TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis

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1 A Supplement to Rheumatology News I N T E R N A T I O N A L TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis Highlights of a Symposium The Biologic Era: Summary of 5 Years of Experience in Rheumatoid Arthritis Treating Rheumatoid Arthritis: Standard Practices in Europe Early Treatment and Remission Induction Reality-Based Algorithm for Treating With Biologics Faculty Professor Paul Emery, MD, FRCP Leeds Teaching Hospitals Trust Leeds, UK Arthur Kavanaugh, MD University of California, San Diego USA Edward C. Keystone, MD, FRCP(C) University of Toronto Canada Professor Iain B. McInnes, PhD, FRCP University of Glasgow Glasgow, UK

2 Rheumatology News I N T E R N A T I O N A L President, Elsevier/IMNG Alan J. Imhoff Vice President, Medical Education & Business Development Sylvia H. Reitman, MBA Program Manager, Medical Education Sara M. Hagan Clinical Editors Virginia Holcombe, PhD, MBA Joanne M. Still National Account Manager Rory Flanagan Graphic Designer Julie Keller Production Specialist Anthony S. Draper TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis 3 Introduction 3 The Biologic Era: Summary of 5 Years of Experience in Rheumatoid Arthritis Arthur Kavanaugh, MD 5 Treating Rheumatoid Arthritis: Standard Practices in Europe Professor Iain B. McInnes, PhD, FRCP 6 Early Treatment and Remission Induction Professor Paul Emery, MD, FRCP 8 Reality-Based Algorithm for Treating With Biologics Edward C. Keystone, MD, FRCP(C) The presentations from which this supplement was developed took place at a symposium held June 9, 2005, in Vienna, Austria. This supplement was supported by an educational grant from The supplement was produced by the medical education department of International Medical News Group. Neither the Editor of RHEUMATOLOGY NEWS INTERNATIONAL, the Editorial Advisory Board, nor the reporting staff contributed to its content. The opinions expressed in this supplement are those of the faculty and do not necessarily reflect the views of the supporter or of the Publisher. Copyright 2005 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Elsevier Inc. will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. FACULTY Paul Emery, MD, FRCP arc Professor of Rheumatology Head, Academic Unit of Musculoskeletal Disease Clinical Director, Leeds Teaching Hospitals Trust Leeds, UK Arthur Kavanaugh, MD Professor of Medicine, Center for Innovative Therapy Division of Rheumatology, Allergy and Immunology University of California, San Diego USA Edward C. Keystone, MD, FRCP(C) Professor of Medicine University of Toronto Canada Iain B. McInnes, PhD, FRCP Professor of Experimental Medicine Centre for Rheumatic Diseases University of Glasgow Glasgow, UK FACULTY AND UNAPPROVED USE DISCLOSURES Faculty/authors must disclose any significant financial interest or relationship with proprietary entities that may have a direct relationship to the subject matter. They must also disclose any discussion of investigational or unlabeled uses of products. Prof Emery has had consulting agreements with Centocor, Inc., and Schering-Plough Corporation. Dr Kavanaugh has conducted research studies for Abbott Laboratories, Amgen Inc., Biogen Idec, Inc., Bristol-Myers Squibb Company, Centocor, and Genentech, Inc. Dr Keystone has received funding for clinical grants from Abbott and Amgen. He has been a consultant to Abbott, Amgen, Centocor, and Schering-Plough. Prof McInnes has had consulting agreements with Centocor and Schering-Plough. INTERNATIONAL MEDICAL NEWS GROUP

3 INTRODUCTION R heumatoid arthritis is the most common form of inflammatory arthritis and can result in significant disability and early death. Its management has changed dramatically as its pathogenesis has become better understood, enabling new disease-modifying antirheumatic drugs (DMARDs) and the introduction of biologic agents. Early and aggressive treatment can improve patient outcome dramatically. Although conventional DMARDs may be effective, their limitations include delayed onset of action, multiple toxicities, and high recurrence rates upon withdrawal. In addition, many patients fail to achieve prolonged or sufficient responses to these therapies and treatment dose or duration may be limited by considerable toxicity. Tumor necrosis factor (TNF) is a key mediator of the inflammatory and destructive process in rheumatoid arthritis and, consequently, TNF inhibitors are potent DMARDs, particularly when combined with methotrexate. The following articles highlight practical considerations for everyday management of patients with rheumatoid arthritis, present the striking results following very early intervention with biologics, and review management of side effects. This supplement is based on a thought-provoking symposium held in Vienna, Austria on June 9, A panel of experts examined the impact of biologic therapy on patient lives. Using an interactive format, Sir David Frost moderated this informative exchange by challenging faculty with probative yet incisive questions regarding rheumatoid arthritis and its treatment. THE BIOLOGIC ERA: SUMMARY OF 5 YEARS OF EXPERIENCE IN RHEUMATOID ARTHRITIS Arthur Kavanaugh, MD R heumatoid arthritis is a chronic and pernicious disease that has devastating consequences for patients. As rheumatoid arthritis slowly erodes the joints, it also slowly erodes a number of aspects of