publication

J Dermatol. 2002;29(5):267–279

Follow up

6 months

Note

Change of (3 months): Count of oral ulcers –2.7 (Starting dapsone), –2.5 (dapsone after placebo), +1.3 (placebo after dapsone), –2.7 (starting with placebo) Size of oral ulcers –0.4 (dapsone), +0.2 (placebo), +1.4 (placebo after dapsone), –0 (starting with placebo) Duration of ulcers –2.2 (dapsone), –4.7 (placebo), +2.3 (placebo after dapsone), +3.3 (starting with placebo) Frequency of oral ulcers –1.7 (dapsone), –0.7 (placebo), +1.6 (placebo after dapsone), +0.6 (starting with placebo) Count of genital ulcers –0.8 (Starting dapsone), –0.9 (dapsone after placebo), +0.4 (placebo after dapsone), +0.4 (starting with placebo) Size of genital ulcers +1.1 (dapsone), –2.3 (placebo), –1.5 (placebo after dapsone), +1.3 (starting with placebo) Duration of genital ulcers +0.2 (dapsone), –6.3 (placebo), –1.5 (placebo after dapsone), +0.5 (starting with placebo) Frequency of genital ulcers –0.3 (dapsone), –0.5 (placebo), +0.3 (placebo after dapsone), +0.7 (starting with placebo)

Adverse events

After 3 months: None 26% (dapsone), 55% (placebo) Nausea 11% (dapsone), 10% (placebo) Dyspepsia 16% (dapsone), 5% (placebo) Anorexia 0% (dapsone), 0% (placebo) Fatigue 16% (dapsone), 25% (placebo) Anaemia 16% (dapsone), 5% (placebo) Headache 21% (dapsone), 5% (placebo)

Morbus Behçet: Methotrexate

Trial

Low-dose weekly Methotrexate for progressive neuropsychiatric manifestations in Behcet’s disease

Substance

5 mg oral MTX/week Increased by 2.5 mg every week up to 10–12.5 mg/w

705

Concomitant medication: Prednisolone £10 mg/day was permitted Colchicine 1 mg/day was permitted Previous medication: Prednisolone n = 4 Colchicine n = 2 I.v. cyclophosphamide n = 1 Mizoribine n = 1 Azatioprine n = 1 Ciclosporin A n = 1 Result

Weekly MTX therapy was beneficial in delaying disease progression of Neuro-Behçet’s symptoms

Patients

6 patients with Behçet’s disease according to the criteria of the International Study Group Neuropsychiatric manifestations were judged to be progressive variety of neurological, including meningitis, dysarthria, ataxia

Authors

Hirohata S, Suda H, Hashimoto T

Publication

J Neurol Sci. 1998;159(2):181–185

Follow up

12 months

Note

The neuropsychological manifestations did not significantly worsen MRI scans did not significantly worsen Intelligence quotients not significantly changed Discontinuation of MTX after 12 months resulted in a mild exacerbation of symptoms IL-6 levels decreased n = 6

Adverse events

Mild liver dysfunction n = 3

706

Morbus Behçet: Methotrexate

Trial

Low dose MTX for progressive Neuro-Behçet’s disease. A follow-up study for 4 years

Substance

Methotrexate 5–7.5 mg/week Increased to 5–15 mg in steps of 2.5 mg every 2 weeks Concomitant medication: Prednisolone £15 mg/day was permitted Colchicine 1 mg/day was permitted 5–10 g folate/week was permitted Previous medication: Prednisolone n = 4 Colchicine n = 2 I.v. cyclophosphamide n = 1 Mizoribine n = 1 Azatioprine n = 1 Ciclosporin A n = 1

Result

Low dose methotrexate had beneficial effects on Neuro-Behçet patients. Treatment was well tolerated

Patients

10 patients, fulfilling the International criteria of Behcet’s disease, with neuropsychiatric manifestations

Authors

Kikuchi H, Aramaki K, Hirohata S

Publication

Adv Exp Med Biol. 2003;528:575–578

Follow up

4 years

Note

Neuropsychiatric manifestations, findings on MRI scans Intelligence quotient were not significantly worsened Cerebrospinal fluid IL 6 decreased in all patients after initiation of treatment Wechsler adult intelligence scale was stable in all but one patient

Adverse events

Mild liver dysfunction n = 3

Morbus Behçet: Mycophenolate mofetil

Trial

Mycophenolate mofetil is ineffective in the treatment of mucocutaneous Adamantiades-Behçet’s disease

Substance

2 g/day mycophenolate mofetil for 6 months If ineffective increased to 3 g/day + 30 mg prednisolone for 1 month Concomitant medication: No information provided Previous medication: No information provided

Result

2–3 g Mycophenolate mofetil/day was not able to control the signs of mucocutaneous Adamantiades-Behçet’s disease

Patients

30 patients, diagnosed by the CART criteria, with active cutaneous disease

Authors

Adler YD, Mansmann U, Zouboulis CC

Publication

Dermatology. 2001;203(4):322–324

Follow up

12 months

Note

The study was discontinued after the sixth patient because of ineffectiveness Mycophenolate mofetil/prednisolone treatment => reduction of the disease activity index 5.2 => 1.3 Withdrawal of prednisolone led to quick relapses

Adverse events

No adverse effects were assessed under Mycophenolate mofetil

707

708

Morbus Behçet: Tacrolimus

Trial

A multicenter clinical open trial of FK 506 in refractory uveitis, including Behçet’s disease. Japanese FK 506 Study Group on Refractory Uveitis

Substance

Tacrolimus 0.05 mg/kg (n = 9) Tacrolimus 0.10 mg/kg (n = 13) Tacrolimus 0.20 mg/kg (n = 7) For 12 weeks Concomitant medication: No information provided Previous medication: Colchicine n = 20 Ciclosporin (CsA) n = 16 Steroids n = 14 Cyclophosphamide n = 1

Result

Tacrolimus was benificial in Behçet`s disease with refractory uveitis

Patients

29 Patients with Behçet`s diseases With refractory uveitis Actively inflamed posterior segment Age 16–76 years

Authors

Mochizuki M, Masuda K, Sakane T, Inaba G, Ito K, Kogure M, Sugino N, Usui M, Mizushima Y, Ohno S, et al

Publication

Transplant Proc. 1991;23(6):3343–3346

Follow up

12 weeks

Note

Improvement of uveitis n = 2 (0.05 mg/kg tacrolimus), n = 6 (0.1 mg/kg tacrolimus), n = 2 (0.20 mg/kg tacrolimus) Dose was increased because of insufficient efficacy n = 7 (0.05 mg/kg tacrolimus), n = 4 (0.1 mg/kg tacrolimus) Improvement after increase of dosage n = 4 (0.05 mg/kg tacrolimus), n = 2 (0.1 mg/kg tacrolimus) Overall efficacy improvement 62%, unchanged 38% Improvement of visual acuitiy 32%, unchanged 50%, decreased 18%

Adverse events

Renal impairment n = 4 Tremor n = 3 Nausea n = 2 Hyperkalemia n = 1 Chest discomfort n = 1

Morbus Behçet: Thalidomide

Trial

Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial

Substance

Thalidomide, 100 mg/day (n = 32) Thalidomide, 300 mg/day (n = 32) Placebo (n = 31) For 24 weeks Concomitant/previous medication: No information was depicted

Result

Thalidomide was effective for treating the oral and genital ulcers and follicular lesions of the Behçet syndrome. No differences were found for 100 mg/d and 300 mg/day

Patients

96 male patients with the Behçet syndrome who met the international criteria Mucocutaneous lesions Without major organ involvement Age 18–35 years Min. 2 episodes of oral or genital ulcerations within 3 months No severe eye disease

Authors

Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H

Publication

Ann Intern Med. 1998;128(6):443–450

Follow up

28 weeks

Note

Complete response 6% (100 mg/day thalidomide), 16% (300 mg/day thalidomide, 300 mg/day); 0% (placebo) Sustained absence of ulcerations n = 10 (100 mg/day thalidomide), n = 9 (300 mg/day thalidomide, 300 mg/day); n = 0 (placebo) Activation in the eye n = 2 (100 mg/day thalidomide), n = 3 (300 mg/day thalidomide, 300 mg/day); n = 9 (placebo) Visual acuity scoring other than perfect n = 1 (100 mg/day thalidomide), n = 0 (300 mg/day thalidomide), n = 5 (placebo) Arthritis attacks n = 7 (100 mg/day thalidomide), n = 4 (300 mg/day thalidomide, 5 mg/day); n = 11 (placebo) Epididymitis n = 2 (100 mg/day thalidomide), n = 1 (300 mg/day thalidomide, 5 mg/day); n = 3 (placebo) Both thalidomide dosages led to significant increases in the number of erythema nodosum lesions Polyneurophathia developed in four patients

709

710

Adverse events

Morbus Behçet: Thalidomide

Sedation 50% (placebo), 84% (100 mg thalidomide), 87% (300 mg thalidomide) Fatigue 44% (placebo), 65% (100 mg thalidomide), 68% (300 mg thalidomide) Sleeplessness (16% (placebo), 25% (100 mg thalidomide), 19% (300 mg thalidomide) Numbness 28% (placebo), 28% (100 mg thalidomide), 23% (300 mg thalidomide) Tingling 25% (placebo), 34% (100 mg thalidomide), 26% (300 mg thalidomide) Constipation 25% (placebo), 59% (100 mg thalidomide), 65% (300 mg thalidomide) Transient rash 0% (placebo), 6% (100 mg thalidomide), 10% (300 mg thalidomide) Headache 34% (placebo), 38% (100 mg thalidomide), 29% (300 mg thalidomide)

Morbus Behçet: Etanercept

Trial

Short-term trial of Etanercept in Behçet’s disease: a double-blind, placebo-controlled study

Substance

Etanercept 25 mg twice a week (n = 20) Placebo (n = 20)

711

Concomitant medication: Prednisolone n = 2 (ETN), n = 2 (placebo) Indomethacin n = 1 (ETN), n = 0 (placebo) Naproxen n = 0 (ETN), n = 1 (placebo) Topical corticosteroids n = 0 (ETN), n = 4 (placebo) Paracetamol n = 1 (ETN), n = 4 (placebo) Ornidazole n = 1 (ETN), n = 0 (placebo) Azathioprine n = 1 (ETN), n = 1 (placebo) Previous medication: Colchicine withdrawal n = 11 (ETN), n = 7 (placebo) Azathioprine withdrawal n = 0 (ETN), n = 5 (placebo) Result

Ethanercept was effective in suppressing mucocutaneous manifestations

Patients

40 male patients suffering from Behçet’s disease, fulfilling the criteria of the International Study Group, with Age 18–45years Male gender Active disease, min 1 pos. out of: Min. one episode with oral or genital ulcerations Swollen joints Erythema nodosum within 3 months Pos. Pathergy test Swollen joints

Authors

Melikoglu M, Fresko I, Mat C, Ozyazgan Y, Gogus F, Yurdakul S, Hamuryudan V, Yazici H

Publication

J Rheumatol. 2005;32(1):98–105

Follow up

4 weeks + 3 months

Note

Change after 4 months: Pos. Pathergy –12 (ETN), –12 (placebo) Monosodium titrate (mm3) –1144 (ETN), –944 (placebo) Genital ulcers –0.6 (ETN), –0.43 (placebo) Nodular lesions +0.3 (ETN), –0.68 (placebo) Papulopustular lesions 0 (ETN), –0.49 (placebo) Swollen joints +0.34 (ETN), –0.25 (placebo)

Adverse events

Diarrhoea n = 1 (ETN), n = 0 (placebo) GI-Symptoms n = 1 (ETN), n = 0 (placebo) Increased liver enzymes n = 0 (ETN), n = 1 (placebo)

712

Morbus Behçet: Infliximab

Trial

Efficacy, safety, and pharmacokinetics of multiple administration of Infliximab in Behçet’s disease with refractory uveo-retinitis

Substance

Infliximab 5 mg/kg (n = 7) Infliximab 10 mg/kg (n = 6) After onset of ocular attacks: Colchicine was permitted Subconjunctival decadron injection or 20–40 mg of prednisolone administered orally for 1–4 weeks Previous medication: 2.36–5.88 mg/kg Ciclosporin/day was discontinued at study entry

Result

Administration of infliximab in patients with Behcet’s disease with refractory uveo-retinitis suppressed the frequency of ocular attacks

Patients

13 patients with Behçet’s disease Accompanied by refractory uveo-retinitis Despite ciclosporin treatment

Authors

Ohno S, Nakamura S, Hori S, Shimakawa M, Kawashima H, Mochizuki M, Sugita S, Ueno S, Yoshizaki K, Inaba G

Publication

J Rheumatol. 2004;31(7):1362–1368

Follow up

26 weeks

Note

Numbers of ocular attacks (mean/14 day, pre/post treatment) 3.5 => 1.0 (5 mg/kg), 3.8 => 0.2 (10 mg/kg) Visual acuity improved n = 5 out of 7 cases (5 mg/kg IFX), n = 4 out of 6 cases (10 mg/kg IFX) Oral aphthous ulceration disappeared n = 2 out of 2 (5mg/kg IFX), n = 2 out of 3 (10 mg/kg IFX)

Adverse events

Patients with adverse events n = 7 (5 mg/kg IFX), n = 6 (10 mg/kg IFX) Number of adverse events n = 43 (5 mg/kg IFX), n = 30 (10 mg/kg IFX) Diarrhoea 57.1% (5 mg/kg IFX), 16.7% (10 mg/kg IFX) Common cold 57.1% (5 mg/kg IFX), 0% (10 mg/kg IFX) Malaise 42.9% (5 mg/kg IFX), 16.7% (10 mg/kg IFX) Nausea 42.9% (5 mg/kg IFX), 16.7% (10 mg/kg IFX) Pyrexia 28.6% (5 mg/kg IFX), 33.3% (10 mg/kg IFX) Headache 14.3% (5 mg/kg IFX), 33.3% (10 mg/kg IFX) Increased systolic blood pressure 14.3% (5 mg/kg IFX), 33.3% (10 mg/kg IFX) Epigastric distress 28.6% (5 mg/kg IFX), 0% (10 mg/kg IFX) Vomiting 28.6% (5mg/kg IFX), 0% (10 mg/kg IFX) Decreased diastolic blood pressure 28.6% (5 mg/kg IFX), 0% (10 mg/kg IFX) Arthralgia 0% (5 mg/kg IFX), 33.3% (10 mg/kg IFX) Constipation 0% (5 mg/kg IFX), 33.3% (10 mg/kg IFX)

