THE YEAR IN RHEUMATIC DISORDERS 2001
THE YEAR IN RHEUMATIC DISORDERS 2001 Edited by
JSH GASTON Department of Medicin...
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THE YEAR IN RHEUMATIC DISORDERS 2001
THE YEAR IN RHEUMATIC DISORDERS 2001 Edited by
JSH GASTON Department of Medicine, Addenbrookes Hospital Cambridge, UK
CLINICAL PUBLISHING SERVICES OXFORD
Clinical Publishing Services Ltd Oxford Centre for Innovation Mill Street, Oxford 0X2 OJX, UK Tel: +44 1865 811116 Fax: +44 1865 251550 Web: www.clinicalpublishing.co.uk © JSH Gaston 2001 First published 2001 This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing Services Ltd A catalogue record for this book is available from the British Library ISBN 0-203-01190-2 Master e-book ISBN
ISBN 0 9537339 1 2 (Print Edition) The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work. Commissioning Editor: Jonathan Gregory
Contents
Foreword R Schumacher
vi
Preface JSH Gaston
vii
Part I Novel therapies 1.
Cyclooxygenase (COX)-2-specific non-steroidal antiinflammatory drugs SJ Hailwood
2.
Inhibition of tumour necrosis factor (TNF) α MS Lillicrap and JSH Gaston
26
3.
Additional targets of anticytokine therapy in rheumatoid arthritis MS Lillicrap and JSH Gaston
55
4
Part II Pathogenesis of rheumatoid arthritis 4.
Genetics of rheumatoid arthritis MS Lillicrap
5.
Matrix metalloproteinases in rheumatoid arthritis MS Lillicrap
83 102
Part III Spondyloarthropathics and paediatric rheumatology 6.
Spondyloarthropathies JSH Gaston
117
7.
Juvenile arthritis SJ Hailwood
147
8.
Juvenile dermatomyositis SJ Hailwood
186
v
Part IV Connective tissue diseases 9.
Systemic lupus erythematosus and the antiphospholipid antibody syndrome RA Watts and DM O’Gradaigh
199
10.
Systemic sclerosis RA Watts
222
11.
Vasculitis
A.
Assessment and therapy RA Watts
230
B.
Giant cell arteritis RA Watts and CA Speed
237
Part V Degenerative disorders and soft tissue rheumatism 12.
Osteoarthritis DM O’Gradaigh
246
13.
Osteoporosis DM O’Gradaigh
255
14.
Soft tissue rheumatism CA Speed
269
List of Abbreviations
297
Index of Papers Reviewed
303
General Index
317
Foreword
The last year has seen a variety of important advances that are chronicled and analysed in The Year in Rheumatic Disorders 2001. Professor Hill Gaston and his colleagues have selected reports felt to have current and lasting implications. Focus, as readers will note, is on relatively common and important problems. The huge effort involved should be appreciated by the readers. I am amazed how current and pertinent the material is. The most dramatic developments in this period have been related to therapy of several of our prominent rheumatic diseases. In an era of almost endless interpretations of this literature by partial and impartial reviewers, it is important that we see analyses as presented in this volume. We need to continue to consider how to put these advances in perspective for ourselves and our patients as we discuss treatment in our journal clubs and conferences. Basic studies reviewed often suggest ideas for future improved disease characterization and therapy. Although new therapies are helping and in some cases have less toxicity, they are far from the full answer. The new coxibs still provide only partial relief of symptoms in osteoarthritis. Anticytokine therapy, although slowing radiographic progress in rheumatoid arthritis, does not produce remissions and at present only rarely provides the 70–80% or more improvements that patients ultimately need. There is still much to do. We look forward to the Year in Rheumatic Disorders 2002, 3, 4 and 5. Can we guess from the basic studies where the next giant steps will come? Papers reviewed here reflect a wide selection from centres and journals around the world, making ideas and opinions from the leading research scientists from many countries available in this one publication. Although, like most rheumatologists, I am a voracious reader, I found fascinating papers that I had missed. I have enjoyed the thoughtful, scholarly analyses of these papers by the authors. I invite readers to compare them with their own thoughts and implications in their different practices and countries. H.Ralph Schumacher Jr, MD Professor of Medicine University of Pennsylvania School of Medicine Philadelphia, PA
Preface
The function of this volume is to give a fairly concise overview of developments in rheumatology over approximately a 12-month period. Essentially, a rheumatologist held incommunicado for a year in a journal and internet-free zone, and anxious to know what has happened to their subject in the interim, should be able to feel that they are up to speed again after looking through this book. Alternatively, it provides a useful resource for the rest of us who might not quite have found the time to read absolutely all of the relevant journals during the year. The scope is deliberately wide, reflecting the nature of rheumatology; rheumatologists may genuinely need to know what advantages do the cyclooxygenase-specific non-steroidal anti-inflammatory drugs offer, what’s the most reliable way to diagnose carpal tunnel syndrome, and what’s the latest cytokine (Answer; inter-leukin-23). For this reason articles cannot be comprehensive in quite the same way as some other current contents volumes. Personal biases of the reviewers in selecting articles has, therefore, been given full rein, the only criterion being whether the reviewer found the article interesting and relevant. The other point to make as editor is that an entirely rational organization of the selected papers has eluded us; for instance, most papers on anti-tumour necrosis factor therapies are in a single section, but the paediatric chapter includes a paper on the use of etanercept in juvenile idiopathic arthritis. The placing of papers on rarer diseases such as Behçet’s is also rather arbitrary. If a paper you expected to see is missing from one of the sections, check whether it might not have been included in another one. Lastly, my thanks are due to each of my co-authors for timely provision of manuscripts, my long-suffering secretary Hazel Mould for logistic support, and the staff at Clinical Publishing Services, particularly Rosemary Osmond, Penny Bowers and Jonathan Gregory. Hill Gaston