patients lives, causing them to change their daily activities, how they interact with friends and coworkers, and what they do to earn a living. Most important, rheumatoid arthritis changes how patients function in their family life and diminishes their ability to enjoy their lives. TREATMENT OPTIONS EXPANDED The disease-modifying antirheumatic drugs, including prednisone, methotrexate, nonsteroidal antiinflammatory drugs, and combinations of these drugs still play a role in the treatment of patients with rheumatoid arthritis. These agents help relieve inflammation and pain in many cases. However, these drugs are not effective in halting the progression of joint destruction, and the natural history of rheumatoid arthritis is that disability and radiographic progression of the disease increase steadily over a period of years (Figure 1). Fortunately, recent research has led to Figure 1. Rheumatoid Arthritis: Inflammation Drives Disability Severity Early Intermediate Late Inflammation Disability Radiographs Source: Data derived from Kirwan JR. J Rheumatol. 1999;26: ; Scott DL. Rheumatol. 2000;39: Duration of Disease (Years) improvements in how patient status and disease progression are evaluated. In addition, research leading to new understanding about the pathogenesis of rheumatoid arthritis allowed the development of more targeted therapies in the form of biologic agents. Currently, three such agents, which target and inhibit tumor necrosis factor (TNF), have been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis. These are infliximab, etanercept, and adalimumab. The TNF inhibitors target and neutralize inflammatory cytokines. In many patients with rheumatoid arthritis, use of these agents rapidly reduces signs and symptoms of joint inflammation and TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis 3

4 Recent research has led to improvements in how patient status and disease progression are evaluated. Dr Kavanaugh inhibits joint destruction as demonstrated on x-rays. These effects on rheumatoid arthritis can result in improved quality of life and preservation of functional status. LONG-TERM CLINICAL EXPERIENCE WITH TNF INHIBITORS To date, about 750,000 patients worldwide have been treated with TNF inhibitors for inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn s disease, and psoriasis. Most patients with rheumatoid arthritis respond to anti-tnf therapy, and some achieve remission. Some patients have no response to such treatment, and some have adverse effects. Experience with TNF inhibitors also has demonstrated that efficacy requires continuous therapy. When treatment is discontinued, the signs and symptoms of rheumatoid arthritis recur, so remission of the disease is a more appropriate term than cure. Nevertheless, the dramatic clinical successes seen with TNF inhibitors have tangibly changed physicians expectations: today, the publication of a new study prompts questions about how many patients receiving these agents achieved remission of clinical signs and symptoms and had x-ray evidence that joint damage did not progress. Since the introduction of biologics, the gold standard for rheumatoid arthritis therapy is methotrexate combined with one of the three TNF inhibitors etanercept, infliximab, or adalimumab. All of these biologic agents are effective, but their pharmacokinetic and pharmacodynamic profiles differ considerably. Preliminary evidence from uncontrolled studies indicates that switching among agents to overcome inadequate efficacy or poor tolerability may be beneficial for some patients. 1 The efficacy of all three agents has been well established in patients with rheumatoid arthritis, with demonstrated improvements in signs and symptoms, functional status and quality of life, and inhibition of radiographic progression. All three also have achieved even better results in early rheumatoid arthritis. SAFETY OF BIOLOGICS Accumulated safety data indicate that it is reasonable to regard long-term safety with guarded optimism. Although TNF inhibitors are not free from side effects, the large and growing clinical experience with these agents provides some assurance that adverse effects related to their use are largely understood and can be managed. The mechanism of action of TNF inhibitors increases the risk for infections, including opportunistic infections. For example, opportunistic fungal infections, such as Candida albicans and Aspergillus fumigatus, may be provoked by TNF inhibition. 2 For some adverse effects, including Figure 2. Rheumatoid Arthritis Therapy: Comparing the Options TNF Inhibitors IL-1 Inhibitors MTX Other DMARDs Aggressive/ Combination DMARDs NSAIDs/COX-2 Prednisone Efficacy in Signs and Symptoms Quality of Life lymphoma and serious infections, the increased prevalence of these conditions among patients with rheumatoid arthritis particularly those with severe and active disease makes the determination of the extent of any additional treatment-related risk more difficult to discern. In addition, other factors such as concomitant medications and comorbid disease also may contribute to the risks for adverse effects. A heightened risk of infection, particularly from tuberculosis (TB), seems clear and can be understood on a mechanistic basis, as TNF is central to host defense against TB. 3-5 Precautions should be taken to prevent TB in potential candidates for TNF inhibitor treatment. Prior to initiating therapy, patients should be screened for TB, according to national guidelines, and latent infections should be treated with antimicrobial agents prior to starting therapy with a TNF inhibitor. 