Morbus Behçet: Infliximab

713

Trial

Efficacy of Infliximab in the treatment of uveitis that is resistant to treatment with the combination of Azathioprine, Ciclosporin, and corticosteroids in Behçet’s disease: an open-label trial

Substance

5 mg/kg Infliximab Concomitant medication: 5 mg/kg ciclosporin/day was discontinued 2 mg/kg azathioprine/day was prolonged 300 mg isoniacid was added if necessary Previous medication: Combination therapy: 2 mg/kg azathioprine/day 5 mg/kg ciclosporine/day >7.5 mg prednisolone/day

Result

Infliximab suppressed the occurrence of uveitis attacks, had a corticosteroidsparing effect, and had favourable implications for the visual prognosis of patients with resistant Behçet’s uveitis

Patients

13 patient with Behcet’s disease who met the criteria of the International Study Group ³ 2 uveitis attacks involving the posterior segment in the last 6 months Despite receiving treatment with the combination of azathioprine, ciclosporine, and prednisolone (>7.5 mg/day) No visual loss No severe manifestations

Authors

Tugal-Tutkun I, Mudun A, Urgancioglu M, Kamali S, Kasapoglu E, Inanc M, Gül A

Publication

Arthritis Rheum. 2005;52(8):2478–2484

Follow up

54 weeks

714

Note

Morbus Behçet: Infliximab

Uveitis attacks n = 2.4 (previous 6 months), n = 1.0 (treatment period), n = 1.9 (observation period) Daily prednisone (mg/day) 27.6 (previous 6 months), 14.1 (treatment period), 28.1 (observation period) Mean occurrence of: Fatigue 0.33 (week 0–22), 0.55 week (23–54) Oral ulcers 0.13 (week 0–22), 0.46 (week 23–54) Genital ulcers 0 (week 0–22), 0.05 (week 23–54) Papulopustular lesions 1.07 (week 0–22), 1.31 (week 23–54) Erythema nodosum 0 (week 0–22), 0 (week 23–54)

Adverse events

Respiratory infections n = 7 (week 0–22), n = 3 (week 23–54) Headache n = 5 (week 0–22), n = 0 (week 23–54) Hypertension n = 1 (week 0–22), n = 0 (week 23–54) Infusion reaction n = 1 (week 0–22), n = 0 (week 23–54) Rash n = 1 (week 0–22), n = 0 (week 23–54) Dishydrosiform eczema n = 1 (week 0–22), n = 0 (week 23–54) Contact dermatitis, pruritus n = 1 (week 0–22), n = 0 (week 23–54) Lower back pain n = 1 (week 0–22), n = 0 (week 23–54) Renal colic n = 0 (week 0–22), n = 1 (week 23–54) Inguinal hernia n = 0 (week 0–22), n = 1 (week 23–54)

Morbus Behçet: Interferon alfa-2b

715

Trial

Interferon alfa-2b, Colchicine, and Benzathine penicillin versus Colchicine and Benzathine penicillin in Behçet’s disease: a randomised trial

Substance

3 million U interferon alfa-2b (IFN) s.c. every other day for first 6 months (n = 67) Control patients (n = 68) Concomitant medication: 1.5 mg colchicine 1.2 million units benzathine penicillin i.m. every 3 weeks Attacks: 1 mg/kg prednisolone/day 2–2.5 mg/kg azathioprine/day

Result

Interferon alfa-2b, colchicine, and benzathine penicillin were all effective in treating treat eye disease and extraocular manifestations of Behçet’s disease

Patients

135 patients with Behcet’s disease who met the criteria of the International Study Group Established disease ³2 months No previous therapy for Behçet’s disease

Authors

Demiroglu H, Ozcebe OI, Barista I, Dündar S, Eldem B

Publication

Lancet. 2000;355(9204):605–609

Follow up

12 months

Note

Risk of eye involvement 8% (IFN), 27% (control) Attack rates (mean/year): Eye involvement 0.2 (IFN), 1.02 (control) Arthritis 0.29 (IFN), 0.87 (control) Vascular events 0.06 (IFN), 0.24 (control) Oral ulcers 5.52 (IFN), 6.68 (control) Genital ulcers 0.72 (IFN), 1.18 (control) Skin lesions 1.17 (IFN), 1.84 (control) Visual-acuity loss n = 2 (IFN), n = 13 (control) Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon Pseudotumour cerebri n = 1 (IFN), n = 1 (control) Hemiparesis n = 0 (IFN), n = 1 (control) Bilateral pyramidal-tract disease n = 0 (IFN), n = 1 (control)

Adverse events

Deep-vein thrombosis of the lower extremity n = 4 (IFN), n = 12 (control) Budd-Chiari syndrome n = 0 (IFN), n = 1 (control) Pulmonary arterial aneurysm n = 0 (IFN), n = 1 (control) A mild and tolerable flu-like syndrome (IFN) Mild and asymptomatic neutropenia and thrombocytopenia (IFN) Transient alopecia (IFN) Abdominal cramping (both groups) Nausea (both groups) Vomiting (both groups) Diarrhoea (both groups) Mild depression (both groups)

716

Morbus Behçet: Interferon alfa-2a

Trial

Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study

Substance

Interferon alfa-2a, 6 × 106 IU, s.c. 3 times a week (n = 23 + 2, who failed to complete the study) Placebo (n = 21 + 4, who failed to complete the study) Previous therapy: No systemic therapy £12 weeks prior randomization No topical therapy £4 weeks prior randomization

Result

Interferon alfa-2a was an effective alternative treatment for mucocutaneous, ocular and joint manifestations of Behçet disease

Patients

50 patients with Behçet’s disease with Behcet’s disease who met the criteria of the International Study Group No hepatic, renal, cardiovascular, infectious, or other autoimmune disease No irreversible bilateral eye disease No active cerebral or retinal vasculitis Age 16–55

Authors

Alpsoy E, Durusoy C, Yilmaz E, Ozgurel Y, Ermis O, Yazar S, Basaran E

Publication

Arch Dermatol. 2002;138(4):467–471

Follow up

3 months

Note

Withdrawal because of severe eye disease n = 1 (IFN), n = 2 (placebo) Withdrawal because of progressive mucocutaneous and articular symptoms n = 1 (IFN), n = 1 (placebo) Patients with ocular symptoms (n = 6): Decrease in the severity and the frequency of attacks n = 5 (IFN), n = 3 (placebo) Complete response n = 2 (IFN), n = 0 (placebo) Partial response n = 13 (IFN), n = 3 (placebo) Overall response n = 15 (IFN), n = 3 (placebo) Duration and pain of oral ulcers, frequency of genital ulcers and papulopustular lesions decreased Frequency and duration of erythema nodosum–like lesions, thrombophlebitis, and articular symptoms was decreased

Side effects

Mild, flulike symptoms 78% Alopecia 4.3% Leukopenia 4.3% Diarrhoea 4.3%

Abbreviations

a A/SIP ACR Ada ALAT or ALT ANA ANCA APGAR APLASA APS AS ASQol Assess. ATG AUC Aza BAL BASDAI BASFI BASMI BASRI BILAG BMD BROSG BVAS BVAS-WG CCP CHC(C) CHC/CHCC COPD CK

Year/s Acute/subacute interstitial pneumonia American Colledge of Rheumatology Adalimumab Alanin-Aminotransferase Anti Nuclear Antibodies Anti Neutrophil Cytoplasmatic Antibodies Scoring of newborn children: Activity, Pulse, Grimace, Appearance, Respiration Antiphospholipid Antibody Acetylsalicylic Acid Antiphospholipid Syndrome Ankylosing spondylitis Ankylosing Spondylitis Quality of Life Index Assessment Antithymocyte globulin Area under the curve Azathioprine Bronchoalveolar lavage Bath ankylosing spondylitis Disease activity index Bath ankylosing spondylitis functional index Bath ankylosing spondylitis Metrical index Bath Ankylosing Spondylitis Radiology Index for the spine British Isles Lupus Assessment Group Bone mineral density The British Rheumatoid Outcome Study Group Birmingham Vasculitis Activity Score Birmingham Vasculitis Activity Score- Wegener’s granulomatosis Cyclic citrullinated peptide Chapel Hill Consensus Conference Chapel hill consensus conference Chronic Obstructive Pulmonary Disease Creatinine (Phospho-) Kinase

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8, © Springer-Verlag London Limited 2011

717

718

CRP CsA CSS CTD CZP d DAS28 DAS44 DEI DLCO DLQI DMARDs dsDNA EBMT ESR ETN EULAR FEV1 FFS FK506 FSH FVC GCA gGT GMCF GN Gol HAQ HCQ HDL HepASA HRCT HSCT HSN i.m. i.v. IFX INH INR IPF IVIG J Kco LDL Lef

Abbreviations

C reactive protein Ciclosporin Churg Strauss Syndrome Connective Tissue Disease Certolizumab pegol day Disease activity score counted on 28 joints Disease activity score counted on 44 joints Disease extension index (vasculitis) Carbon monoxide diffusing capacity Dermatology Life Quality Index Disease modifaying anti rheumatic drugs double strand DNA European Group for Blood and Marrow Transplantation Erythrocyte sedimentation rate Etanercept European league against rheumatism Forced expiratory volume of the first second Five factor score Tacrolimus Follicle stimulating hormone Forced vital capacity Giant cell arteriitis Gamma-Glutamyl-Transferase Granulocyte-macrophage colony stimulating factor Glomerulonephritis Golimumab Health assessment questionnaire Hydroxychloroquine High densitiy Lipoproteins Heparin and Aspirin High resolution computer tomogram Haematopoietic stem cell transplantation Henoch-Schönlein purpura nephritis Intramuscular Intravenously Infliximab Isoniacid International Normalized Ratio Intrapulmonary Fibrosis Intravenous immunoglobulin Journal Coefficient of gas transfer Low Densitiy Lipoproteins Leflunomide

719

Abbreviations

LERA LINK LMW mm MPA MRI mRSS mSASSS MTX n NASHA neg NSAID OTIS p.o. PAH PAN PASI PMR pos PSARC PsoA Pt PTT RA RAIN RF SAE SF-36 SHS SIS SJC SLAM-R SLEDAI SLEPDAI SLICC-DI Sqm SSc SSZ TBI TC TEAE TJC TLC TLI

Late Early rheumatoid Arthritis Longitudinal Investigation of NSAIDs in Knee Osteoarthritis Low molecular weight Millimetre Microscopic polyangiitis Magnetic resonance imaging Modified Rodnan skin score Modified Stoke AS Spine Score Methotrexate Number Non-animal stabilised hyaluronic acid Negative Non steroidal anti rheumatic drug Organ Transplantation & Immunogenetics System per os Pulmonary Arterial Hypertension Polyarteritis nodosa Psoriasis Area and Severity Index Polymyalgia rheumatica Positive Psoriatic Arthritis Response Criteria Psoriasis Arthritis Patient Prothrombin time Rheumatoid Arthritis Rheumatoid Arthritis Investigational Network Rheumatoid Factor Severe adverse events Short Form 36 Sharp van der Heijde Score National Institutes of Health SLE Index Score (SLE) Swollen joint count Systemic Lupus Activity Measure Systemic Lupus Erythematosus Disease Activity Index SLEDAI adapted for pregnancy Systemic Lupus International Collaborating Clinics Disease Index Squaremeter Systemic Sclerosis Sulfasalazine Total body irradiation Total cholesterol Treatment-Emergent Adverse Events Tender joint count Total lung capacity Total lymphoid irradiation

720

Toc UA UCLA VAS VDI VERA VLDL vs. w WG

Abbreviations

Tocilizumab Undifferentiated Arthritis University of California, Los Angeles Visual analogue scale Vasculitis damage index Very Early rheumatoid Arthritis Very low densitiy Lipoproteins Versus Week Wegener’s granulomatosis

Index

A Aaron, S.L., 306 Abdellatif, M., 318 Abe, T., 76, 248 Abeles, M., 508 Abidi, M., 523 Abrahamowicz, M., 439 Abramowicz, D., 429, 683 Abramson, S.B., 410 Abu-Raghif, A.R., 704 Abud-Mendoza, C., 133, 138 Accardo-Palumbo, A., 468 Adams-Huet, B., 418 Adebajo, A., 96 Adler, Y.D., 707 Adu, D., 432, 628 Adya, C.M., 473 Agarwal, G.G., 23 Agarwal, S., 271 Aggarwal, A., 61 Agron, L., 591 Ahern, M.J., 33 Ahmadieh, H., 700 Ahonen, J., 106 Aitchison, R., 176, 178 Akre, F., 264 Aktunç, T., 701 Al-Hashimi, I., 572 Ala-Houhala, M., 685 Alarcón, G.S., 416 Alarcon-Segovia, D., 493 Alberighi, O.D., 363, 413 Albertsson, K., 7 Albuquerque, E.M., 421 Alcalay, D., 520 Alcocer, J., 493 Alecock, E., 281, 285, 287, 293 Alepa, F.P., 316, 376

Aletaha, D., 258 Alfieri, G., 100 Allaart, C.F., 64, 65, 160, 247, 253, 254, 257, 262, 263 Allen, G.L., 589 Almond, N.E., 531 Alocer-Varela, J., 433 Alpsoy, E., 716 Alten, R., 11, 126, 128, 285, 321, 346, 347, 351, 356, 360 Altieri, P., 413 Altman, R.D., 30 Alvanou, E., 495 Alvaro-Gracia, J.M., 176 Amadi, A., 530 Amante, E.J., 229 Amiransari, B., 700 Amor, B., 308, 314, 525 Amoura, Z., 520 Andersen, L.S., 102, 103 Anderson, D., 472 Anderson, R.J., 376 Andrade, L.E., 417 Andrassy, K., 637, 658 André, M.H., 643 Andrews, B., 508 Antikainen, M., 685 Antoni, C.E., 232, 393, 395, 397, 399, 401, 402 Aouba, A., 580 Appel, A.M., 337 Appel, G., 443 Appelboom, T., 126, 576 Apras, S., 499 Aramaki, K., 706 Aranda, R., 130, 131, 135, 137, 140, 142, 146 Arène, J.P., 620, 635, 643 Aries, P.M., 673

