Unmet Needs in RA: The Role of Anti-TNF Therapy

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1 A SUPPLEMENT TO Rheumatology News Unmet Needs in RA: The Role of Anti-TNF Therapy Therapeutic Issues in RA Clinical Practice Roy Fleischmann, MD (Chair) Clinical Professor of Medicine University of Texas Southwestern Medical Center Co-Medical Director Metroplex Clinical Research Center (MCRC) Dallas, Texas Examining the Link Between RA and CVD Philip J. Mease, MD Head, Seattle Rheumatology Associates Clinical Professor University of Washington School of Medicine Seattle, Washington Emphasis on Early Diagnosis and Treatment in RA Ronald F. van Vollenhoven, MD, PhD Associate Professor of Rheumatology Rheumatology Clinic Karolinska University Hospital Stockholm, Sweden RELEASE DATE: November 2009 EXPIRATION DATE: October 31, 2010 ESTIMATED TIME TO COMPLETE THIS ACTIVITY: 2 hours This activity is co-provided by ONECONSORTIUM members, Creative Educational Concepts, Inc. (CEC), and Global Academy for Medical Education, LLC, a division of Elsevier This supplement was supported by educational grants from and

2 A SUPPLEMENT TO Rheumatology News Unmet Needs in RA: The Role of Anti-TNF Therapy TOPIC HIGHLIGHTS PAGE Therapeutic Issues in RA Clinical Practice 4 Roy Fleischmann, MD (Chair) Examining the Link Between RA and CVD 8 Philip J. Mease, MD Editorial support in the development of this supplement was provided by Global Academy for Medical Education, LLC, a division of Elsevier. Emphasis on Early Diagnosis and Treatment in RA 11 Ronald F. van Vollenhoven, MD, PhD CME Post-Test 16 This supplement was developed through telephone interviews with the faculty. This supplement was produced by the Global Academy for Medical Education, LLC, a division of Elsevier. Neither the editor of Rheumatology News, 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 2009 by Elsevier Inc. and its Licensors. 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. Global Academy for Medical Education, LLC ACTIVITY GOALS Rheumatoid arthritis (RA) is a chronic and systemic autoinflammatory disease affecting approximately 1.3 million people in the United States. RA is characterized by persistent synovitis, destruction of joint bone and cartilage, extra-articular complications, functional impairment and disability, and increased premature mortality. In particular, a growing volume of evidence has shown an association between RA and cardiovascular disease and clinical events. RA is one of a number of immunemediated inflammatory disorders that share common pathophysiologic processes implicating a variety of cell types and cytokines. Blockade of these cellular and molecular targets by current and investigational treatments continues to achieve considerable clinical success. Early recognition offers an opportunity for interventions that may limit joint damage and minimize consequences of uncontrolled inflammation. Clinical guidelines recommend initiating RA therapy with conventional disease-modifying antirheumatic drugs, with methotrexate representing the most potent of the agents. If patients achieve an inadequate response to conventional therapies, newer biological agents should be initiated. Inhibitors of tumor necrosis factor (TNF) are the most widely used agents in this category. Recent studies have provided new insights into the therapeutic potential of

3 anti-tnf agents to disrupt RA pathophysiology. Data have demonstrated benefits with use of TNF inhibitors in early RA, in combination therapy with methotrexate, and in sequence. Several studies have shown improved function, productivity, and quality of life among patients treated with TNF inhibitors. Some evidence suggests that the anti-inflammatory effects of TNF inhibitors may help ameliorate the cardiovascular risk associated with RA. Better understanding of contemporary principles of RA clinical management can improve disease control and preserve functional capacity. LEARNING OBJECTIVES After completing this educational activity, participants should be able to: Recognize the potential benefits of early diagnosis and treatment of RA Assess principles of aggressive therapy Describe relationships between RA and cardiovascular disease Appreciate the impact of RA on patient productivity and quality of life and the effects of therapy on those outcomes. TARGET AUDIENCE This educational activity is designed for rheumatologists and other health care professionals involved in the clinical management of patients with RA. DISCLOSURES Dr Fleischmann is a consultant for Abbott Laboratories, Amgen, Inc, Centocor, Inc, and UCB. He has received grant/research support