6,7 Once official TB screening guidelines are systematically implemented for potential candidates for treatment with TNF inhibitors, the risk for TB decreases markedly. 8 Nevertheless, because of the potential for cutaneous anergy among patients with rheumatoid arthritis and because of the risk of acquiring primary infections de novo, close observation during therapy is mandatory. 9 Inhibiting X-ray Damage Safety Infections Other Continued on page 10 Cost very good; good; fair; poor COX=cyclooxygenase; DMARD=disease-modifying antirheumatic drugs; IL=interleukin; MTX=methotrexate; NSAIDs=nonsteroidal antiinflammatory drugs; TNF=tumor necrosis factor. Source: Courtesy of Arthur Kavanaugh, MD. 4 TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis

5 TREATING RHEUMATOID ARTHRITIS: STANDARD PRACTICES IN EUROPE Professor Iain B. McInnes, PhD, FRCP A survey designed to evaluate current treatment practices in rheumatoid arthritis was conducted among rheumatologists (N=522) in five European countries: France, Germany, Italy, Spain, and the United Kingdom. Not surprisingly, methotrexate was identified as the firstline antirheumatic therapy of choice by 72% of surveyed physicians, but its deficiencies were also recognized: slow to take effect, unlikely to achieve remission, and relatively poor retardation of joint damage. STATUS AND GOALS Surveyed rheumatologists routinely depended upon joint erosions (84%), high C-reactive protein (CRP) levels (82%), or high erythrocyte sedimentation rate (82%) to determine degree of disease control and, therefore, whether intervention with a biologic agent was warranted. Key treatment goals when initiating biologic therapy included retarded progression of joint erosion (46%), better rate of remission (44%), reduced pain and discomfort (41%), reduced inflammation and swelling (38%), as well as improved quality of life via improved physical mobility (34%). EXPECTATIONS WITH A BIOLOGIC Clinical response was most commonly assessed by office examination (81%), patient feedback (79%), reduced CRP level (77%), and improved Disease Activity Score (DAS28) with a 28-joint count (75%). However, magnitude of DAS28 improvement expected from biologic therapy varied widely, ranging from less than 0.6 (3%) to more than 3.6 (5%). In fact, a DAS less than 2.6 (remission) was achieved by 1 year among some patients who received initial treatment with methotrexate and infliximab for active rheumatoid arthritis in its early stages. 1 Moreover, compared with patients administered methotrexate alone Surveyed rheumatologists routinely depended upon joint erosions (84%), high C-reactive protein (CRP) levels (82%), or high erythrocyte sedimentation rate (82%) to determine degree of disease control... in this same study, remission (DAS <2.6) was observed for one in every three patients treated with the combination therapy. NOT ALL BIOLOGICS Professor McInnes ARE CREATED EQUAL When patients fail to respond or do not respond optimally to their tumor necrosis factor (TNF) inhibitor therapy, most polled rheumatologists (87%) believed that switching to another biologic might provide additional improvement. Nearly half (47%) switched to another TNF inhibitor when there was a partial response, and two thirds (65%) switched biologics in cases of nonresponse. These results suggest that rheumatologists do not widely believe that all biologics are the same in their ability to achieve results. In fact, in a retrospective evaluation of patients who had been switched from one TNF inhibitor to another because of poor response, clinical benefit could be significant. 2 Among patients switched from etanercept to infliximab, the mean DAS28 improved significantly (P<0.05) from 4.8 to 3.6, and the mean best percentage of improvement in the numeric American College of Rheumatology (ACR-N) criteria for an individual patient improved from 17.2 to 40.4 (P=0.08). Similarly, among patients switched from infliximab to etanercept, the latter treatment also provided at least comparable clinical efficacy. In another study of patients responding inadequately to therapy with methotrexate and etanercept therapy (N=27), switching to methotrexate and infliximab provided additional clinical and radiographic benefits. After 16 weeks, 8 (61%) of 13 infliximab-treated patients achieved an ACR20 response compared with only 4 (29%) of 14 etanercept-treated patients. 3 LOST OPPORTUNITY Despite these considerable advantages from treatment with TNF inhibitors, biologics were not always prescribed when appropriate, according to 59% of the rheumatologists interviewed. Among the 306 rheumatologists voicing this opinion, reasons for not prescribing a biologic included clinical reasons (62%), cost or resources to administer and monitor therapy (54%), and patient preference (40%). UNITED BUT NOT UNIFORM The survey highlighted differences among European countries in their standard rheumatology practices. Whereas rheumatologists in France saw an average of 23 patients monthly, more than 40 patients were seen by rheumatologists in Spain and Italy, and more than 80 patients, on average, were seen monthly in the United Kingdom and Germany. Accordingly, when asked about monitoring patients with active rheumatoid arthritis, French rheumatologists were the only national group who saw their patients as often as they wanted. Continued on page 11 TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis 5