R. Müller and J. von Kempis (eds), Clinical Trials in Rheumatology, DOI: 10.1007/978-1-84996-384-8, © Springer-Verlag London Limited 2011

721

722 Aringer, M., 447 Ariza-Andraca, R., 433 Arkfeld, D.G., 195 Arnold, R., 521 Arpaia, G., 541 Arreghini, M., 98 Arriola, E., 500, 504 Assmann, K.J., 434 Atkins, C., 163 Atra, E., 417 Atsumi, T., 171 Atteno, M., 372 Atzeni, F., 100 Au, T.C., 412, 445 Austin, H.A., 427 Austin, H.A. 3rd, 424 Azarmina, M., 700 Azuma, J., 278, 289, 291 Azuma, K., 552 Azuma, T., 450 B Babinet, P., 629 Baca, S., 602 Bacon, P.A., 1, 124, 521, 628, 637, 639, 668 Badesch, D.B., 474, 476, 481, 482 Bae, S.C., 225 Baethge, B., 20 Bahrt, K., 148 Baker, D., 242, 258 Baker, H.W., 458 Baker, P., 94 Bala, M., 258 Balaban, D., 466 Baldassare, A.R., 73, 75 Baleydier, A., 358 Balint, G., 279 Ballem, P.J., 461 Balow, J.E., 424, 427 Bambara, L.M., 303, 699 Bambara, M.L., 268 Bañares, A., 319, 598 Banga, J.D., 540 Baraliakos, X., 321, 351, 356, 360 Barbui, T., 471 Barile-Fabris, L., 433 Barista, I., 715 Barnes, C.G., 695 Barnett, E.V., 411 Baron, G., 358, 577 Baron, M., 511 Barozzi, L., 608

Index Barr, W., 508 Barrett, J., 459 Barrier, J.H., 591 Barron, K.S., 649 Barst, R.J., 482 Bartoli, E., 614 Bartunková, J., 558 Basaran, E., 716 Bathon, J.M., 117, 118, 144, 197, 199, 242, 258 Battafarano, N., 98 Baudo, F., 471 Baum, B.J., 575 Baumann, M.H., 494 Baumgaertner, M., 321 Baumgartner, S.W., 195, 213 Bayliss, C., 33 Bazzi, S., 541 Beacham, J.A., 529, 531 Bear, M.B., 179, 181, 187 Beaulieu, A., 285, 327 Beck, E., 321 Beck, K., 156, 160 Becker, H., 571 Becker, J.C., 126, 128, 130, 131, 133, 135, 137, 138, 140, 142, 144, 146, 149, 150 Bedocs, N.M., 663 Behr, J., 488 Behrens, F., 366, 368 Bekker, P., 222 Belch, J.J., 537, 540 Belcher, G., 530, 533 Bell, C.L., 83 Bell, P., 538 Bellamy, N., 511 Belmont, H.M., 410 Beltrán Gutiérrez, J., 489 Belzunegui, J., 604 Bender, J.C., 2 Benitez-Del-Castillo, J.M., 319 Bennett, R., 183 Bensen, W.G., 78 Bensen, W.M., 117 Berden, J.H., 434 Berenbaum, F., 174 Beretta, L., 502 Berg, P.A., 470 Berger, R.G., 120 Berman, A., 142, 250 Bernstein, J., 690 Berrettini, M., 471 Berruti, V., 541 Berry, H., 1

Index Bertouch, J., 314 Besenthal, C., 521 Beswick, E.J., 310, 312 Beutler, A., 344, 391, 395, 397, 399, 401, 402 Beveridge, T., 38 Beyene, N.B., 100 Biasi, D., 303, 699 Bielefeld, P., 631 Bijl, M., 434 Bijlsma, J.W.J., 4, 67, 163, 169, 566, 568, 597, 612 Billings, S., 35 Bindi, P., 631 Bingham, C.O. 3rd, 216 Binks, M., 521 Birbara, C.A., 130, 152, 159, 383, 395, 399, 401 Bird, H.A., 373 Birdsall, M., 455 Blaauw, A.A., 67 Black, C.M., 480, 482, 484, 486, 521, 530, 532, 540 Blackburn, W.D., 316, 376 Blåfield, H., 106, 111 Blake, R., 361 Blakely, K.M., 84, 107 Block, J.A., 73 Block, S., 187 Blöckmans, D., 429, 513, 643 Blosch, C.M., 195 Bobbio-Pallavicini, F., 268 Bodin, F., 481 Boerbooms, A.M., 16, 121, 510 Boers, M., 86, 91, 113 Boffa, J.J., 656 Boh, E.E., 390 Böhm, M., 548 Boiardi, L., 608, 617, 618 Bolosiu, H., 207 Bolster, M.B., 500, 504 Bombardier, C., 22, 463 Bombardieri, S., 268, 497 Bonilla, G., 604 Boonen, A., 7, 86, 91 Booth, A., 668 Bootsma, H., 490, 578 Bordin, G., 363 Borenstein, D., 193 Bork, D., 602 Börngen, U., 14 Borofsky, M., 332 Borton, M.A., 75, 78 Both, M., 673

723 Botstein, G.R., 20 Bottasso, B., 542 Botto, M., 699 Boumier, P., 308 Boumpas, D.T., 424, 427 Boussuge, M.P., 341 Bowcock, S.M., 547 Bowman, S.J., 582 Box, J.H., 120, 130, 193 Bradley, J., 33 Brancaccio, V., 471 Branch, D.W., 466, 467 Brandt, A., 68, 305 Brandt, H.C., 305 Brandt, J., 321, 334, 339, 346, 347, 351, 356 Brasington, R.D., 586 Bratt, J., 264, 596 Braun, J., 68, 300, 321, 325, 328, 332, 334, 335, 339, 340, 344, 346, 347, 349, 351, 355, 356, 360 Bray, V., 266 Breban, M., 358 Breedveld, F.C., 24, 26, 49, 64, 65, 81, 156, 160, 165, 217, 232, 233, 235, 237, 238, 247, 253, 254, 257, 262, 263, 521 Bregeon, C., 375 Breitbart, A., 437 Brennan, M.T., 575 Bresnihan, B., 176, 178, 181, 186 Brezinschek, H.P., 193 Brin, S., 53 Brogan, P., 678 Bröll, J., 279 Brooks, P., 314 Brooks, R.H., 95, 416 Brouwer, R.M., 532 Brown, A., 244 Brown, C., 244 Brown, K.K., 488 Brubacher, B., 361 Bruet, A., 635 Bruijn, J.A., 434 Brunetta, P.G., 452 Brunkhorst, R., 633 Bruyn, G.A., 81, 99 Brzezicki, J., 191 Budiman-Mak, E., 316, 376 Bulpitt, K.J., 195 Bunch, T.W., 550, 551 Buono, R., 370 Burch, F.X., 78, 213, 389 Burge, D.J., 195, 201, 388 Burgos-Vargas, R., 60

724 Burmeister, L.F., 57 Burmester, G.R., 156, 169, 183, 191, 214, 219, 273, 277, 321, 347, 351, 356, 360, 393, 397, 402, 543 Bussel, A., 520, 624, 626, 679, 681 Buttgereit, F., 11 Buxbaum, R.J., 316 Buyon, J.P., 410 C Cacoub, P., 629 Calabrese, L.H., 73, 602 Calamia, K.T., 593 Caldwell, J.R., 20, 43, 51, 73, 117, 118 Calguneri, M., 499 Calin, A., 314, 337 Callegari, P., 266 Callen, J.P., 556, 559 Calvo, A., 293 Cameron, B., 557 Campbell-Webster, N., 557 Campion, G., 39 Candela, M., 497 Candon, S., 580 Cannon, G., 43 Cannon, G.W., 51, 117, 118, 199, 316, 376 Cantagrel, A., 89, 281 Cantini, F., 363, 608, 618 Canvin, J., 123 Capdeville, J., 591 Capell, H.A., 6, 13, 71, 92, 109, 114, 125, 373, 532, 537 Caporali, R., 615 Cappelli, M., 667 Caramaschi, P., 303, 699 Cardona-Muñoz, E.G., 431 Carette, S., 511 Carletto, A., 303 Carlson, K.A., 671 Carmona, L., 489 Carneiro, J.R., 438 Caronni, M., 502, 541 Carpentier, P., 484 Carreño, L., 604 Casatta, L., 614 Cassim, B., 479 Castelli, A., 468 Cataldo, M.J., 421 Catanoso, M.G., 617, 618 Cathcart, E.S., 371 Catoggio, L., 511 Cattaneo, R., 429

Index Cazarín-Barrientos, J., 60 Cazzola, M., 100 Ceccarelli, F., 268 Celis, A., 431 Cerinic, M.M., 268, 497 Cervera, R., 429 Chalmers, I.M., 511 Chamley, L.W., 455, 458 Chan, K.W., 426 Chan, T.M., 426, 440 Chang, D.J., 214, 217, 219 Channick, R.N., 481 Chaput de Saintonge, D.M., 15 Chartash, E.K., 152, 154, 159, 161, 167 Charvát, F., 558 Chary-Valckenaere, I., 358 Chatterjee, S., 484 Chatzidionysiou, A., 264 Chaudhry, A.N., 678 Chauhan, R.S., 23 Chen, C.S., 523 Chen, D.Y., 150, 205 Chen, S.L., 323 Chen, Y.H., 205 Chérié-Lignière, E.L., 100 Cherin, P., 554 Chevalet, P., 591 Chiu, P., 306 Choi, H.K., 602 Choquette, D., 327, 420 Chou, S.J., 205 Chow, K.M., 446 Choy, E.H., 8, 72, 188, 378, 380 Christensen, L., 18 Christoforov, B., 629 Chung, L., 563 Churchill, M., 107, 229 Ciccia, F., 343, 468 Cid, M.C., 602, 605 Cimmino, M.A., 615, 618 Cipriani, P., 497 Cividino, A., 22, 420 Clark, C.A., 459 Clark, P., 433 Clark, T.M., 587 Clarke, A., 472 Clarke, S., 124 Claudepierre, P., 358 Clegg, D.O., 83, 316, 318, 335, 340, 376, 416 Clements, P.J., 371, 491, 492, 500, 504, 506, 508, 535 Close, D.R., 269 Clute, L., 57

725

Index Cobankara, V., 499 Cobby, M., 176, 178 Coblyn, J.S., 59, 209 Coche, E., 513 Cochener, B., 581 Codding, C., 142 Codreanu, C., 207, 210, 214, 219, 220 Cogan, E., 513 Cohen, H., 457 Cohen, M.R., 316, 376 Cohen, P., 602, 620, 626, 629, 631, 635, 643, 656 Cohen, S.B., 43, 51, 126, 165, 179, 187, 222, 245, 273, 277, 389 Coleman, P., 117, 118 Collantes, E., 332 Collier, D.H., 508, 538 Collins, L., 427 Collins, M., 124 Combe, B., 89, 135, 174, 189, 210, 220, 358, 375, 577 Combs, J.J., 550 Comina, D.P., 542 Compagnone, D., 159 Conaghan, P.G., 96, 244, 260, 353 Conforti, M.L., 497 Connan, L., 591 Connolly, M.K., 500, 504 Contreras, G., 444 Cook, E.D., 547 Cooke, E.D., 529, 531, 537 Coppock, J., 484 Coppola, R., 542 Corbelli, V., 100 Corbin, D.O., 546 Cordier, J.F., 620, 631, 635, 643, 656 Corkill, M.M., 311 Corluy, L., 255 Cornet, P.L., 142 Cortina, P., 699 Costa, L., 372 Costantini, L., 472 Cöster, L., 264 Cosyns, J.P., 429 Coteur, G., 193 Covelli, M., 561 Covucci, A., 135, 144 Cowchock, F.S., 466 Crane, M., 427 Cravets, M.W., 273, 275, 277 Crawford, B., 117, 118 Creemers, M.C., 302 Crofford, L.J., 523

Cronin, M.E., 564 Crook, S., 663 Crowther, M.A., 472 Crowther, M.R., 459 Crues, J., 266 Csernok, E., 666 Csuka, M.E., 530, 538 Cuhadaroglu, H., 703 Currey, H.L., 15, 38, 313 Curtis, D.L., 117, 118 Cush, J.J., 117, 118, 179, 187, 316, 335, 340, 376 Cutolo, M., 268, 363 Cyr, M., 37 D D’Angelo, A., 471 D’Cruz, D., 429 D’Ingianna, E., 100 da Costa, J., 527 Da Silva, J.C., 341 da Silva, N.A., 287 Dackhammar, C., 264 Dadoniené, J., 432, 637 Dalakas, M.C., 553, 564 Dambrosia, J.M., 553 Danieli, G., 667 Danieli, M.G., 429, 667 Danning, C.L., 427 Danoff, D., 420 Danovitch, G., 492 Danowski, A., 409 Dantis, P.C., 495 Daridon, C., 581 Darmawan, J., 323 Das, S.K., 23 Dasgupta, B., 223, 610 Dass, S., 582 Davas, E.M., 495 Davatchi, F., 323 Dave, M., 457 Davies, J.M., 38, 58 Davis, D., 232 Davis, J.C., 340 Davis, J.C. Jr., 325, 330, 332, 335, 340, 342, 344 Davis, M.J., 310 Davis, P., 306, 503 Davoli, C., 363 Dawes, P.T., 124, 310, 312 de Andrade, J.A., 488 de Beus, W.M., 253, 262