from Abbott, Amgen, Wyeth, and Centocor. Dr Mease is a consultant for Abbott Laboratories, Amgen, Inc, Biogen Idec, Bristol-Myers Squibb Company, Centocor, Inc, F. Hoffman LaRoche Ltd, Genentech, Inc, UCB, and Wyeth Pharmaceuticals. He has received grant/research support from and has served on the speakers bureaus for Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor, Genentech, and Wyeth. Dr van Vollenhoven has nothing to disclose. ACCREDITATION Continuing Medical Education Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. INSTRUCTIONS To receive a statement of credit, you must: Review the full content of the activity and reflect upon its teachings. Go to and successfully complete the posttest (70% or higher). You will have two (2) opportunities to successfully complete the activity. Statements of credit will be immediately available online for all health care professionals who successfully complete the post-test and evaluation. DISCLOSURE DECLARATION It is the policy of CEC to ensure independence, balance, objectivity, scientific rigor, and integrity in its continuing education activities. Those involved in the development of this continuing education activity have made all reasonable efforts to ensure that information contained herein is accurate in accordance with the latest available scientific knowledge at the time of accreditation of this continuing education activity. Information regarding drugs (eg, their administration, dosages, contraindications, adverse reactions, interactions, special warnings, and precautions) and drug delivery systems is subject to change, however, and the reader is advised to check the manufacturer s package insert for information concerning recommended dosage and potential problems or cautions prior to dispensing or administering the drug or using the drug delivery systems. Fair balance is achieved through ongoing and thorough review of all presentation materials produced by faculty and all educational and advertising materials produced by supporting organizations prior to educational offerings. Approval of credit for this continuing education activity does not imply endorsement by CEC of any product or manufacturer identified. UNLABELED-USE DISCLOSURE This activity may include discussions of products or devices that are not currently approved for use by the Food and Drug Administration or that are currently investigational. FEE Complimentary Unmet Needs in RA: The Role of Anti-TNF Therapy 3

4 Introduction D espite advances in management of rheumatoid arthritis (RA), patients often obtain inadequate control of the disease process and associated symptoms. Continued progress in basic and clinical sciences is needed, but improved application of existing knowledge may help extend the potential benefits of therapy to more patients. The development of inhibitors of tumor necrosis factor (TNF) has provided new opportunities for better management of RA. Since their introduction more than a decade ago, TNF inhibitors have evolved from a therapy reserved for patients who have experienced one or more treatment failures to a therapeutic mainstay that helps reduce symptoms, prevent joint damage, and preserve function. The TNF inhibitor class continues to expand with knowledge of RA s underlying pathobiology and the role of TNF in the inflammatory cascade that drives the disease process. Clinical data presented at a recent rheumatology conferences have provided new insights into RA pathogenesis and clinical management and into the role of anti- TNF therapy. Key findings have included: Demonstration of the safety and efficacy of combination therapy containing a TNF inhibitor The potential for sequential use of anti-tnf therapy Earlier onset of action than previously recognized Remission as a realistic goal of therapy Clarification of associations between RA and cardiovascular disease The potential for effective treatment to improve function, productivity, and quality of life for patients with RA. This supplement to Rheumatology News highlights some of the clinical findings. The information combines an examination of recent research developments with an evaluation of the findings applicability to clinical practice. Therapeutic Issues in RA Clinical Practice Roy Fleischmann, MD (Chair) Clinical Professor of Medicine, University of Texas Southwestern Medical Center Co-Medical Director, Metroplex Clinical Research Center (MCRC), Dallas, Texas T he growing number of therapeutic options for treating rheumatoid arthritis (RA) has introduced new considerations for clinical decision making. Clinicians face choices that did not exist as recently as a decade ago: the