Part I Novel therapies
Novel therapies
Introduction This section is divided into three chapters: 1. Cyclooxygenase (COX) -2-specific non-steroidal anti-inflammatory drugs 2. Inhibition of tumour necrosis factor (TNF-α) 3. Additional targets of anticytokine therapy in rheumatoid arthritis (RA) Novel therapies are reviewed, starting with papers on the COX-2-specific nonsteroidal anti-inflammatory drugs. For completeness, results of some trials of these agents in osteoarthritis (OA) are included, and indeed some trials recruited a mixture of RA and OA patients, as the incidence of side-effects in these large trials are relevant to the use of the same drugs in RA. Several papers on the effects of COX-2-specific drugs on renal function, particularly in the elderly, are included, along with the lack of effect of these drugs on platelet function and the potential disadvantage of losing this action in patients predisposed to thrombotic episodes. Chapter 2 collects together papers on the efficacy of TNF-α therapies in RA. Again for immediate comparison, the recent, and much more preliminary, trials of anti-TNF in spondyloarthropathies are also included here. The use of anti-TNF therapies was firmly based on a large body experimental work both in vitro and in relevant animal models. This work continues and the introduction of the antiTNF therapies allows additional observations on RA pathogenesis, particularly the importance of recruitment of inflammatory cells to the joint. Preliminary results on the effects of anti-TNF therapies on bony erosion have been very encouraging, so investigations into the role of TNF in bone absorption by osteoclasts are highly relevant. Lastly, some papers on the newly introduced disease modifying drug, leflunomide, are included in this section because of the recent speculations that this drug’s activity may be mediated through an effect on TNF signalling.
NOVEL THERAPIES
3
Finally, in Chapter 3, papers related to the role of other cytokines in RA are reviewed as these provide actual or potential targets of additional novel therapies in RA. Particular attention is paid to the role of interleukin (IL)-1 in RA and, therefore, the efficacy of the natural IL-1 inhibitor, IL-1 receptor antagonist (IL-1ra). A more recently described cytokine, IL-17 has the interesting property of being wholly T cell-derived but sharing many properties with the macrophagederived cytokines, IL-1 and TNF-α. Thus, a part played by IL-17 in cartilage breakdown and in the formation of erosions would establish a direct link between these aspects of pathology in RA and T lymphocytes. Other T-cell-derived cytokines have been implicated in disease models and by observations with humans; IL-15 plays an important part in both maintaining T lymphocytes and activating them, while IL-4 generally has an anti-inflammatory and anti-joint destructive role in disease models. IL-12 in contrast is derived from non-T cells but influences T-cell differentiation in a proinflammatory direction. Many newly discovered cell surface molecules and cytokines have yet to be integrated into our understanding of RA pathogenesis (e.g. OX40, IL-21, IL-23), but these may also provide targets for disease modulation.
1 Cyclooxygenase-2-specific non-steroidal antiinflammatory drugs
Overview A large number of papers have been published in connection with the introduction of the cyclooxygenase (COX) -2-specific non-steroidal antiinflammatory drugs (NSAIDs). Several very large studies have been conducted with adequate power to detect rates of complications accurately. Although this section of the book is primarily concerned with novel therapies in inflammatory arthritis, papers detailing the use of COX-2-specific drugs are included here for completeness. There is general agreement that the new compounds have similar efficacy to diclofenac, ibuprofen and naproxen, but with a ~10-fold decrease in the incidence of gastric ulceration, down to levels difficult to distinguish from background. As expected, the new drugs do not affect platelets, and this observation can be coupled with a report of thrombotic events in patients with COX-2 inhibition. Such patients seem to have a preexisting pro-thrombotic tendency in whom the loss ,of antiplatelet effects of conventional NSAIDs when changing to a COX-2-specific agent may have been disadvantageous. The large trials suggest that this is not a common situation. Although further work needs to be done, there appear to be no relief from renal side-effects by changing from a conventional NSAID to a COX-2-specific drug. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. P Emery, H Zeidler, T K Kvien, et al. Lancet 1999; 354:2106– 11. BACKGROUND. NSAIDs inhibit COX, which leads to suppression of COX-1-mediated production of gastrointestinal (GI) protective prostaglandins (PGs). GI injury is a common outcome. The efficacy, safety and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, was compared with diclofenac, a nonspecific COX inhibitor.
CYCLOOXYGENASE-2-SPECIFIC 5
INTERPRETATION. Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper GI ulceration or GI adverse events, and tolerability was better. Table 1.1 Mean (SD) arthritis assessment results at week 24
VAS=visual analogue scale. MHAQ=modified health assessment questionnaire. *Independent assessments, graded from 1 (very good: symptom-free with no limitation of normal activities) to 5 (very poor: very severe symptoms that are intolerable and inability to carry out all normal activities). Source: Emery et al. (1999). Table 1.2 GI ulcer frequency
*Among patients with known H. pylori status only. Source: Emery et al. (1999).
Comment A double-blind, randomized study of celecoxib 200 mg versus diclofenac slow release (SR) 75 mg twice daily over 24 weeks. All patients had