726 de Carvalho, A., 102 de Clerck, L.S., 507 De Francisci, A., 497 de Glas-Vos, J.W., 434 de Graaf, R., 121 De Groot, K., 637, 639, 641, 647, 648, 651, 652, 654, 666 de Jager, J.P., 203 de Jong, A.J., 87 de Jong, P.E., 621 de Jonge-Bok, J.M., 253 de Keyser, F., 517 de la Serna, R., 53 de Lind van Wijngaarden, R.A., 683 De Luca, A., 497 de Rooij, D.J., 85 de Ryck, Y.M., 301 De Silva, M., 595, 607 de Sonnaville, P.B., 253 De Vita, S., 614 de Vlam, K., 395, 399, 401 de Vries-Bouwstra, J.K., 65, 247, 253, 254, 257, 262, 263 De Wazieres, B., 591 de Wilde, P., 574 Deblois, P., 629 Decker, J.L., 423 Decuman, S., 517 Deighton, C., 49 Del Puente, A., 372 Delaval, P., 620 Demary, W., 68 Demedts, M., 507 Demetriades, P., 299 Demiroglu, H., 715 Demols, P., 576 Dempsey, J.R., 559 DeNardo, B.A., 555 Denburg, J., 472 Dendrinos, S., 469 Denke, M., 418 Denton, C.P., 480, 484, 486 Depresseux, G., 255, 429, 513 Dequeker, J., 507 Derksen, R.H., 434 Desai, C., 189 Desai, S., 480 Despain, D., 476 Desson, J.F., 631 Détrée, F., 631 Devauchelle-Pensec, V., 581 Devogelaer, J.P., 240 DeVries, T., 201

Index DeWoody, K., 242, 349 Dheda, K., 479 Dhillon, V., 62 Di Giorgio, E., 128 Di Minno, M.N., 372 Di Munno, O., 609 Diamond, B., 410 Díaz-Miguel, C., 489 Dickler, H., 602 Diekman, L., 344 Dien, G., 591 Dietl, J., 470 Dietz, F., 20, 73, 83 Dijkmans, B.A., 24, 26, 65, 81, 86, 91, 99, 113, 247, 253, 254, 257, 262, 263, 301, 314, 325, 330, 337, 349, 365 Dimitrijeviv, M., 39 Dinant, H.J., 597, 612 Dinsmore, S.T., 553 Direskeneli, H., 429 DiVittorio, G., 184 Dixon, A.S., 38 Doering, G., 11 Doesburg, W.H., 16 Doherty, M., 176 Dolan, A.L., 610 Dole, W.P., 534, 535 Domljan, Z., 39, 176 Domschke, W., 571 Dooley, L.T., 395, 399, 401 Dooley, M.A., 443 Dordevic, J., 39 Doria, A., 413 Dormandy, J.A., 532 Dornfeld, L., 411 Dostal, C., 432 Dougados, M., 53, 89, 128, 130, 131, 137, 142, 146, 149, 163, 174, 273, 277, 308, 314, 325, 335, 340, 341, 358 Douketis, J., 472 Dovigo, L., 363 Doyle, M.K., 227, 229 Drosos, A.A., 29, 32 Droste, U., 320 Druzin, M ., 467 du Bois, R.M., 480, 488 Duarte, J.L., 421 Dubois, A., 631 Ducroix, J.P., 629, 656 Duffey, J., 83 Dufton, C., 474, 476 Duhamel, E., 591 Dündar, S., 715

727

Index Dunn, M., 213, 389 Dupond, J.L., 591 Durez, P., 131, 144, 148, 149, 217, 223, 229, 240, 255 Durusoy, C., 716 E Easley, K.A., 593, 602 Eberl, G., 80 Ebner, W., 321 Eckel, G., 266 Eckhoff, P.J., 107 Edelmann, C.M. Jr, 690 Edge, J.C., 559 Edmonds, J., 314 Edwards, A., 313 Edwards, J.C., 269, 407 Efthimiou, P., 560 Egger, M.J., 371, 416 Eguchi, K., 171 Ehyaee, V., 700 Einstein, S.G., 327, 342 Eisen, D., 390 Ejstrup, L., 297 Ekstrand, A., 637 El Kouri, D., 591 Elashoff, R., 500, 504, 506 Eldem, B., 703, 715 Elewaut, D., 517 Ellingsen, T., 102, 103 Elliott, J.R., 84 Elliott, M.J., 232 Ellis, C.N., 374 Ellis, R.W., 480 Ellman, M., 511, 535, 538 Emery, P., 49, 53, 96, 126, 128, 131, 133, 138, 146, 149, 156, 163, 173, 176, 189, 217, 229, 233, 235, 237, 242, 244, 258, 260, 269, 271, 273, 276, 277, 279, 281, 337, 353, 365, 432, 480, 498, 521, 582, 628 Engel, A.G., 550 Engle, E.W., 2 Englert, H., 532 Ensom, M.H., 461 Ensworth, S., 461 Erhardt, C., 72 Erikson, N., 57 Eriksson, P., 670 Erkan, D., 456 Ermis, O., 716 Ernestam, S., 264 Ertenli, I., 499

Esdaile, J.M., 22, 123, 420 Espigado, I., 521 Espirito Santo, J., 527 Esplin, M.S., 467 Ettlinger, R., 20 Euller-Ziegler, L., 358 Evans, S.J., 15 Ewals, J.A., 253 Eymard, B., 554 F Fain, O., 681 Falappone, P.C., 268, 561 Falk, F.G., 366, 368 Falk, R.J., 660 Fardellone, P., 174 Farewell, V.T., 361, 463 Farge, D., 521 Farina, G., 497, 518 Farine, D., 463 Farquharson, R.G., 460 Fatenejad, S., 203, 207, 210, 220, 337, 341 Fauci, A.S., 584, 645, 646 Fauci, S.F., 622 Fautrel, B., 358 Feighery, C., 639 Feldman, B.M., 557 Feldmann, M., 232, 233, 235 Felt, J., 107 Feltelius, N., 307 Ferland, D., 439, 602 Fernandes, L., 610 Fernandez, A., 107 Fernández-Gutiérrez, B., 598 Fernando, I., 117, 118 Ferraccioli, G.F., 268, 363, 413, 614, 615 Ferrante, A., 268, 343, 468 Ferrara, R., 413 Ferrario, F., 683 Ferraro, A.J., 678 Ferraz, M.B., 417 Ferri, C., 268 Fervenza, F.C., 671 Fessler, B.J., 500, 504, 602 Fibbe, W.E., 521 Fiechtner, J.J., 120 Fiehn, C., 55 Fielding, L., 463 Fierer, J., 213 Figueroa, M., 604 Filipowicz-Sosnowska, A., 269, 271 Finazzi, G., 471

728 Finck, B.K., 197, 199, 388 Fine, D.M., 422 Fink, C.O., 651 Fink, S., 58 Finke, J., 521 Fiocco, U., 210, 220 Fiorentini, F., 100 Fiorentino, D.F., 563 Fiorini, T., 100 Fischkoff, S.A., 152, 154, 159, 161, 163 Fisher, J., 124 Fitzcharles, M.A., 22 Fitzgerald, A.A., 22, 123, 306 Flaxenberg, P., 68 Fleischmann, M.R., 73 Fleischmann, R.M., 43, 159, 183, 184, 193, 195, 197, 199, 229, 245, 271, 335 Flipo, R.M., 174 Flores-Suárez, L.F., 641, 662 Flynn, J.A., 602 Foley, N.M., 480 Font, J., 429 Ford, I., 13, 92 Ford, P.M., 526 Forgie, M., 472 Forre, O., 25, 27 Forsberg, S., 106 Forslind, K., 264 Fortin, P.R., 439, 472, 602 Fournié, B., 358 Fowler, P.D., 124 Fox, R., 43, 51 Fraga-Mouret, A., 433 Fragiadaki, K.G., 487 Francx, L., 507 Frankel, E., 390 Franklin, R.D., 465 Franks, A.G. Jr., 528 Franssen, M.J., 302 Fraser, A.D., 244, 365 Fraser, D.D., 564 Fraser, P.A., 59 Fraser, S.M., 373 Fresko, I., 693, 711 Fretzin, S., 404 Freundlich, B., 212, 214, 217, 219 Fries, R., 548 Friman, C., 106 Fritz, C., 360 Fritz, J., 674 Fritzler, M.J., 503, 518 Frost, A., 474, 476, 481, 482 Fudman, E.J., 120

Index Fuentes de la Mata, J., 433 Fujii, T., 171, 450 Fukuda, T., 171 Fulminis, A., 497 Fumagalli, M., 100 Furies, R.A., 273 Furst, D.E., 20, 43, 51, 57, 73, 75, 78, 117, 118, 152, 154, 159, 167, 195, 216, 233, 235, 237, 238, 266, 393, 397, 402, 484, 491, 500, 504, 506, 508, 511, 521, 523, 538 G Gabrielli, A., 497 Gaitonde, M., 484 Galeazzi, M., 268, 429 Galiè, N., 474, 476, 482 Gallagher, S.C., 572 Gallazzi, M., 98 Gamez-Nava, J.I., 304, 431 Gámir Gámir, M.L., 489 Gang, W., 446 Gansauge, S., 437 Gao, I., 55 García de la Peña-Lefebvre, P., 489 García-de la Torre, I., 431 Garcia-Gonzalez, A., 304, 431 Garcia-Gonzalez, C., 431 Garcia-Sanchez, J., 319 Garnero, P., 113 Garrido Ed Ede, R., 429 Garrison, L., 195 Gaskin, G., 637, 683 Gaubitz, M., 210, 212, 220, 571 Gaudin, P., 358 Gause, A., 652 Gaylis, N., 227, 266 Gayraud, M., 629, 643 Ge, Z., 133 Geborek, P., 264 Geenen, R., 568 Geerts, W., 472 Geher, P., 341 Geidel, H., 27 Genant, H.K., 133, 138, 140, 144, 149, 178, 186 Généreau, T., 554, 626 Generini, S., 497 Genovese, M.C., 117, 118, 130, 137, 148, 173, 197, 199, 222, 225, 273, 277, 287, 293, 381, 563 Gent, M., 459, 472

729

Index George, L., 266 Georgiou, P.E., 29 Gerards, A.H., 65, 99, 247, 257, 365 Gerber, M.J., 474 Gerli, R., 268, 615, 618 Germain, B.F., 83 Geusens, P.P., 210, 220, 250, 349, 399, 401 Ghoei The, H., 81 Ghofrani, H.A., 474, 476 Giacomelli, R., 268, 497 Giardina, A.R., 343 Giarratano, A., 468 Gibson, T., 311 Gilmer, K., 266 Gilson, B., 635 Ginsberg, J.S., 459, 472 Ginzler, E., 443 Girelli, D., 699 Gladman, D.D., 361, 366, 378, 380, 383, 385, 391, 393, 397, 399, 401, 402 Glickstein, S., 84 Gluck, O., 94, 95 Gluckman, E., 521 Göbel, U., 633, 658 Godeau, B., 629 Godwin, J.D., 523 Goebel, K.M., 14 Goei Thè, H.S., 24, 99 Goekoop-Ruiterman, Y.P., 65, 247, 253, 254, 257, 262, 263 Goel, N., 193 Goetz, J., 577 Goffe, B.S., 388 Gogus, F., 693, 711 Goh, N.S., 480 Golden, H.E., 20 Golden, J., 500, 504 Golder, W., 346 Goldin, J., 500, 504, 506 Goldlust, B., 572 Goldman, A., 150 Goldschmeding, R., 568 Goldstein, R., 37 Gomes, J.A., 527 Gomez-Reino, J.J., 144, 287, 293, 391 Gömör, B., 321 Gonzalez-Lopez, L., 304, 431 Gooch, K.L., 333 Gooley, T.A., 523 Gordon, C., 432, 452 Goronzy, J.J., 593 Gota, C.E., 587 Gottenberg, J.E., 580

Gottlieb, A.B., 390, 404 Gough, A., 96, 203 Goupille, P., 89, 375 Gourley, M.F., 424, 427 Goycochea, M.V., 60 Graninger, W.B., 447 Granneman, G.R., 154 Grant, E., 123 Grasedyck, K., 321 Grassi, W., 144, 268 Grassnickel, L., 334 Gratwohl, A., 521 Greaves, M., 460 Greco, S., 413 Green, D., 472 Green, M.J., 96 Greenstein, A., 244, 353 Greenwald, M.W., 187, 273, 277 Gregorini, G., 637, 639, 641 Gribnau, F.W., 17, 302 Griffing, W.L., 593 Griffith, M., 668 Griffiths, B., 96, 432, 498 Grigor, C., 109 Grillet, B.A., 262 Grimes, S.M., 547 Grober, J.S., 374 Groff, G.D., 56 Gromnica-Ihle, E., 11, 320, 346, 347, 351, 356 Grootscholten, C., 434 Grosbois, B., 591 Gross, W.L., 602, 637, 639, 641, 647, 648, 651, 652, 654, 666, 673 Gruber, B., 538 Gu, J., 293 Guillevin, L., 484, 520, 580, 602, 620, 624, 626, 629, 631, 635, 643, 656, 679, 681, 683 Guimbal-Schmolck, C., 68 Gül, A., 429, 713 Güler-Yüksel, M., 262 Gunnarsson, I., 451 Gupta, A.K., 374 Guttadauria, M., 371 Guzzo, C., 395, 399, 401, 404 H Haagsma, C.J., 3, 85, 87 Haakenson, C.M., 376 Haar, D., 18 Haas, M., 422

730 Hachulla, E., 484, 577, 580, 631 Hadley, S., 107 Hafström, I., 7, 27 Hagen, E.C., 434, 637, 662 Hagerty, D.T., 128, 130, 277 Haibel, H., 300, 305, 321, 328, 334, 339, 356 Haines, K., 410 Haire, C., 107 Hakala, M., 106, 111, 116, 337 Hakola, M., 70, 106 Hale, L., 458 Halkier-Sorensen, L., 540 Hall, S.T., 217, 223, 225 Halla, J.T., 371 Hallahan, C.W., 646 Hällgren, R., 307 Halter, D.G., 399, 401 Hamburger, J., 582 Hamidou, M.A., 591, 635, 656 Hamilton, T.A., 374 Hammad, T., 668 Hammer, M., 321 Hampson, R., 6, 13, 92 Hamuryudan, V., 697, 701, 702, 709, 711 Han, C., 258 Han, J., 223, 250, 258, 344, 355 Han, K.H., 247, 254, 257 Handel, M.L., 183 Hanke, P., 68 Hannah, M.E., 463 Hannonen, P., 27, 70, 106, 111, 116 Hanrahan, P.S., 187 Hansen, G.V., 102, 103 Hansen, I., 102, 103 Hansen, T.M., 18 Hanyu, T., 171 Hao, W.K., 426 Haq, S.A., 323 Hara, M., 76 Harada, T., 171 Haraoui, B., 144 Harnam, N., 333 Harper, L., 641, 668 Harriman, G.R., 233, 235 Harris, J., 38 Harris, R.E., 73 Harrison, B.C., 476 Harrison, M.J., 456 Harrison, W., 33 Hartman, S., 184 Hashimoto, H., 76, 171, 248 Hashimoto, J., 278, 283 Hashimoto, T., 705