concept of treating RA to clinical remission, optimal sequencing of therapies, multiple strategies for combination therapy, and the feasibility of switching from one biologic therapy to another biologic in the same class. The development of inhibitors of tumor necrosis factor-α (TNF) has been an important factor in the revolution of clinical practice in treating patients with RA. By targeting a principal component of the inflammatory cascade that drives RA, TNF inhibitors have revolutionized therapy and provided much of the impetus for exploration of new strategies to improve management of this chronic, debilitating disease. Data reported at recent meetings of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have highlighted many of the emerging clinical issues in RA. The studies also have provided insights into the ability of TNF inhibitors to help resolve some of these issues. Early Remission and Duration of Remission Remission as a goal of RA therapy has progressed from the concept of rare occurrence to a legitimate clinical goal. Recognition that joint damage occurs early in the disease process has led to more aggressive treatment strategies in patients with early RA. It has recently become clear that the time course to remission influences the duration of remission. Schipper et al 1 examined this issue in a study involving 356 patients whose disease duration averaged 2 weeks and who had received RA treatment for at least 2 years. Investigators used the defined remission of a Disease Activity Score 28 (DAS28) joint count <2.6. The primary outcome was the time to first remission, as achieved by means of local clinical practice. The secondary outcome was sustained remission, calculated by the continuity rewarded (ConRew) scoring system, a weighted sum of DAS28 remission scores for all evaluations during follow-up. 2 The patients mean age was 61 years, two thirds were female, 71% were positive for rheumatoid factor (RF), and their baseline DAS28 was a mean of 4.8. The patients were followed at 3-month intervals. The data showed that 45% of the patients were in remission during at least one follow-up interval. The time to first remission averaged 107 weeks. Logistic regression analysis showed that a lower baseline DAS28 was associated with more rapid attainment of remission (P<0.0001) and that men achieved remission sooner than did women (84 vs 122 weeks). Patients who attained remission had a median ConRew score of 3, meaning that half of the patients who achieved remission had three or more remission periods that lasted at least 3 months. Importantly, the analysis showed that the principal determinant of sustained remission (lasting more than 6 months) was a shorter time to first remission (P<0.0001). Increasingly, clinicians strive to achieve clinical remission in patients with RA; that is my goal in my own clinical practice. This study provides objective evidence to show that earlier attainment of remission translates into a longer duration of remission. The study also reinforces the value of an aggressive approach to treatment in early RA in order to try to reach remission sooner rather than later. RF 4 Unmet Needs in RA: The Role of Anti-TNF Therapy

5 Combination Therapy to Achieve Remission The previously described study would suggest that aggressive treatment of early RA enhances the potential to achieve a sustainable clinical remission. Most clinical RA researchers and practicing clinicians consider many approaches to aggressive therapy, including combination therapy. Over the past decade, TNF inhibitors have evolved into the principal component of therapeutic combinations for RA in patients who do not achieve remission with disease-modifying antirheumatic drug (DMARD) monotherapy, such as methotrexate (MTX). Emery et al 3 presented data from the first clinical trial that had used clinical remission, defined by the DAS28, as the primary outcome measure. Treatment consisted of MTX and etanercept compared to MTX alone with respect to clinical, radiographic, and functional effects. The initial analysis focused on 12-month results in 542 randomized patients. Entry criteria for the study included a disease duration 2 years, no prior exposure to MTX, and active RA, defined by a DAS plus an erythrocyte sedimentation rate 28 mm/h or C-reactive protein level 20 mg/l. The primary end point was the proportion of patients achieving DAS28 remission (<2.6) and the change in modified total Sharp Score (mtss) from baseline to 52 weeks. Secondary Results of this study clearly showed that combination therapy with MTX and a TNF inhibitor in early RA is superior to MTX monotherapy with