6 EARLY TREATMENT AND REMISSION INDUCTION Professor Paul Emery, MD, FRCP R heumatoid arthritis was originally perceived as a benign disease. The realization of its severity, in terms of outcome, led to new strategic approaches that, in combination with new therapies, have dramatically improved outcome. It is now clear that progressive disability can be prevented, or at least delayed, when effective therapy begins sufficiently early in the disease process. Ideally, synovitis should be treated from the moment it becomes clinically detectable. 1 Thus, rapid suppression of inflammation within this early window of opportunity optimizes outcomes, making remission feasible. Early and aggressive use of traditional disease-modifying antirheumatic drugs (DMARDs) and study of the newer biologic agents have shown improved patient outcomes and slowing of radiographic progression of joint damage. The tumor necrosis factor (TNF) inhibitors etanercept, infliximab, and adalimumab, used alone or in combination with methotrexate in patients with early or established rheumatoid arthritis, consistently improve signs and symptoms as well as function, with a dramatic slowing of radiographic damage. These agents, combined with optimal doses of methotrexate, currently constitute the best therapeutic regimen for the management of patients with rheumatoid arthritis failing to respond adequately to traditional DMARDs....rapid suppression of inflammation within this early window of opportunity optimizes outcomes, making remission feasible. Professor Emery AIMING LOW AND STILL FAILING Until the introduction of biologics, initial treatment of rheumatoid arthritis involved nonsteroidal antiinflammatory drugs (NSAIDs) and traditional DMARDs to reduce pain and inflammation, the early symptoms of the disease. 2 However, NSAIDs do not affect the disease progression that leads to structural joint damage, and they are notorious for producing gastrointestinal and other side effects. Although traditional DMARDs may delay disease progression, they take effect slowly, patients fail to experience prolonged or sufficient responses, and their dose and duration may be limited by serious side effects. 3 Modest treatment goals were limited to palliative control of signs and symptoms and preservation of some degree of functional capacity. Halting progression of structural damage was unlikely and remission was extremely rare. Quality of life was commonly compromised and life expectancy was shortened. WHAT IS REMISSION? Controlled clinical studies measure antirheumatic efficacy in terms of American College of Rheumatology (ACR) response, a composite score of tender joint count, swollen joint count, patient s pain assessment, physician s and patient s global assessment of disease, the Health Assessment Questionnaire, and the acute-phase markers erythrocyte sedimentation rate and/or C-reactive protein. An ACR20 response represents a minimal improvement of 20% in both tender and swollen joint counts as well as three of the other five variables. ACR50 and ACR70 responses are determined similarly. For purposes of judging efficacy in clinical trials, remission has been defined as an ACR70 response, a Disease Activity Score (DAS) lower than 1.6, or a DAS28 less than 2.6; DAS and DAS28 evaluations are based on 44 swollen joint counts and 28 tender, swollen joint counts, respectively. Thus, remission has been defined clinically. However, sensitive imaging has revealed persistent and substantial synovitis in patients with clinical remission who are treated with DMARDs. Therefore, perhaps true remission should be considered a state of low disease activity without synovitis and with no progression of structural damage. DMARDs can produce clinical remission but rarely produce remission in terms of synovitis. This is one explanation for progressive structural damage often evident among patients with good clinical responses. EARLIER IS BETTER The likelihood of erosive disease increases with the time delay between onset of rheumatoid arthritis and initiation of proper management; 45% of patients have joint erosions within 4 months of symptom onset 4 ; 60% of patients suffer erosive disease by 1 year 5 ; up to 93% of patients have some degree of radiographic damage within 2 years of disease onset. 6 Treatment as early as 3 months with traditional DMARDs improves longterm outcome and functional ability. 5 In a prospective study, radiographic damage stopped progressing for patients whose treatment began within 15 days of referral; in contrast, patients whose treatment was delayed up to 4 months showed substantial joint damage. 7 Several clinical trials indicate that early and aggressive treatment of rheumatoid arthritis is optimal for disease control and prevention of subsequent deformities. When compared with methotrexate monotherapy, etanercept monotherapy acted more rapidly to decrease symptoms and slow joint damage in patients with active, recent-onset rheumatoid arthritis (N=632). 8 In this same patient population, a 2-year follow-up demonstrated better disease modification, 9 and improvements in 6 TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis

7 functional and quality-of-life benefits were maintained at least 3 years. 10 When compared with methotrexate monotherapy, infliximab combined with methotrexate significantly increased the ACR response (P 0.03) and decreased the mean Sharp score (P 0.001) among patients with early rheumatoid arthritis. 11 Also for patients with active recentonset rheumatoid arthritis (N=1,049), combination therapy with methotrexate and infliximab provided greater clinical, radiographic, and functional benefits than did treatment with methotrexate alone. 12 REMISSION ACCOMPLISHED Very early use of infliximab in poorprognosis rheumatoid arthritis (N=20) was evaluated in a randomized, doubleblind, placebo-controlled study that attempted remission induction using methotrexate with or without infliximab for 12 months. 13 The primary endpoint was metacarpophalangeal joint synovitis measured by magnetic resonance imaging (MRI) at 0, 4, 14, and 54 weeks; images were scored by independent professionals blinded to study drug identity. Study patients had not been treated previously and most exhibited normal x- rays. At diagnosis, all patients were administered methotrexate and folate prophylaxis and were randomly assigned to receive infusions of either infliximab or placebo at 0, 2, 6, and 14 weeks plus every 8 weeks thereafter. Concomitant corticosteroids were not permitted. Figure 1. MRI Results: Erosive Sites Number of Erosive Sites Time (weeks) MRI=magnetic resonance imaging; MTX=methotrexate. Source: Quinn et al. 13 Remission induction with infliximab plus methotrexate significantly reduced MRI evidence of synovitis and erosions (P=0.0125) at 1 year (Figure 1). Moreover, more infliximab-treated patients fulfilled ACR50 (78% vs 40%) and ACR70 (67% vs 30%) improvement criteria and had greater functional benefit than did placebo-treated patients. At 2 years, 1 year after stopping therapy, remission was sustained in 70% of infliximab-treated patients. Despite infliximab withdrawal, functional and quality-of-life benefits also were sustained at this time point (Figure 2). Levels of C-reactive protein (CRP), a Infliximab+MTX Placebo+MTX P= marker of inflammation, reflect degree of inflammatory burden of rheumatoid arthritis. CRP levels were significantly reduced among patients receiving infliximab. In fact, after a single infusion of infliximab, mean levels normalized. Therefore, CRP measurement appears to be a useful tool in determining whether a patient requires more aggressive therapy. According to the survey of European rheumatologists presented in this supplement, CRP levels are used by most rheumatologists to develop treatment strategies and a drop in CRP levels represents successful control of inflammation. Figure 2. Sustained Remission Achieved % Change Anti-TNF treatment MTX Treatment Years 2 HAQ MTX + Placebo HAQ MTX + Infliximab RAQoL MTX + Placebo RAQoL MTX + Infliximab HAQ=Health Assessment Questionnaire; MTX=methotrexate; RAQoL=Rheumatoid Arthritis Quality of Life; TNF=tumor necrosis factor. Source: Quinn et al. 13 THE BEST (BEHANDEL-STRATEGIEEN) STUDY A randomized, single-blind clinical trial in patients with rheumatoid arthritis evaluated four treatment strategies: sequential monotherapy, step-up combination therapy, and combination therapy initiated with either prednisone or infliximab. 14 The treatment strategy using infliximab as initial therapy combined with methotrexate was the most effective; by 12 months, more than 40% of patients were in clinical remission and by 2 years, most of the patients had stopped infliximab because remission continued. After 2 years, initial combination therapy resulted in more rapid clinical and functional improvement, lower relative risk of Continued on page 10 TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis 7

8 REALITY-BASED ALGORITHM FOR TREATING WITH BIOLOGICS Edward C. Keystone, MD, FRCP(C) D isease remission is no longer an unattainable treatment goal in rheumatoid arthritis, but, because joint damage is largely irreversible, intervention as early as feasible is recommended. Rapid control of inflammation is key to long-term disease control. If sufficiently early in the disease process, inflammation control prevents radiographic damage or its progression and prevents or normalizes functional loss. Toward this end, treating physicians often proceed through traditional therapy in a matter of months, delaying more effective biologic therapy no longer than necessary (Table). Traditional disease-modifying antirheumatic drugs (DMARDs) may delay progression of rheumatoid arthritis, but they take effect slowly, may lose efficacy over time, and are frequently intolerable at optimal doses. Furthermore, despite their optimal use, clinically active synovitis and progressive structural articular damage are experienced by 25% to 50% of treated patients. 1 Due principally to the introduction of biologic agents, however, treatment conventions for rheumatoid arthritis have been revised radically. FIRST MONTHS CRITICAL When methotrexate fails to yield a therapeutic response, commonly its dose is escalated from 10 to 20 mg/week. 2 Patients who displayed some improvement after the first month of high-dose (20-25 mg/week) methotrexate often continued to improve for up to 3 to 6 months after the high dose before a response plateau was obvious. 