Index Hassanein, K., 700 Hatakeyama, A., 171 Haubitz, M., 633 Haugeberg, G., 353 Hausch, R., 84 Hawker, G.A., 459 Hawkins, R., 492 Hayat, S.J., 448 Hayem, G., 577 Haynes, B.F., 622 Hazes, J.M., 65, 247, 253, 257, 263 Hazleman, B.L., 1, 188, 533, 595, 607 Haznedaroglu, I.C., 499 Heaton, J.M., 565 Hegedus, R., 266 Heijde, D., 189, 344 Heilig, B., 55 Heitz, W., 68 Heldmann, F., 328 Helfgott, S.M., 209 Helfrick, R., 144 Heller, M., 647 Helliwell, P., 96 Hellmann, D.B., 602, 663 Hellmich, B., 652, 654, 673 Hellström, H., 264 Henderson, E., 72 Henderson, N., 92 Henderson, W.G., 316, 376 Hene, R.J., 566 Henes, J.C., 674 Henriksson, E.W., 451 Henry, Y.D., 358 Hensor, E., 260, 353 Henstorf, G., 523 Hergesell, O., 658 Herlyn, K., 651 Hermann, J., 321 Hermann, K.G., 355 Hernández-Rodríguez, J., 602 Hernández-García, C., 598 Herrada, J., 465 Herrick, A., 484 Herrick, A.L., 480 Herson, S., 554 Hertenstein, B., 521 Hessen, E.W., 273 Hessey, E.W., 271 Hetland, M.L., 102, 103 Hettema, M.E., 490 Heurkens, A.H., 67 Hicks, J.E., 564 Hiepe, F., 521 Hillis, S., 491

731

Index Hirakata, M., 171 Hirohata, S., 705, 706 Hirose, I., 171 Hirsh, J., 472 Hizli, N., 697 Hobart, J.M., 464 Hochberg, M.C., 2 Hoen, B., 631 Hoffman, D.B., 602 Hoffman, G.S., 584, 586, 587, 602, 605, 645, 646, 663 Hogan, S.L., 660 Holl-Ulrich, K., 673 Hollingsworth, P., 33 Holmberg, L., 523 Holt, P.A., 2 Homik, J., 306 Hondros, D., 495 Hong, P., 511 Hopkins, R., 373 Horger, M., 674 Hori, S., 712 Hornung, D., 470 Horslev-Petersen, K., 102, 103 Horwitz, D.A., 195 Houlihan, E., 461 Housley, E., 546 Houssiau, F.A., 240, 255, 429, 513 Houssin, A., 520 Howie, A.J., 628 Hoyles, R.K., 480 Hoyng, C.B., 574 Hsia, E.C., 223, 225, 227, 229 Hsieh, H.J., 452 Hsieh, T.Y., 205 Hsu, B., 344 Hsu, V.M., 484, 500, 504 Hua, Y., 161 Huber, A.M., 687 Hudry, C., 358 Hudson, N.P., 120 Huffstutter, J.E., 148 Huitfeldt, B., 313, 314 Huizinga, T.W., 64, 262 Hulsmans, H.M., 64 Humbert, M., 486 Hummers, L.K., 516 Hunder, G.G., 589, 593, 602, 618 Hunter, J.A., 6, 92, 125, 373 Hurd, E., 73, 83, 179 Hurley, F., 43 Hurst, N.P., 62 Huscher, D., 543 Huston, G., 96

I Iannone, F., 561 Ibanez de Kasep, G., 493 Ichikawa, Y., 248 Ide, H., 171 Iervolino, S., 372 Iglehart, I.W. 3rd, 2 Ikeda, K., 582 Iking-Konert, C., 654 Ilie, V., 410 Illa, I., 553 Illei, G.G., 427 Ilstrup, D.M., 550 Ilva, K., 106 Imbimbo, B., 609 Impastato, R., 343 Imura, Y., 450 Inaba, G., 698, 708, 712 Inanc, M., 713 Inase, N., 171 Inman, R.D., 327, 335, 340, 344 Innes, A., 193 Inokuma, S., 171 Ioannidis, J.P., 495 Ippoliti, A., 492 Iradier, T., 319 Irimajiri, S., 76 Isaacs, J., 96 Isçimen, A., 701 Isenberg, D.A., 188, 407, 432, 443, 452 Ishiguro, N., 171 Isogai, S., 171 Ito, K., 708 Ittah, M., 580 Iwamoto, I., 171 Iwata, S., 450 Izumiyama, T., 171 J Jacki, S., 55 Jackson, J.M., 390 Jacobs, J.W., 4, 67 Jacobs, P., 86, 91 Jacomy, D., 631 Jacquot, C., 631 Jagiello, P., 570 Jain, R., 418 Jais, J.P., 624 Jajic, I., 39 Jamin, C., 581 Janin, A., 577 Janzen, R., 14 Jara, L.J., 433

732 Jarosová, K., 558 Jarrett, S., 244, 260, 353 Jarrousse, B., 624, 626, 631, 681 Järvenpää, S., 116 Järvinen, P., 106 Jayne, D.R., 443, 637, 639, 641, 643, 668, 678, 683 Jego, P., 591 Jeka, S., 11 Jennette, J.C., 660 Jeong, H.J., 688, 689 Jesús, N.R., 421 Jeurissen, M.E., 16, 121 Jhangri, G.S., 306 Jiang, Y., 178 Jimenez, S.A., 535, 538 Jobanpurta, P., 311 Johnsen, A.K., 209 Jones, G., 293 Jones, P., 124, 366 Jones, R.B., 678 Jónsdóttir, T., 451 Joseph, K., 14 Joseph, L., 22, 420 Joshi, L., 676 Jousse, S., 358 Jousse-Joulin, S., 581 Jover, J.A., 598 Joy, M.S., 660 Joyce, J.W., 589 Juanola, X., 341 Juhlin, R., 314 Julian, J., 472 Julkunen, H., 106, 116 Junker, P., 102, 103 Jurik, A.G., 103 K Kafka, S., 201 Kafková, J., 558 Kagen, L.J., 560 Kahan, A., 525 Kaine, J., 43, 51, 73 Kaine, J.L., 75, 117 Kakker, R., 473 Kalden, J.R., 41, 46, 49, 156, 203, 232, 233, 235, 237, 238, 242, 258, 337, 393, 397, 402 Kallenberg, C.G.M., 490, 566, 578, 621 Kaltwasser, J.P., 27, 366, 368 Kalunian, K.C., 416, 602 Kamali, S., 713 Kamatani, N., 171

Index Kaminska, E., 511 Kanamono, T., 171 Kantor, S.M., 117, 118 Kanz, L., 674 Kaplan, S.B., 371 Karahashi, T., 171 Karim, Z., 244, 365 Karsh, J., 37 Kary, S., 169 Kasamatsu, T., 171 Kasapoglu, E., 713 Kashyap, A., 521 Kasitanon, N., 422 Kasteler, J.S., 556 Kästner, P., 68 Kater, L., 566 Katsaraki, A., 32 Katsichti, P., 487 Kaufman, L.D., 535, 538 Kaul, M., 163, 171 Kautiainen, H., 106, 111, 116 Kavanaugh, A.F., 118, 161, 165, 167, 191, 271, 391, 393, 395, 397, 399, 401, 402, 404, 418 Kawabata, D., 450 Kawahito, Y., 171 Kawai, S., 278, 283, 289, 291 Kawald, A., 543 Kawasaki, Y., 691 Kawashima, H., 712 Kay, J., 223, 227 Kazokoglu, H., 703 Kearon, C., 472 Keenan, G., 245, 397, 402 Keenan, G.F., 238 Keiserman, M., 142 Keller, C., 7 Kellner, H., 346, 347, 351 Kelly, S., 148 Kempeni, J., 160 Keogh, A., 482 Keogh, K.A., 671, 675 Kern, J., 538 Kerr, D.R., 213 Kerr, G.S., 584, 645, 646 Kerstens, P.J., 65, 113, 121, 247, 253, 257, 262, 263 Keystone, E.C., 117, 118, 135, 152, 154, 161, 167, 189, 195, 197, 199, 201, 225, 237, 242, 258, 273, 277, 281, 385, 393, 402 Khandker, R., 220 Khanna, D., 266, 504, 506 Khariouzov, A., 334 Khellaf, M., 656

733

Index Khoshaba, B., 8 Khuy, T., 520 Kikuchi, H., 706 Kim, H.J., 506 Kim, J.H., 688, 689 Kim, M., 410 Kim, P.K., 688, 689 Kim, S.I., 344 Kincaid, W., 109, 114 King, J., 687 King, T.E. Jr., 488 Kingdom, J.C., 459 Kingsley, G.H., 8, 72 Kinsella, M.B., 494 Kiraz, S., 499 Kirby, J.D., 529, 531, 537, 547 Kircik, L., 390 Kirkham, B., 393, 402 Kirwan, J., 313 Kishimoto, T., 278, 279, 283, 291 Kiss, R., 576 Kissin, E., 518 Kivitz, A.J., 213, 325, 330, 335, 340, 381, 389 Klareskog, L., 203, 207, 225, 451 Klashman, D., 602 Klassen, L., 107 Klassen, T., 687 Klein, R., 470, 674 Klersy, C., 615, 618 Klinkhoff, A.V., 123 Klippel, J.H., 424, 427 Klooker, P., 658 Koch, K.M., 633 Koch, S., 674 Koehnke, R., 57 Koenig, A., 219 Koenig, A.S., 217 Koetter, I., 674 Kogure, M., 698, 708 Kohler, J.A., 57 Koike, T., 449 Kok, M.R., 575 Kondo, H., 76, 171, 248 Kontomerkos, A., 299 Koota, K., 106 Kopp, E.J., 30, 117, 118 Korn, J.H., 484, 538 Korpela, M., 106, 111, 116 Koskimies, O., 685 Kosmorsky, G., 602 Kötter, I., 521 Kovacs, I.B., 547 Kovacs, M.J., 472

Kovalenko, W., 503 Koyama, N., 171 Kraag, G., 94, 95 Kraishi, M.M., 187 Krause, A., 321, 346, 360 Kremer, J.M., 58, 117, 118, 128, 130, 131, 133, 138, 140, 146, 150, 179, 201, 245, 281 Krueger, G.G., 391, 395, 399, 401 Krueger, K., 11 Krüger, K., 160 Kruize, A.A., 566, 568 Kuga, Y., 171 Kujala, G., 535 Kumagai, S., 171 Kumar, A., 473 Kuntz, J.L., 375 Kunynetz, R., 404 Kupersmith, M., 600 Kupper, H., 156, 160, 163, 169, 325, 328, 330, 332, 333 Kurihara, Y., 552 Kurki, P., 27 Kuroda, T., 171 Kuroiwa, T., 427 Kutteh, W.H., 465 Kvien, T.K., 27, 41, 45, 46, 210, 220, 277, 314 Kwan, B.C., 446 Kyle, M.V., 533 Kyndt, X., 656 L La Montagna, G., 370 Laan, R.F., 3, 99 Laasonen, L., 27, 106, 111 Lacaille, D., 439 Lachenbruch, P.A., 491, 492 Laforet, P., 554 Lafyatis, R., 518 Lai, F.M., 446 Lai, K.N., 426 Laing, B., 33 Lalloo, U.G., 479 Lally, E., 508 Lam, C.W., 436 Lam, G.K., 516 Lambert, C.M., 62 Lambert, M., 656 Lambert, R.G., 327 Lampe, M., 55 Lamprecht, P., 673 Lan, J.L., 205 Lancaster, L., 488

734 Landewé, R.B., 24, 26, 81, 91, 99, 189, 191, 227, 342, 355, 365 Landzberg, M., 482 Lange, M.L., 195 Langford, C.A., 587, 649, 650, 659 Lanoux, P., 635 Lapadula, G., 268, 561 Lard, L.R., 64 Larkin, J., 6 Larsen, A., 41, 45, 46 Lashey, N., 465 Laskin, C.A., 459, 463, 472 Lassoued, S., 629 Latinis, K.M., 452 Lau, C.S., 412, 537 Lauque, D., 620, 631 Lauridsen, U.B., 102, 103 Lauwerys, B.R., 240, 255 Lawrence, D.A., 58 Laxer, R.M., 557 Le Bars, M., 137, 148 le Cessie, S., 263 Le Guern, V., 580, 643 Le Loët, X., 358 Le Noach, J., 656 Le Strat, A., 591 Le Thi Huong Du, D., 624 Le Thi Huong, D., 681 Leakan, R.A., 575 Leavitt, R.Y., 584, 645 Leclercq, B., 444 LeClercq, S., 306 Leconte, I., 482, 488 Lee, D.B., 411 Lee, J., 281 Lee, J.S., 688, 689 Leeb, B., 232 Lees, B., 480 Leff, J.A., 209 Leff, R., 107 Leff, R.D., 84 Leff, R.L., 564 Legerton, C.W., 149 Lehman, A.J., 123 Lehtinen, K., 309 Leirisalo-Repo, M., 27, 89, 106, 111, 116, 309, 314, 337 Leitman, S.F., 564 LeMaistre, C.F., 523 Lemmel, E.M., 53 Lemmens, A.M., 16 Lems, W.F., 113, 247, 257 Lenschow, D.J., 586

Index Lenz, O., 444 Léon, A., 626, 679, 681 Leon, M., 126, 128 Lesavre, P., 631 Letellier, P., 591, 620 LeVeque, F.G., 572 Levine, T.D., 562 Levy, J., 668 Levy, R.A., 421, 456 Levy, Y., 429 Levy-Neto, M., 585 Lewin, I.V., 310 Lhote, F., 624, 626, 629, 631, 679, 681 Li, E.K., 436, 446 Li, F.K., 426, 440 Li, G., 504, 506 Li, J., 216 Li, N.F., 271, 504 Li, P.K., 446 Li, S., 404 Li, T.C., 130, 131, 133, 137, 138, 142, 146, 148, 150, 462 Liang, P., 586 Licata, G., 468 Liddell, H.S., 455 Lidsky, M.D., 35 Liebling, M.R., 411 Lifermann, F., 656 Lightman, S.L., 676 Ligtenberg, G., 434 Lin, C., 142 Lin, S.L., 342 Lindegaard, H., 102, 103 Lindsley, H.B., 20, 117, 118 Lino-Pérez, L., 60 Lioté, F., 375 Lipsky, P.E., 233, 235, 237, 238 Lisi, L., 188 Listing, J., 305, 328, 334, 339, 346, 347, 351, 356, 360 Liu, T., 184 Lium, D., 222 Ljung, L., 264 Locatelli, F., 521 Locati, M., 100 Lochhead, A., 62 Lock, P., 109 Locker, G.A., 602 Lockshin, M.D., 456 Loew-Friedrich, I., 41, 43, 46 Logullo, F., 667 Lok, C., 624, 679 Lombardo, G., 699