respect to achieving DAS28 remission. The data also demonstrated that clinical remission is associated with radiographic nonprogression and significant improvement in patient function as measured by the HAQ. The data provided further support for aggressive treatment of early RA as defined by the combination of MTX and a TNF inhibitor. Clinicians often begin treatment with high-dose MTX monotherapy as approximately one third of patients will achieve DAS28 end points included attainment of low disease activity (DAS28 3.2), radiographic nonprogression (mtss 0.5), and the proportion of patients with a normal Health Assessment Questionnaire (HAQ) score ( 0.5). At enrollment, 92% of patients had severe RA (DAS28 5.1); 21% had prior exposure to DMARDs. After 52 weeks of treatment, 50% of patients in the combination arm of MTX and etanercept achieved DAS28 remission versus 28% of patients treated with MTX alone (P<0.001). Low disease activity was achieved in 64% of patients treated with the combination compared to 41% of the MTX monotherapy group (P<0.001). Significantly less radiographic progression occurred in the combination arm (mean mtss with combination therapy vs with MTX monotherapy, P<0.001). Radiographic nonprogression was observed in 80% of patients treated with the combination compared with 59% of patients in the monotherapy arm (P<0.001). A significantly greater percentage of patients in the combination group had a HAQ score 0.5 (55% vs 39%, P<0.001). Serious adverse events were reported by 12% of patients treated with MTX and etanercept versus 13% of those treated with MTX monotherapy. Rates of serious infection and malignancy were similar in the two treatment arms; no patient in either group developed tuberculosis or demyelinating disease. remission with MTX alone, and this is cost-effective. If the patient does not have a significant clinical response, as defined by a clinically important change in the DAS28 (or another validated measure of clinical activity such as the Clinical Disease Activity Index) after 8 weeks, an anti-tnf agent could be added to the treatment regimen. If the patient does have a clinically meaningful response to MTX alone, continue monotherapy for an additional 8 weeks and then re-evaluate the patient. The goal is to determine as quickly as possible whether remission is feasible with MTX monotherapy or will require the addition of a TNF inhibitor. RF Feasibility and Value of Sequential Anti-TNF Therapy In clinical practice, many physicians have used another TNF inhibitor in the treatment of patients with RA who have not had an adequate response to the first (or second) TNF inhibitor. However, until recently, evidence-based scientific support for this practice had been lacking. Smolen et al 4 conducted an objective evaluation of the strategy of using a different TNF inhibitor in patients with a history of failure or incomplete response to anti-tnf therapy. The study examined sequential anti-tnf therapy with golimumab, a recent addition to the TNF inhibitor class. The study included 461 patients who had been treated with one or more anti-tnf agents, which had been discontinued for any reason, including lack of efficacy, adverse events, or financial considerations. All of the patients had active RA, as defined by at least four tender and swollen joints. The patients were randomized to placebo or to 50 or 100 mg of golimumab, administered subcutaneously every 4 weeks. The primary end point was the proportion of patients who exhibited at least 20% improvement in disease activity at 14 weeks by ACR criteria (ACR20). Investigators also assessed improvement in HAQ score from baseline to week 24. The patients randomized to the trial had an RA duration of 9 to 10 years; 97% of the patients tested positive for RF or anticyclic citrullinated peptide antibody, including 72% who tested positive for both. Almost 80% of the patients were on disease-modifying therapy at entry (primarily MTX), which was continued during randomized treatment. Almost 60% of patients had discontinued prior anti- TNF therapy because of lack of efficacy. At week 14, 18.1% of placebo patients had achieved an ACR20 response compared with 35.3% of patients treated with 50 mg of golimumab and 37.9% of those treated with 100 mg, which was statistically significant (P<0.001; Table 1). In the subgroup of patients who discontinued anti-tnf therapy because of lack of efficacy, 35.7% achieved an ACR20 response by 14 weeks with 50 mg of golimumab and 42.7% with 100 mg of golimumab. In contrast, 14% of placebo patients had an ACR20 response by week 14 Unmet Needs in RA: The Role of Anti-TNF Therapy 5