3 On the other hand, however, when high-dose methotrexate fails completely to benefit a particular patient, more effective treatment should not be delayed more than a month after initiating high-dose methotrexate, according to a study comparing etanercept with methotrexate. Among subjects with active early rheumatoid arthritis (N=632), it was evident that patients who ultimately failed to respond to methotrexate had improved less than 20%, according to ACR criteria, after the first month, on average, of high-dose methotrexate. Thus, subsequent therapeutic gain is unlikely for patients who completely fail to respond after the first month of highdose methotrexate. In practical terms, therefore, this type of patient probably would benefit from a rapid switch to a different medication. Similarly, even patients who respond well during the first month of high-dose methotrexate are unlikely to improve further after 6 months of the high dose; therefore, if response is inadequate at this time point, no further delay in trying a different medication should occur. HYDROXYCHLOROQUINE, SULFASALAZINE, OR NEITHER? Because methotrexate monotherapy frequently produces less than 50% improvement, many physicians add other DMARDs to methotrexate to manage clinical symptoms. Whereas the combination of methotrexate and hydroxychloroquine is commonly used in the United States, many European clinicians prefer the combination of methotrexate and sulfasalazine. All the Table. Treatment Goals for Rheumatoid Arthritis Control inflammation rapidly Prevent radiographic progression Prevent disability Improve life expectancy Induce remission or cure ACR=American College of Rheumatology; MTX=methotrexate; TNF=tumor necrosis factor. Source: Lipsky et al., 5 Kremer et al., 6 Breedveld et al. 7 same, little evidence supports the addition of either to methotrexate partial responders. LEFLUNOMIDE EFFECT NOT SUSTAINED Treatment options when high-dose methotrexate fails to yield a therapeutic response include switching to another DMARD such as cyclosporine, leflunomide, or a biologic. One pertinent database-driven study involved patients with established rheumatoid arthritis for whom at least two DMARDs, including methotrexate, had failed or not been tolerated, who were switched to either infliximab (n=135), etanercept (n=166), or leflunomide (n=103). 4 Treatment response was similar for the tumor necrosis factor (TNF) inhibitors, which performed better than did leflunomide. Furthermore, based on survival analysis, treatment continued for at least 20 months among 79% and 75% of patients administered etanercept and infliximab, respectively, compared with only 22% administered leflunomide. TNF INHIBITORS ADDRESS UNMET NEEDS Superior Efficacy and Sustainability: Several studies have evaluated the effects of TNF inhibitors on the signs and symptoms of rheumatoid arthritis. Among more than 50% of subjects, an ACR20 response (at least 20% but less than 50% improvement) was obtained within a few weeks of initiating treatment with infliximab, 5 etanercept, 6 or adalimumab. 7 Such response levels were reached in the following weeks in 60% of patients and were maintained for more than 5 years in ongoing trials. 5-7 Among patients who previously had had an incomplete response to methotrexate monotherapy, infliximab combined with methotrexate provided significant improvement in physical function (P 0.006) and quality of life (P 0.011) when compared with methotrexate alone. 8 Furthermore, the 8 TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis

9 proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for patients receiving the combination therapy, compared with 16% for patients who were administered methotrexate monotherapy. Rapid Onset of Action: Among patients with persistently active rheumatoid arthritis despite methotrexate therapy (N=428), a double-blind study demonstrated not only that treatment with infliximab plus methotrexate was more efficacious than methotrexate alone, but also that improvement in ACR20 responses was evident by 2 weeks. 8 In a similarly designed trial with adalimumab (N=619), rapid ACR20 responses were also evident within 2 weeks. 9 Radiographic Progression Halted: Within this same study population of patients with persistently active rheumatoid arthritis despite methotrexate therapy (N=428), infliximab combined with methotrexate halted the progression of joint damage whether or not a clinical response was evident, yet joint damage increased when methotrexate mono therapy was continued. 5,10 After 52 weeks of therapy, patients with active rheumatoid arthritis despite methotrexate therapy (N=619) who were treated with adalimumab plus methotrexate exhibited improvements in radiographic endpoints, namely Sharp, erosion, and joint-space-narrowing scores. 9 SWITCHING TNF INHIBITORS Although no controlled studies of headto-head comparisons have been conducted, clinical trials and postmarketing experience indicate that the three TNF inhibitors etanercept, infliximab, and adalimumab offer comparable efficacy; 50% to 70% of patients achieve a clinically significant improvement. 11 Nevertheless, clinical response may differ for particular patients; lack of response to one agent does not preclude a therapeutic response to another TNF inhibitor. Thus, if one TNF inhibitor is inadequately effective, loses its effect, or causes intolerable side effects, switching to a different TNF inhibitor is a reasonable approach. Among patients with active rheumatoid arthritis, previous lack of efficacy with etanercept (n=20) did not Figure. Switching From Etanercept to Infliximab Etanercept Infliximab Improvement (%) CRP=C-reactive protein. Source: Hansen et al. 12 Swollen Joint Count Tender Joint Count Disease remission is no longer an unattainable treatment goal in rheumatoid arthritis... AM Stiffness (mins) Daily Prednisone (mg/day) Dr Keystone CRP (mg/dl) predict lack of efficacy with infliximab (Figure); degree of improvement was similar in both groups. 