735

Index Longy-Boursier, M., 631 Lopez-Longo, J., 604 Lopez-Soto, A., 602 Lortholary, O., 626 Lottenburger, T., 102, 103 Louie, J., 216 Lovatt, G.E., 695 Loveless, J.E., 273 Lovino, C., 363 Lovy, M., 201 Löw-Friedrich, I., 39 Lowenstein, M.B., 293 Ludivico, C., 602 Luggen, M.E., 117, 118, 126, 130, 137, 150, 316, 376 Lui, S.L., 426 Luijtens, K., 191 Luis, M., 60 Lunardi, C., 699 Luosujärvi, R., 116 Luqmani, R.A., 602, 628, 639, 641 Luta, G., 12 Luukkainen, R., 106, 309 Luyten, F.P., 255 Lynch, D., 506 M M’Seffar, A., 22 Macchioni, L., 608 Macchioni, P., 363, 617, 618 Macfarlain, D.G., 311 Macfarlane, D., 72 Macfarlane, J.D., 232 MacGregor, S.N., 464 Machácek, S., 558 Machold, K.P., 80 Macintyre, C.C., 546 Mack, M., 344, 391 MacKay, A., 547 Mackay, M., 410 Mackie, S., 260 MacPeek, D., 212 Madden, J., 276 Maddison, P.J., 530, 532 Madhok, R., 6, 13, 92, 532, 537, 540 Magadur-Joly, G., 591 Magder, L.S., 409, 422 Maglione, W., 542 Mahowald, M.I., 316 Mahowald, M.L., 376 Mahr, A., 620, 635, 643, 656 Maier, A.L., 59, 209

Maini, R.N., 232, 233, 235, 237, 238, 242, 258, 279 Maioli, C., 542 Maisonobe, T., 554 Major, G., 314 Makkena, R., 316, 376 Makrakis, E., 469 Makris, M., 462 Maksymowych, W.P., 306, 327 Malagari, K., 495 Malaise, M.G., 156, 163, 169, 203 Malaviya, A.N., 473 Malcangi, G., 667 Maleknia, T., 303 Malesci, D., 268, 370 Malghem, J., 255 Mallée, C., 253 Mallek, J.A., 84, 107 Mamun, K., 266 Manaster, B.J., 376 Mancarella, L., 268 Mandel, F.P., 463 Mandell, B.F., 602 Manganelli, P., 618 Manganelli, S., 268 Manger, B., 27, 393, 402 Manger, K., 654 Manguso, F., 372 Manicourt, D.H., 240 Manno, C., 413 Manny, J., 575 Mansmann, U., 707 Mansour, K., 578 Mant, T.G., 531 Manzini, C., 618 Maragou, M., 495 Marasini, B., 542 Marcelli, C., 358 Marchesoni, A., 98, 363 Marchioli, R., 471 Marder, G., 410 Mariette, X., 169, 174, 358, 577, 580 Markenson, J.A., 117, 118, 197, 199 Markert, E.R., 27 Markland, J., 511 Marks, C.R., 120, 122 Markusse, H.M., 86, 91 Marmont, A., 521 Marrott, P., 538 Marsters, P.A., 238 Martín Mola, E., 203, 219 Martin, M., 96 Martin, R.W., 197, 199, 508, 538

736 Martín-Mola, E., 604 Martinez Taboada, V.M., 604 Martinez, A., 521 Martini, A., 521 Marzo-Ortega, H., 353 Marzusch, K., 470 Mascagni, B., 541 Mason, D., 191 Mason, D. Jr, 189 Mason, R.M., 38 Massara, A., 268 Massarotti, M., 542 Masson, C., 580 Mastaglio, C., 100 Masuda, K., 698, 708 Mat, C., 693, 697, 702, 709, 711 Mathieu, A., 429 Mathur, D.S., 23 Matsubara, T., 171 Matsuda, T., 171 Matsumoto, A., 73 Matsumoto, I., 449 Matsumura, R., 171 Matsuoka, S., 552 Matteson, E.L., 223, 227, 593 Matucci Cerinic, M., 484 Mavrikakis, M., 487 Mayes, M., 484, 500, 504, 508, 535 Mayes, M.D., 523, 538 Mazlumzadeh, M., 593 Mazzantini, M., 609 McCabe, D., 176, 178, 179, 181 McCans, J., 526 McCarey, D.W., 13 McCloskey, D.A., 534, 535 McCrosky, S., 553 McCune, W.J., 374 McDonagh, K.T., 523 McDonald, F., 92 McDonnell, N.D., 195 McDougall, J., 455 McEntegart, A., 71 McFarlin, J., 418 McGonagle, D., 96, 276, 353 McGoon, M.D., 474, 476 McHugh, N.J., 480, 530 McInnes, I.B., 13, 92, 391 McKay, J.D., 287 McKendry, R.J., 37, 94, 95, 544 McKendry, R.J. Jr, 120 McLaine, P., 687 McLaughlin, B., 523 McLaughlin, G.E., 20

Index McLaughlin, V.V., 474, 476 McMahon, A.D., 109, 114 McRorie, E., 62, 602 McSweeney, P.A., 521, 523 Mease, P.J., 189, 191, 195, 209, 245, 330, 366, 378, 380, 381, 383, 385, 386, 388, 389, 391, 399 Medich, J., 381, 383 Medsger, T.A. Jr., 508, 535, 538 Meinao, I.M., 417 Mejias, E., 376 Mejias, M., 316 Mekki, Q.A., 75, 78 Meliconi, R., 608 Melikoglu, M., 711 Melo-Gomes, J., 207, 214, 219 Mendelsohn, A., 404 Mengle-Gaw, L.J., 75, 78 Menkes, C.J., 525 Menozzi, G., 100 Menter, A., 404 Merenmies, J., 685 Merkel, P.A., 484, 518, 538, 586, 602, 605 Merrien, D., 656 Merrill, J.T., 452 Merviel, P., 520 Metersky, M., 500, 504 Metwally, M., 462 Metz, J., 388 Metzler, C., 652, 654 Meusser, S., 89 Meyer, O., 174 Meyrick Thomas, R.H., 547 Micallef, E., 541 Miceli, M.C., 343 Michael, J., 628 Miehle, N., 654 Mielke, F., 321 Mihajlovic, D., 39 Mikuls, T.R., 84 Milani, S., 609 Miles, S., 96, 498 Milleck, D., 320 Miller, B.L., 491 Miller, F.W., 564 Miller, L.C., 555 Mimori, T., 450 Mimura, T., 171 Minoda, S., 171 Miranda, P.C., 225 Miranda-Limón, J.M., 433 Mirapeix, E., 637, 683 Misra, R., 61

737

Index Mitnick, H.J., 600 Mitra, P., 149 Mitseas, C., 299 Miyake, S., 171 Miyasaka, N., 171, 248, 278, 283, 289, 291, 449 Mizushima, Y., 708 Mladenovic, V., 39 Mo, D., 462 Mochizuki, M., 708, 712 Modafferi, D., 183 Mody, G.M., 479 Mok, C.C., 412, 445 Mola, E.M., 214, 337 Molitor, J.A., 393, 402, 484, 523 Möllby, H., 596 Molloy, E.S., 587 Monteagudo-Sáez, I., 169 Montecucco, C., 169, 268, 615 Monti, G., 100 Moore, G., 107 Morado, I.C., 598 Morassut, P., 37 Moreland, L.W., 20, 43, 51, 73, 126, 128, 131, 133, 138, 146, 152, 154, 179, 187, 195, 197, 199, 209, 222, 229, 245, 508 Moroni, G., 413 Morrison, E., 6, 92 Morvan, J., 581 Mosca, M., 413 Moss, H., 498 Moss, K., 188 Möttönen, T., 70, 106, 111, 116 Mouthon, L., 635, 643, 656 Moutsopoulos, H.M., 156, 495, 570 Mubarak, K., 500, 504 Mudivarthy, S., 391 Mudun, A., 713 Müftüoglu, A., 701 Mühler, M., 648 Muir, J., 424 Mukai, M., 171 Mulder, J., 121 Mullaly, P.M., 58 Mulleman, D., 174 Muñoz-Valle, J.F., 304 Munro, R.A., 92 Murasawa, A., 171 Murata, N., 283 Murphy, E., 537 Murphy, F.T., 227 Muscoplat, C.C., 572 Musial, J., 471

Musikic, P., 39, 176 Mutru, O., 309 Mysler, E.F., 287 N Nab, H.W., 212 Nacci, F., 268 Nachman, P.H., 660 Nadashkevich, O., 503 Naeyaert, J.M., 517 Nagaoka, S., 171 Nagaya, I., 248 Najim, R.A., 704 Nakabayashi, K., 171 Nakae, K., 698 Nakagawa, N., 171 Nakajima, A., 698 Nakajima, H., 171 Nakamura, S., 712 Nakata, S., 171 Nakayamada, S., 450 Nakazaki, S., 171 Nanki, T., 171 Nash, P., 46, 163, 223, 229, 366, 368 Nash, R.A., 523 Nasonov, E.L., 287 Nasution, A.R., 323 Natarajan, K., 130 Nawata, M., 450 Nayiager, S., 142, 144 Neal, J.S., 227 Neerhof, M.G., 464 Nell, V.P., 80 Nelson, J.L., 523 Nemcová, D., 558 Nesher, G., 590 Neuer, A., 470 Neumann, I., 662 Neumann, V., 373 Neuwelt, C.M., 452 Newlands, P., 480 Newmark, R., 186, 222 Ng, W.L., 412 Nguyen, N., 484 Ni, L., 342 Niccoli, L., 608 Nishikawa, T., 171 Nishimoto, N., 278, 283, 289, 291, 449 Nissilä, M., 106, 309 Nived, O., 432 Nizam, S., 260 Noble, L.S., 465

738 Noertersheuser, P.A., 154 Nojima, Y., 171 Nölle, B., 647, 673 Nordborg, E., 596 Norris, H., 458 Nowack, R., 658, 662 Nuamah, I., 126, 130 Nuamah, I.F., 128, 131 Nuki, G., 176, 181, 602 Nurmohamed, M.T., 301 Nuutinen, M., 685 Nuver-Zwart, I.H., 17 Nzeusseu Toukap, A., 240, 255, 513 O O’connor, P.J., 244, 353 O’Dell, J.R., 84, 107 O’Hanlon, D., 511 O’Nan, P., 444 Oates, J.C., 452 Occhipinti, G., 609 Oding, R., 264 Oed, C., 39, 41, 45, 46 Oguchi, T., 171 Oguz, V., 695 Ohkubo, M., 552 Ohno, S., 708, 712 Oka, M., 70 Okamoto, A., 171 Olech, E., 266 Olguín-Ortega, L., 433 Olive, P., 89 Olivieri, I., 314, 341, 363, 608 Olman, M., 500, 504 Olschewski, H., 474, 476 Olsen, N., 43, 51 Onishi, K., 171 Origgi, L., 502, 541 Ormälä, T., 685 Orozco-Barocio, G., 431 Orte Martínez, J., 489 Ory, P.A., 342, 378, 380, 383, 389 Osada, H., 552 Osone, Y., 171 Ostergaard, M., 102, 103 Osterland, C.K., 420 Ota, S., 171, 557 Otero, C., 553 Otsuka, T., 171 Oudiz, R.J., 474, 476 Outland, J.D., 559 Overfield, S., 149

Index Owen-Smith, B., 38 Ozaki, S., 171, 552 Ozbalkan, Z., 499 Ozcebe, O.I., 715 Ozgurel, Y., 716 Ozturk, M.A., 499 Ozyazgan, Y., 693, 695, 697, 701, 702, 709, 711 P Pacheco-Tena, C., 60 Pacor, M.L., 303, 699 Padula, A., 363, 608 Paget, S.A., 600 Pagnoux, C., 620, 643, 656 Paimela, L., 89, 106, 111 Pakas, I., 495 Pall, A., 628 Palmer, W., 107, 225 Pälvimäki, I., 106 Panay, G.S., 72 Panayi, G.S., 610 Pande, I., 473 Pande, J.N., 473 Pandya, S., 61 Pangan, A.L., 332 Panni, B., 98, 100 Paolazzi, G., 618 Paolozzi, L., 341 Papa, N.D., 542 Papadopoulos, I.A., 29 Papamichael, C., 487 Papasavvas, G., 72 Papo, T., 656 Papp, K., 391 Pardo, V., 444 Pareek, A., 23 Park, J.M., 688, 689 Park, S.H., 144 Park, W., 229 Parker, S., 557 Parsley, E., 500, 504 Parvin, M., 700 Pascual, M.J., 521 Pasero, G., 363, 609 Passweg, J.R., 521 Patel, A., 187 Patel, J., 188 Patel, K., 237 Patra, K., 173 Pattison, N.S., 455 Patz, P., 622