6 Table 1. Anti-TNF Therapy After Prior Anti-TNF Exposure PBO (P=0.006 for golimumab 50 mg; P<0.001 for 100 mg golimumab). Rates of adverse events and serious adverse events were similar in the golimumab and placebo groups. No patient discontinued treatment because of adverse events. Improvement in HAQ scores from baseline averaged 0.0 in the placebo group versus a clinically significant 0.3 in each of the golimumab groups (P<0.001; Table 1). More than half of patients in each golimumab group had 0.25 improvement in HAQ score compared with 34.2% of placebo patients (P<0.01 for golimumab 50 mg; P<0.001 for golimumab 100 mg; Table 1). The importance of this study is the objective support it provides for our previous intuitive practice. Many, if not most, clinicians have used another TNF inhibitor in patients who did not respond or lost response to one anti-tnf agent, assuming that the switch to a different TNF inhibitor might lead to a significant response. Previous attempts to quantify the frequency and value of anti-tnf switching had relied on retrospective analyses, patient registry data, or other data sources that lacked firm controls, but most did GLM 50 mg GLM 100 mg GLM 50 mg and 100 mg Combined n Week 14 ACR20 28 (18.1%) 54 (35.3%)* 58 (37.9%)* 112 (36.6%)* ACR50 10 (6.5%) 25 (16.3%) 31 (20.3%)* 56 (18.3%)* Week 24 HAQ (improvement from baseline) * 0.3* 0.3* HAQ ( 0.25 improvement from baseline) 53 (34.2%) 77 (50.3%) 82 (53.6%)* 159 (51.9%)* GLM = Golimumab; PBO=Placebo; TNF = tumor necrosis factor; ACR = American College of Rheumatology; HAQ = Health Assessment Questionnaire. *P<0.001; P <0.01. Source: Smolen et al. 4 Efficacy of Sequential Anti-TNF Therapy The availability of multiple anti-tnf therapies has led to questions about the durability of response and, specifically, whether response rates are similar after one versus more than one anti-tnf therapy. Glass et al 5 addressed this issue by analyzing data from the Brigham and Women s Rheumatoid Arthritis Sequential Study (BRASS) registry. The registry is a longitudinal cohort study that includes data on patients medication history and annual medication use, disease activity, functional status, and fatigue. suggest that a switch is worthwhile in a proportion of patients. This is the first well-controlled study showing that use of another anti-tnf agent after an anti-tnf failure can be effective. The study demonstrated that a TNF inhibitor can be effective in RA in patients who have received as many as three prior anti-tnf agents. It might be reasonable to assume that similar results would be observed with other TNF inhibitors, but this study of golimumab is the first to provide objective evidence from a randomized, placebo-controlled clinical trial. RF Of almost 1,000 patients enrolled, 532 had a history of anti-tnf therapy. Investigators evaluated whether patients were still taking a first TNF inhibitor, still using a second or third anti-tnf agent, discontinued a single anti-tnf agent, or discontinued two or three anti-tnf agents. At the time of the analysis, 79% of the 532 patients remained on anti-tnf therapy, including 59% who were still using their first TNF inhibitor, 22% who had been treated with two agents, and 6% who had used three anti-tnf agents. Follow-up among current users of anti-tnf therapy averaged 44 months. Of the 111 patients who discontinued anti-tnf therapy, 65% stopped after one drug, 30% after two, and 5% after three (Table 2). The four groups of patients had moderately severe RA, as indicated by a mean DAS28 of 3.2 to 5.1, but patients still on their first anti-tnf agent had a lower mean DAS28 than that of the other three groups. Fatigue scores were higher among patients on their second or third anti-tnf therapy than among those still on their first agent in the class (Table 2). Almost half of the patients continued to use MTX and nonsteroidal anti-inflammatory drugs, and the proportion did not differ among the four groups. However, steroid use was significantly lower among patients still taking their first anti-tnf agent than among those in the other three groups (32% vs 49% to 67%, P<0.0001). Although the majority of patients remained on anti-tnf therapy for an average of almost 4 years, patients using their second or third TNF inhibitor had higher DAS28 and fatigue scores. One interpretation of the findings is that patients who switch from one anti-tnf agent to another do not achieve the same benefit as do patients who are successfully treated with the first agent in the class. The findings might also indicate that patients treated with two or three anti-tnf agents have more severe disease and require additional therapy for RA. 6 Unmet Needs in RA: The Role of Anti-TNF Therapy