12 In another study (randomized, single-blind) of subjects whose rheumatoid arthritis failed to respond adequately to etanercept plus methotrexate, switching to infliximab plus methotrexate achieved an ACR20 response for 61% of the infliximab-treated subjects (n=13), compared with only 29% of those who continued therapy with etanercept and methotrexate (n=14), after 16 weeks; this differential response was noted as early as 2 weeks (31% vs 14%, respectively). 13 Other studies have confirmed that a substantial number of patients with rheumatoid arthritis who experience inadequate efficacy with one TNF inhibitor may attain at least an ACR20 response when switched to another. 14,15 CONCLUSIONS High-dose methotrexate is more effective than is low-dose methotrexate, and the addition of hydroxychloroquine or sulfasalazine in patients failing methotrexate imparts unlikely additional benefit. If no response to methotrexate is obvious after 1 month of reaching peak doses of 20 to 25 mg/week, expedient switching to another treatment modality is recommended. Conversely, when a therapeutic response to methotrexate is apparent, its maximum impact may not be attained for another 5 months of treatment. Many of the needs unmet by traditional DMARDs, including rapid onset of action, good efficacy, and long duration of action, are addressed by TNF inhibitors. Moreover, although efficacy appears comparable across TNF inhibitors, switching between these agents often proves effective. REFERENCES 1. Haraoui B. The anti-tumor necrosis factor agents are a major advance in the treatment of rheumatoid arthritis. J Rheumatol Suppl. 2005;72: Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol. 1989;16: Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343: Geborek P, Crnkic M, Petersson IF, Saxne T; Continued on page 11 TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis 9

10 The Biologic Era Continued from page 4 In clinical studies of rheumatoid arthritis, no overall increase in the rates of developing solid malignancy has been seen with any TNF inhibitors. The observed increase in lymphoma rates in patients with rheumatoid arthritis as compared with those in the general population may reflect the actual incidence in the type of refractory severe rheumatoid arthritis patient most often treated with these agents. Longer periods of observation and larger databases are needed to define this risk more clearly. CONCLUSIONS The roster of therapeutic options for the treatment of rheumatoid arthritis now includes TNF inhibitors (Figure 2 on page 4), which are highly effective in inhibiting the progression of joint destruction and, consequently, disease-related disability. Although therapy with TNF inhibitors has been associated with side effects, including serious infections, these drugs can be administered with an acceptable safety margin by appropriate selection of patients, screening for latent and active TB, and monitoring patients for infection and other toxicities. REFERENCES 1. Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. The benefit/risk profile of TNFblocking agents: Findings of a consensus panel. Semin Arthritis Rheum. 2005;34: Filler SG, Yeaman MR, Sheppard DC. Tumor necrosis factor inhibition and invasive fungal infections. Clin Infect Dis. 2005;41(suppl 3):S208- S Bieber J, Kavanaugh A. Consideration of the risk and treatment of tuberculosis in patients who have rheumatoid arthritis and receive biologic treatments. Rheum Dis Clin North Am. 2004;30: Scheinfeld N. Adalimumab: A review of side effects. Expert Opin Drug Saf. 2005;4: Briefing document, FDA Arthritis Advisory Committee meeting; Bethesda, Md; March 4, Carmona L, Gomez-Reino JJ, Rodriguez- Valverde V, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum. 2005;52: Furst DE, Cush J, Kaufmann S, Siegel J, Kurth R. Preliminary guidelines for diagnosing and treating tuberculosis in patients with rheumatoid arthritis in immunosuppressive trials or being treated with biological agents. Ann Rheum Dis. 2002;61(suppl 2):ii62-ii Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD; BIOBADASER Group. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: A multicenter activesurveillance report. Arthritis Rheum. 2003; 48: Aletaha D, Smolen JS. Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for rheumatoid arthritis: An observational study. J Rheumatol. 2002;29: Early Treatment and Remission Induction Continued from page 7 progressive disease, and fewer treatment adjustments. CONCLUSIONS Traditional DMARDs may delay disease progression but they take effect slowly, often fail to provide a prolonged or sufficient response, and their use may be limited by serious toxicity. Moreover, DMARDs may produce clinical remission but they rarely stop the progression of structural damage. TNF inhibitors, combined with optimal doses of methotrexate, currently constitute the best therapeutic regimen for the management of patients with rheumatoid arthritis. Because the probability of joint erosion increases with the time lapse between onset of rheumatoid arthritis and initiation of proper management, early treatment is essential for disease control and prevention of subsequent deformities. Substantial and sustained remission, far outlasting drug withdrawal, has been accomplished by very early intervention with methotrexate and infliximab. REFERENCES 1. Quinn MA, Conaghan PG, Emery P. The therapeutic approach of early intervention for rheumatoid arthritis: What is the evidence? Rheumatology. 