739

Index Paulsen, G., 107 Paulsen, J., 647, 648 Paulus, H.E., 154, 213, 491, 492 Pavelka, K., 165, 176, 189, 203, 210, 220, 279 Pay, S., 499 Pazarli, H., 695, 701 Pazdur, J., 225 Peaceman, A.M., 467 Pearson, S.B., 480 Pease, C.T., 96, 582 Pedersen, J.K., 102, 103 Pedersen, R.D., 203, 207, 212, 214, 217, 219 Peeters, A.J., 64, 86, 91, 253 Peldan, K., 89 Pelletier, S., 554 Peluso, R., 372 Pennec, Y., 577, 581 Peppas, C., 495 Perdok, R.J., 378, 380, 381, 383 Perdriger, A., 358, 577 Pereira, R.M., 585 Perez, J.L., 165 Perino, A., 468 Pers, J.O., 581 Pertuiset, E., 635 Peter, H.H., 484, 521 Petera, P., 429, 432 Peterfy, C.G., 140, 144, 149, 277 Peters, N.D., 297 Petersen, J., 279 Peterson, M.G., 456, 600 Petersson, I.F., 264 Petri, M., 409, 422, 456 Petrillo, G.F., 58 Petrovic, R., 429 Pettersson, E., 637 Pham, T., 358 Phillips, A.C., 538 Pichlmeier, U., 68 Piirainen, H., 106 Pijpe, J., 578 Pillemer, S.R., 575 Pincus, T., 12, 94, 95 Piontud, M., 629 Pipitone, N., 8, 617 Planchon, B., 591 Plant, M.J., 72 Plotz, P.H., 564 Plouffe, L., 466 Podenphant, J., 102 Polisson, R.P., 416 Politi, E.N., 29 Pons-Estel, B.A., 229

Ponsot, G., 549 Ponti, A., 502 Ponticelli, C., 413 Poon, F.W., 6 Poór, G., 50 Pope, J.E., 484, 511 Popert, A.J., 124 Popovic, R., 429 Popoviv, M., 39 Porter, D.R., 6, 71, 92, 109, 114, 125 Porter, J., 535 Pothos, M., 687 Pottier, M.A., 591 Pottier, P., 591 Poulakos, J., 183 Pourrat, J., 520 Prayson, R., 602 Prentice, H.G., 521 Prestele, H., 27 Prieur, A.M., 549 Principato, A., 343 Prins, A.P., 99 Pritchard, C., 148 Proietti, M., 497 Proudman, S.M., 96 Provost, G., 529 Puéchal, X., 174, 577, 602, 620, 635, 656 Pulido, T., 482 Pulsatelli, L., 608 Puolakka, K., 106, 111, 116 Purkiss, S., 461 Pusey, C.D., 637, 641, 668, 676, 683 Q Qi, K., 146, 149 Queirós, M., 527 Quenby, S., 460 Quinn, M.A., 244, 260 R Racewicz, A.J., 271 Rademaker, M., 529, 531, 547 Radu, A.S., 585 Raemen, F., 279, 341 Raghu, G., 488 Raghupathy, R., 448 Ragin, A., 464 Rahman, M.U., 223, 225, 227, 229, 250, 605 Rahman, P., 327 Rai, R., 457 Raimondi, M., 502

740 Rainisio, M., 481, 484 Rajantie, J., 685 Ramanan, A.V., 557 Ramos, R.C., 421 Ramos-Niembro, F., 493 Ramos-Remus, C., 285 Rantalaiho, V., 116 Rasker, J.J., 510 Rasmussen, K.J., 18 Rasmussen, N., 637, 639, 641, 683 Rau, R., 9, 45, 89, 156, 160, 176 Rauz, S., 582 Ravaud, P., 358, 577 Read, C., 500, 504 Reading, J.C., 371 Reda, D.J., 316, 318, 376 Reece, E.A., 466 Reece, R.J., 96 Regan, L., 457 Reich, K., 386 Reinhold-Keller, E., 647, 648, 651, 654, 666 Remer, C.F., 435 Renaudineau, Y., 581 Rendt-Zagar, K.E., 605 Reveille, J.D., 325 Revicki, D.A., 333 Rhedda, A., 526 Ribi, C., 620 Riccieri, V., 362 Rich, E., 484 Rich, W.J., 179 Richards, A., 582 Richards, N.T., 628 Richardson, C., 96 Richmond, M., 600 Richter, C., 55, 666 Riemekasten, G., 543 Rietveld, J., 81 Riley, D.J., 500, 504 Rinaldi, N., 437 Ring, E.F., 530 Risler, T., 674 Risselada, A., 451 Ritchie, J.W., 463 Ritchlin, C.T., 378, 380, 383 Ritter, J., 266 Robbins, I.M., 481 Robbins, S., 186, 222 Roberts, C.J., 38, 480 Roberts, W.N., 20 Robertson, D., 217, 219 Robertson, R., 498 Robles, M., 144

Index Rochel, E., 55 Rockwitz, K., 68 Rodeheffer, R.J., 545 Rodríguez Rubio, S., 489 Rodríguez-Valverde, V., 604 Roecker, E.B., 474, 476 Rojas, J., 266 Rommer, J.A., 545 Ronday, H.K., 64, 247, 257, 262 Ronkainen, J., 685 Roodenburg, J.L., 578 Rooney, T.W., 20 Rosen, C.F., 366 Rosenburg, R., 41, 45 Rosenthal, P., 410 Roth, D., 444 Roth, M.D., 500, 504, 506 Röther, E., 55 Rothfield, N.F., 500, 504, 538 Rothschild, B., 20 Rottem, M., 584 Roudaut, A., 581 Roué, I.Q., 581 Roufosse, F., 513 Roux, S., 481, 482, 488 Rovensky, J., 285 Royer, I., 631 Rozman, B., 39, 41, 45, 49, 176, 432 Rubbert-Roth, A., 285 Rubenstein, J., 389 Rubin, L.J., 474, 476, 481, 482, 486 Rubinow, A., 590 Ruderman, E.M., 117, 118, 195, 216, 378 Rudwaleit, M., 300, 305, 328, 334, 339, 356 Ruel, M., 629 Ruivard, M., 635, 656 Russel, F.J., 85 Russell, A.S., 128, 133, 138, 146, 163 Rutstein, J., 73 Rynes, R.I., 58 S Saag, K., 73 Saatçi, O., 703 Saccardo, F., 100 Sack, M., 20, 73 Saeki, Y., 171 Saip, S., 709 Saito, K., 171, 449, 450 Sajjadi, H., 700 Sakane, T., 708 Sakkas, E., 469

Index Salaffi, F., 268, 363, 614 Salama, A.D., 676, 678 Salazar-Paramo, M., 431 Saldate, C., 142 Saleem, B., 260 Salisbury, P.L. III., 572 Salmon, I., 576 Salonen, D., 327, 389 Salsano, F., 497 Salvarani, C., 337, 363, 605, 608, 615, 617, 618 Salvi, A., 667 Sambo, P., 497 Sambrook, M., 92 Sambrook, P.N., 210, 220 Sammaritano, L., 456 Samuelson, C.O., 371 Sanchez, A., 281 Sanchez-Ortiz, A., 431 Sanda, M., 203 Sandhu, S., 62 Sankar, V., 575 Sanmartí, R., 337 Sano, H., 171 Sany, J., 163, 203, 212, 337 Saraux, A., 581 Saravelos, S., 462 Sardina, M., 541 Sarzi-Puttini, P., 100 Sasaki, T., 171 Sasso, E.H., 173, 380, 381 Sato, E.I., 417, 438 Satoh, M., 552 Satoi, Y., 73 Sattar, N., 13 Saunders, S.A., 114 Sauvezie, B., 577 Savage, C.O., 628, 641, 668, 678, 683 Sawada, S., 171 Scarpa, R., 372 Scarpellini, M., 100 Schaeffler, A., 11 Schaeverbeke, T., 174 Schaible, T.F., 232 Schaller, J.G., 555 Schattenberg, A.V., 521 Schattenkirchner, M., 45, 46, 49, 89, 156, 160 Schaufelberger, C., 596 Schaumann, D., 633 Schechtman, J., 183, 184, 271 Scheetz, R.J., 602 Schellong, S., 633 Schenk, Y., 67

741 Scherbakov, O., 13 Schewe, S., 356, 360 Schiff, M.H., 30, 43, 51, 73, 130, 137, 142, 148, 150, 159, 179, 184, 191, 195, 197, 199, 201, 209, 216, 242, 245, 325, 330, 332 Schinco, P., 471 Schlüter, B., 571 Schmidely, N., 137 Schmidt, W.A., 320 Schmitt, W.H., 662 Schnabel, A., 666 Schned, E., 602 Schneider, M., 346, 347, 351, 356, 360 Schneider, R., 557 Schneider, U., 393, 402 Schnitzer, T., 73 Schotte, H., 571 Schousboe, J., 602 Schouten, H.J., 86 Schraufnagel, D.E., 500, 504 Schroeder, D.R., 671 Schumacher, H.R., 316 Schumacher, H.R. Jr., 376 Schurek, H.J., 633 Schwartz, B.D., 75, 78 Schwartzman, S., 560 Schwarz-Eywill, M., 437 Schwebig, A., 339 Scioscia, C., 561 Scorza, R., 502, 541 Scott, D.G., 188, 424 Scott, D.L., 8, 41, 45, 46, 72, 124 Sebastiani, G.D., 429 Sebba, A.I., 20, 293 Secchi, M.E., 268 Segal, A.M., 602 Segurado, O.G., 167 Seibold, J.R., 484, 500, 504, 508, 511, 523, 534, 535, 538 Seifert, H., 39 Seigneuric, C., 631 Senécal, J.L., 420 Senocak, M., 702 Sensi, F., 362 Senter, R.G., 73 Seo, P., 675 Serdaroglu, S., 695 Seror, R., 580 Settas, L., 163, 203, 341 Severi, C., 100 Sfikakis, P.P., 487 Shafforth, M.F., 124 Shanahan, J.C., 452

742 Sharada, B., 473 Shariat, K., 548 Sharman, V.L., 15 Sharp, J., 43, 51, 165 Sharp, J.T., 35, 122, 161, 173, 378, 380, 383, 389 Sharquie, K.E., 704 Shaw, R.A., 2 Shaw, T.M., 269, 271, 273, 277 Shen, Y.K., 404 Shenberger, K.N., 56 Sheps, S.G., 589 Shergy, W.J., 126, 131, 144, 187 Sherrer, Y., 73, 130, 602 Shima, Y., 449 Shimakawa, M., 712 Shin, J.I., 688, 689 Shin, Y.H., 688, 689 Shinjo, S.K., 585 Shipley, M.E., 1 Sholl, J.S., 464 Sholter, D., 306 Shulman, H., 523 Shulman, L.E., 36 Sibilia, J., 131, 174, 337, 577, 580 Sibley, J., 511 Siegel, E.L., 389 Siegel, M.T., 374 Siegert, C., 637 Sieper, J., 300, 305, 321, 325, 328, 330, 333, 334, 337, 339, 341, 344, 346, 347, 349, 351, 356, 360 Sierakowski, S., 11 Siewertsz Van Reesema, D.R., 4 Sili-Scavalli, A., 362 Silman, A., 695 Silver, R., 500 Silver, R.K., 464, 467 Silver, R.M., 467, 494, 504 Silverman, E.D., 557 Silverman, S.L., 316, 376 Simianer, S., 160 Simms, R.W., 484, 500, 504, 518, 538 Simon, A., 554 Simon, P., 679 Simonneau, G., 481, 482 Simpson, K., 117, 118 Sinclair, A., 443 Singer, J.Z., 416 Singh, A., 217, 220 Sinico, A., 637 Sinico, R.A., 429, 641, 683 Siri, D.A., 293

Index Sisson, B.A., 555 Sitbon, O., 481 Siu, Y.P., 445 Siva, A., 709 Skeith, K.J., 306 Skjodt, H., 102, 103 Skopouli, F.N., 495, 570 Skosey, J.L., 416 Sleckman, J., 83 Smit, A.J., 490, 540 Smith, C.D., 420, 439, 511, 544 Smith, C.R., 545 Smith, D.B., 245 Smith, J.A., 575 Smith, K.G., 678 Smith, M., 188 Smith, R.E., 531 Smith, V.P., 517 Smolen, J.S., 41, 45, 46, 80, 191, 210, 220, 227, 232, 233, 235, 237, 238, 242, 258, 279, 285, 393, 397, 402, 432, 447 Snaith, M.L., 407 Sneller, M.C., 584, 602, 646, 649, 650, 659 Sobel, A., 520, 679 Soheilian, M., 700 Sokka, T., 12 Solau-Gervais, E., 358 Solinger, A.M., 184, 340 Solomons, N., 443 Soloninka, C.A., 463 Solsky, M.A., 371 Solvkjaer, M., 18 Song, I.H., 305 Songcharoen, S., 142 Sonnenblick, M., 590 Sopwith, M., 188 Sordet, C., 580 Sörensen, H., 49, 334, 339, 346, 347, 351, 356, 360 Soubrier, M., 174, 602 Soueidan, S.A., 553 Sowa, J., 36 Spadaro, A., 362 Spanò, A., 372 Specks, U., 671, 675 Spencer-Green, G.T., 165, 199 Speyer, I., 64 Spiegel, L., 557 Spiera, H., 600 Spiera, R.F., 600 Spijkervet, F.K., 578 Spinnato, J., 467 Spitzer, K.A., 459, 463

743

Index Srivastava, R., 23 St Clair, E.W., 233, 235, 237, 238, 242, 258 Stablein, D.M., 120, 122 Stähler, G., 488 Stamatelopoulos, K.S., 487 Stamler, D.A., 73 Stamm, T.A., 80 Stanworth, D.R., 310 Staudt, L.S., 494 Steen, V., 500, 504, 508 Steen, V.D., 416, 535 Stefanadis, C., 487 Stegeman, C.A., 621, 683 Stein, C.M., 73, 95 Stein, D.P., 553 Stein, M., 94 Steinberg, A.D., 423, 424, 427 Steinberg, M., 537 Steiner, G., 447 Steinfeld, P., 9 Steinfeld, S.D., 128, 131, 365, 378, 576, 577 Stengaard-Pedersen, K., 102, 103 Stephenson, M.D., 461 Stern, C., 458 Stern, M., 631 Sterz, M.G., 491, 492 Steven, M., 92 Stevens, M.B., 2 Stevens, R.M., 269 Stevens, S.R., 390 Stevenson, J.T., 75 Stienstra, Y., 490 Stirling, A., 109, 114 Stone, J.H., 602, 605, 663 Stoner, J., 107 Storb, R., 523 Strand, V., 39, 43, 50, 51, 117, 118, 159, 189, 191, 193 Strange, C., 494, 500, 504 Strober, B.E., 390 Strollo, D., 506 Stroumza, P., 520 Strusberg, I., 229, 250 Studynková, J., 558 Sturfelt, G., 432 Sturrock, R.D., 1 Suda, H., 705 Suematsu, E., 171 Sugawara, S., 76 Sugimoto, K., 171 Sugino, N., 708 Sugita, S., 712 Sugiyama, E., 171

Sullivan, K., 521 Sullivan, K.M., 523 Sumi, Y., 171 Sumida, T., 171, 449 Sun, G., 183, 187 Sunderam, K.R., 473 Sunderkötter, C., 543 Sutton, J.D., 2 Suzuki, H., 691 Suzuki, J., 691 Suzuki, Y., 171 Svendsen, A., 102, 103 Svensson, B., 7 Swaak, A.J., 510 Swanson, H., 602 Swearingen, C.J., 12 Swinson, D.R., 1 Szczepanski, L., 269, 271 Szechinski, J., 11, 133, 138, 269, 279, 341 Szeto, C.C., 436, 446 T Tabarki, B., 549 Taccari, E., 362 Taggart, A.J., 212 Tak, P.P., 277 Takada, K., 449 Takahashi, H., 171 Takasugi, K., 171 Takeuchi, T., 171, 248, 278, 283, 289, 291, 449 Talar-Williams, C., 646, 649, 650, 659 Tam, L.S., 436, 446 Tamayo, R.P., 493 Tan, A.L., 276, 353 Tanaka, T., 171 Tanaka, Y., 449, 450 Taneichi, K., 171 Tang, C.S., 440 Tang, S., 426 Tani, K., 171 Tannenbaum, H., 161 Tapson, V.F., 481 Tardieu, M., 549 Tarp, U., 102, 103 Tarshish, P., 690 Tashkin, D.P., 500, 504, 506 Tatsis, E., 647 Taylor, H.G., 312 Taylor, L., 276 Taylor, P.C., 279 Taylor, S.R., 676 Taylor, T.H., 56, 316, 376

744 Tebib, J., 375 Teixeira, A., 554 Teleman, A., 264 Ten Wolde, S., 254 Teng, J., 137, 138, 140 Teoh, L.A., 152 Teoh, L.S., 154, 161 ter Borg, E.J., 67 Tervaert, J.W., 621, 637, 639 Tesar, V., 637, 641 Tesser, J.R., 94, 95, 183, 184, 197, 199 Testa, S., 471 Thaçi, D., 368 The, H.S., 26 Theander, J., 264 Theodore, A., 500, 504 Thomas, R.H., 529 Thompson, C., 333 Thompson, P., 313 Thomson, D., 279 Thomson, E.A., 6, 71 Thomson, G.T.D., 327, 381, 383 Thorne, J.C., 22 Thörner, A., 264 Thriene, W., 346 Tierney, A., 92 Tikly, M., 45 Tindall, E.A., 131, 195 Tirri, E., 497 Tirri, R., 370 Tizziani, V.A., 585 To, C.H., 445 Todesco, S., 163, 413 Toes, R.E., 64 Tognoni, G., 471 Tokunaga, M., 450 Toma, S., 171 Tomsic, M., 293 Tong, K.H., 445 Tonietti, G., 497 Tony, H.P., 281, 321 Torley, H.I., 95, 532 Tornero-Molina, J., 207 Torre, J., 332 Torres, F., 474, 476 Tosi, S., 98 Totalities, M.C., 273 Tousoulis, D., 487 Townes, A.S., 36 Tozman, E., 444 Tran, D., 557 Tran-Johnson, T.K., 572 Trape, G., 358

Index Triolo, G., 268, 343, 468 Trivedi, M., 572 Trotta, A., 618 Trotta, F., 268 Troum, O., 266 Trujillo-Hernandez, B., 431 Tsakonas, E., 22, 420 Tsang, P., 461 Tse, K.C., 440 Tseng, C.E., 410 Tsifetaki, N., 570 Tsuboi, S., 171 Tsuji, T., 171 Tsuji, W., 213, 335, 340, 342, 389 Tsujimura, S., 450 Tsukamoto, M., 171 Tucker, L.B., 555 Tugal-Tutkun, I., 713 Tuggle, C., 602 Tugwell, P., 94, 95 Tunn, P.D., 124 Tura, B.R., 421 Turney, J.H., 432 Turtinen, J., 685 Tutuncu, Z., 393, 402 Tüzün, B., 701 Tüzün, Y., 695, 697, 701, 702 Tyndall, A., 521 Tyrrell, P.N., 557 Tzioufas, A.G., 169 U Uchida, S., 76 Uddhammar, A., 596 Ueno, S., 712 Uffmann, M., 80 Uhlfelder, M.L., 663 Ullman, S., 540 Umino, T., 171 Unalp-Arida, A., 456 Unger, B., 18 Unnebrink, K., 169 Uppal, S.S., 448, 473 Urayama, A., 698 Urbani, G., 699 Urgancioglu, M., 713 Urowitz, M.B., 120 Usui, M., 708 Usui, Y., 171 Utset, T.O., 452 Uysal, O., 693, 702 Uysal, S., 693

Index V Valentini, G., 268, 497 Valero Expósito, M., 489 Valesini, G., 268 Vallance, R., 109, 114 van Aken, J., 64 van Albada-Kuipers, G.A., 597, 612 van Bijsterveld, A., 566 van Booma-Frankfort, C., 597, 612 van Damme, P., 574 van de Laar, M.A., 86, 91 van de Putte, L.B., 3, 16, 17, 46, 85, 87, 121, 156, 160, 163, 302, 510, 521, 574 van den Borne, B.E., 26, 81 Van den Bosch, F., 126, 383 van den Brink, H.R., 86 van den Hoogen, F.H., 510, 521, 574 van den Wall Bake, A.W., 434 van Denderen, J.C., 86, 91, 301 van der Bijl, A.E., 254 van der Heijde, D.M., 7, 17, 86, 91, 96, 191, 203, 207, 214, 219, 235, 238, 242, 258, 283, 325, 330, 332, 333, 335, 340–342, 349, 355, 397, 401, 402 van der Heijden, A., 566 van der Horst-Bruinsma, I.E., 301, 341 van der Kooij, S.M., 65, 262, 263 van der Linden, S., 86, 91, 314, 337 van der Lubbe, P.A., 262 van der Paardt, M.J., 301 van der Veen, M.J., 67, 597, 612 van der Woude, F.J., 658, 662, 683 van Dongen, H., 64 van Everdingen, A.A., 4 van Gestel, A.M., 3 van Groenendael, J.H., 65, 247, 257 van Houwelingen, H.C., 434 van Imhoff, G.W., 578 van Krugten, M.V., 247, 254, 257 van Kuijk, A.W., 365 van Laar, J., 521 van Lier, H.J., 510 Van Praet, J.T., 517 van Riel, P.L., 3, 17, 53, 85, 87, 156, 160, 163, 212, 302 van Rijthoven, A.W., 24 van Roon, E.N., 568 van Roon, J.A., 568 van Schaardenburg, D., 263 van Tuyl, L.H., 113 van Vollenhoven, R.F., 165, 173, 191, 193, 264, 271, 281, 451

745 van Woerkom, J.M., 568 van Zeben, D., 65, 86, 247, 253, 257, 263 van’t Hof, M.A., 85 Vander Cruyssen, B., 517 VanderStoep, A., 388 Vandooren, B.R., 517 Vanhille, P., 635, 641 Vanoli, M., 541 Vanthuyne, M., 513 Varga, J., 500, 504, 508, 535, 538 Vargas, E., 598 Vargas, F., 433 Vasconcelos, C., 429 Vasey, F.B., 316, 376 Vasunilashorn, S., 506 Vaughan, E.M., 424, 427 Vazquez-Del-Mercado, M., 304 Vazquez-Mellado, J., 60 Veale, D., 498 Veale, D.J., 96, 365, 480 Velagapudi, R.B., 154 Venalis, A., 432 Vencovsky, J., 191, 193, 558 Vere, D.W., 38 Verhoeven, A.C., 86, 91 Verschueren, P., 240, 255 Verstappen, S.M., 67, 568 Vestergaard, A., 103 Veys, E., 314, 337 Vidal, E., 629 Viganego, F., 523 Viger, K., 518 Vilela, V.S., 421, 456 Vinzio, S., 656 Viscuso, T., 502 Visser, K., 64 Vissink, A., 578 Visvanathan, S., 223, 225, 227, 229, 266, 344, 356, 391, 605 Vital, E.M., 582 Vivino, F.B., 572 Vlachoyiannopoulos, P.G., 495 Vollenhoven, R.V., 189 von Hinüber, U., 68 von Wilmowsky, H., 548 Voorhees, J.J., 374 Voskuyl, A.E., 113 Vosse, D., 342 Voswinkel, J., 673 Voulgari, P.V., 29, 32 Vratsanos, G., 140, 149 Vree, T.B., 85 Vuori, K., 106

746 W Wagner, C., 223 Währisch, J., 68 Wajdula, J.S., 203, 207, 210, 220, 341 Wakefield, R.J., 96, 365 Wakitani, S., 171 Walker, D., 341 Wall, B., 83 Wallace, D.J., 83, 266, 393, 402, 435, 452 Walsh, B., 602 Waltbrand, E., 264 Walter, N., 163 Waltuck, J., 117, 118 Wanchu, A., 23 Wang, B., 242 Ward, J.R., 316, 371, 376, 416 Ward, R.H., 376 Warrick, J.H., 494 Wasko, M.C., 197, 199 Wassenberg, S., 9, 393, 397, 402 Watson, H.R., 530, 532, 540 Watt, I., 176, 178 Waytz, P., 107 Weaver, A.L., 43, 51, 195, 197, 199 Weaver, C.A., 84 Weening, J.J., 434 Wees, S., 107 Weier, R., 393, 402 Weinberg, M.A., 378, 381 Weinblatt, M.E., 59, 135, 150, 152, 154, 167, 179, 195, 209, 216 Weiner, S.R., 508, 535 Weinstein, A., 371, 508, 538 Weisman, M.H., 20, 117, 118, 152, 154, 165, 213, 233, 235, 237, 238, 266, 316, 376, 393, 397, 402, 435, 508 Weiss, R., 242 Welch, K.E., 20 Wellborne, F., 383 Wells, A.U., 480 Wells, G., 94, 95 Wellsbury, J., 480 Wendling, D., 358 Wener, M.H., 523 Wesiroglou, G., 299 Wesley, R., 564 Westedt, M.L., 64, 91, 247, 257 Westhovens, R., 45, 86, 91, 128, 133, 138, 140, 144, 146, 149, 240, 250, 255, 365, 513 Westman, K.W., 637, 641, 683 Weyand, C.M., 593, 605 White, B., 500, 504, 508, 538 Wiekowski, M., 225 Wiens, B.L., 474

Index Wierth, S., 320 Wiesenhutter, C., 73 Wiesmüller, G., 55 Wigley, F.M., 500, 504, 508, 516, 534, 535, 538, 545 Wilke, S.W., 56 Wilke, W.S., 602 Wilkens, R.F., 83, 371 Willan, A.R., 526 Willeke, P., 571 Williams, B., 176 Williams, G.R., 128 Williams, H.J., 416 Williams, I.A., 1 Williams, J.W., 371, 535 Williams, P., 72 Williams, S., 277 Williamson, P., 349, 355 Willkens, R.F., 120, 122, 416 Wilson, S., 472 Wise, C., 535 Wise, R.A., 500, 504, 534, 535 Wisemandle, W., 75 Wisememandle, W., 78 Wisloff, F., 471 Witte, S., 11 Wofsy, D., 443 Wojtulewski, J., 72 Wolbink, G.J., 578 Wolff, S.M., 622 Wollenhaupt, J., 144, 227, 366 Wollheim, F.A., 27 Wong, C.K., 436 Wong, R.L., 325, 327, 328, 330, 332, 333, 383 Wong, W.K., 508 Wong, W.S., 412 Wood, D.A., 546 Woodland, J., 15, 38 Woods, A., 516 Woodworth, T., 285, 287, 293 Woody, J.N., 232 Wörnert, M., 264 Worthington, J.W., 550 Wortmann, R., 122 Wu, Z., 225 Wui Poon, F., 92 X Xia, H.A., 390 Ximenes, A.C., 144 Xu, W., 229, 605 Xu, Z., 223, 344

747

Index Y Yacura, W., 472 Yamada, H., 552 Yamada, T., 171 Yamagata, H., 171 Yamaji, K., 171 Yamamoto, K., 171, 278, 283, 289, 291, 449 Yamamura, M., 171 Yamasaki, M., 552 Yamasaki, Y., 552 Yan, A., 306 Yan, S., 355 Yan, X., 506 Yarboro, C.H., 424, 427 Yazar, S., 716 Yazici, H., 693, 695, 697, 701, 702, 709, 711 Yazici, Y., 456 Yeadon, C., 420 Yee, C.S., 432 Yeilding, N., 266 Yeung, M., 463 Yilmaz, E., 716 Yim, C.W., 412 Ying, K.Y., 412 Yli-Kerttula, U., 106, 309 Yocum, D.E., 20, 73, 75, 78, 94, 95, 250, 266 York, M., 518 Yoshida, S., 171 Yoshinaga, Y., 171 Yoshizaki, K., 278, 712 Yoshizawa, Y., 171 Youinou, P., 581 Young, A., 72 Young, M. Jr, 205

Younge, B.R., 593 Ytterberg, S.R., 671 Yurdakul, S., 693, 695, 697, 701, 702, 709, 711 Z Zandbelt, M.M., 574 Zanderigo, A.M., 455 Zarnitsky, C., 174 Zea Mendoza, A.C., 489 Zeidler, H.K., 9, 27, 89, 156, 314, 321, 346, 347, 351, 356, 360 Zeng, Q., 323 Zerbini, C.A., 53 Zhang, D., 452, 490 Zhao, D., 323 Zhou, B., 395, 397, 399, 401, 402 Zhou, L., 340 Zhou, X., 148 Zhou, Y., 227 Zickert, A., 264 Zikou, A.K., 29, 32 Ziminski, C.M., 2 Zink, A., 346, 347, 351 Zivkovic, M., 39 Zizic, T.M., 2 Zochling, J., 321 Zoma, A., 92 Zoppini, A., 362 Zouboulis, C.C., 707 Zrubek, J., 225, 391 Zummer, M., 439 Zwinderman, A.H., 81, 247, 253, 257, 262 Zwingenberger, K., 709