2001;40: American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46: Conaghan PG. Drug therapy of rheumatoid arthritis. Curr Ther. 2000;41: McQueen FM, Stewart N, Crabbe J, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis. 1998;57: Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS. Early referral recommendation for newly diagnosed rheumatoid arthritis: Evidence based development of a clinical guide. Ann Rheum Dis. 2002;61: Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol. 1989;16: Lard LR, Visser H, Speyer I, et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: Comparison of two cohorts who received different treatment strategies. Am J Med. 2001;111: Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343: Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: Two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46: Kremer JM, Weinblatt ME, Fleischmann RM, et al. Etanercept (Enbrel) added to background methotrexate in rheumatoid arthritis: Continued observations. Arthritis Rheum. 2002; 46(suppl):S Smolen JS, Emery P, Bathon J, et al. Treatment of early rheumatoid arthritis with infliximab plus methotrexate or methotrexate alone: Preliminary results of the ASPIRE trial. Presented at the Annual European Congress of Rheumatology; June 18-21, 2003; Lisbon, Portugal. Abstract 0P St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum. 2004;50: Quinn MA, Conaghan PG, O'Connor PJ, et al. 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. Arthritis Rheum. 2005;52: Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, van Zeben D, et al. Clinical and radiological efficacy of different treatment strategies: 2 year follow-up of the BeSt study. Ann Rheum Dis. 2005;64(suppl 3): TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis

11 Treating Rheumatoid Arthritis Continued from page 5 CONCLUSIONS The results of this survey reinforce the need for producing rapid, measurable results in treating this progressive disease. Whereas methotrexate was the first treatment of choice, its slow onset of action, low remission rates, and limited effect on persistent joint erosion were recognized as critical shortcomings. Inflammation and joint damage prompted the use of biologics, and, in the face of an inadequate response, switching to another biologic agent was regarded prudent. REFERENCES 1. St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum. 2004;50: van Vollenhoven R, Harju A, Brannemark S, Klareskog L. Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versa: Data from the STURE registry showing that switching tumour necrosis factor alpha blockers can make sense. Ann Rheum Dis. 2003;62: Furst D, Yocum D, Weisman M, et al. Infliximab provides additional clinical and radiographic benefits in RA patients who have an inadequate response to etanercept. Ann Rheum Dis. 2005;64(S111):427. Reality-Based Algorithm Continued from page 9 South Swedish Arthritis Treatment Group. Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: Clinical experience using a structured follow up programme in southern Sweden. Ann Rheum Dis. 2002;61: Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343: Kremer JM, Weinblatt ME, Fleischmann RM, et al. Etanercept (Enbrel) added to background methotrexate in rheumatoid arthritis: Continued observations. Arthritis Rheum. 2002;46(suppl): S Breedveld FC, Rau R, van Riel PL, et al. Sustained efficacy over 5 years with adalimumab (Humira) in patients with active rheumatoid arthritis. Arthritis Rheum. 2003;48(suppl):S Maini R, St Clair EW, Breedveld F, et al. 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. Lancet. 1999;354: Keystone E, Kavanaugh A, Sharp J, et al. Adalimumab (D2E7), a fully human antitnf- monoclonal antibody, inhibits the progression of structural joint damage in patients with active RA despite concomitant methotrexate therapy. Arthritis Rheum. 2002;46(suppl):S Lipsky P, van der Heijde D, St Clair W, et al. 102-week clinical and radiologic results from the ATTRACT trial: A 2-year, randomized, controlled phase 3 trial of infliximab (Remicade) in patients with active rheumatoid arthritis despite methotrexate. Arthritis Rheum. 2000;43(suppl):S Haraoui B. Is there a rationale for switching from one anti-tumor necrosis factor agent to another? J Rheumatol. 2004;31: Hansen KE, Hildebrand JP, Genovese MC, et al. The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis. J Rheumatol. 2004;31: Furst D, Yocum D, Weisman M, et al. Infliximab provides additional clinical and radiographic benefits in RA patients who have an inadequate response to etanercept. Ann Rheum Dis. 2005;64(S111): Bombardieri S, Tzioufas AG, McKenna F, Michel BA, Webber DG, Kupper H. Efficacy evaluation of adalimumab (Humira ) in patients with single and multiple prior biologics in the ReAct trial. Arthritis Rheum. 2004;50(suppl):S Haraoui B, Keystone EC, Thorne J, Pope J, Asare C, Leff J. The Canadian Biologic Observational Switchover Survey (BOSS): Switching from infliximab to etanercept leads to successful treatment of rheumatoid arthritis. Ann Rheum Dis. 2003;62(suppl 1):178. TNF Inhibitors: A New Era in the Treatment of Rheumatoid Arthritis 11