7 Table 2. RA Outcomes by Anti-TNF Treatment History Anti-TNF History This study suggests that patients can benefit from switching anti-tnf therapies, but that patients seem to derive less benefit from subsequent treatment than from the initial TNF inhibitor. Coming from a registry, the data have some notable limitations. The quality of response to anti-tnf therapy and the reasons for discontinuation are unclear. The data from this registry suggest that disease activity was not tightly controlled. With aggressive treatment and tight control, a 90% rate of remission and low disease activity have been achieved in some clinical trials. RF Anti-TNF Agent Superior to DMARD After MTX Failure MTX remains the cornerstone of therapy for RA. However, a substantial proportion of patients have an inadequate response to MTX by not achieving remission or low disease activity or diminution of response over time. Many clinicians have used add-on therapy with one or more nonbiologic DMARDs in these patients. The emergence of TNF inhibitors as a treatment for RA has raised questions about this conventional approach to MTX failure. van Vollenhoven et al 6 compared a strategy of adding a conventional DMARD or the TNF inhibitor infliximab to RA therapy after MTX failure. Investigators conducted an open-label, randomized clinical trial involving 487 patients with RA with symptom duration <1 year. All patients started treatment with MTX titrated to 20 mg/wk. After 3 to 4 months, patients who had an inadequate response n Treatment (mo) DAS mhaq Fatigue Still on first anti-tnf agent Ongoing, >1 anti-tnf agent Stopped, 1 anti-tnf agent Stopped, >1 anti-tnf agent All values expressed as mean. RA = rheumatoid arthritis; TNF = turmor necrosis factor; DAS = Disease Activity Score; mhaq = modified Health Assessment Questionnaire. Source: Glass et al. 5 (DAS28 >3.2) but could tolerate MTX were randomized to one of two treatment strategies. One group received add-on therapy with the combination of sulfasalazine 1000 mg BID and hydroxychloroquine 400 mg/d. The remaining patients received infliximab, a 3-mg/kg infusion at baseline, 2, and 6 weeks and then every 8 weeks thereafter. Within each treatment arm, one therapeutic switch was allowed in the event of intolerance. Patients randomized to conventional DMARDs could receive cyclosporine in place of the sulfasalazine-hydroxychloroquine combination, and patients in the infliximab arm could be switched to etanercept. The primary outcome was a good response by EULAR criteria at 12 months. Secondary outcomes included EULAR moderate response and ACR responses. Among patients randomized to DMARD add-on therapy, 25% achieved a good EULAR response compared with 39% in the anti-tnf arm (P=0.0160). Respective ACR20, ACR50, and ACR70 responses were achieved by 28%, 15%, and 7% of patients in the DMARD combination arm versus 42%, 25%, and 12% in the anti-tnf arm (P<0.05 for ACR20 and ACR50). An analysis based on the time from initiation of MTX monotherapy showed that 47% of patients randomized to anti-tnf therapy achieved good EULAR responses compared with 32% of those in the DMARD arm (P=0.0107). Respective ACR20, ACR50, and ACR70 responses were 45%, 34%, and 15% with the DMARD combination compared with 59%, 48%, and 28% for patients randomized to the TNF inhibitor (P<0.03 for all comparisons). The authors concluded that in those patients who do not have a satisfactory response to MTX monotherapy, the addition of anti-tnf therapy is clinically superior to add-on therapy with conventional DMARDs. These data came from the first randomized, controlled trial to assess what many clinicians have long believed: namely, that anti-tnf therapy offers the best opportunity for a good response or remission after initial treatment of RA with MTX in those patients with an inadequate response to initial MTX monotherapy. The results suggest a treatment paradigm that begins with MTX. If a patient does not achieve the desired outcome after 3 to 4 months, add a TNF inhibitor to the therapy. The study demonstrated superior results with an anti-tnf inhibitor than with a conventional DMARD as add-on therapy to initial MTX treatment. RF REFERENCES 1. Schipper L, Fransen J, van Riel P. Time to achieve remission determines time to be in remission. Ann Rheum Dis. 2009;68(suppl):Abstract OP van der Heijde D, Klareskog L, Boers M, et al. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis. 2005;64: Emery P, Breedveld FD, Hall S, et al. 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. Lancet. 2008;372: Smolen JS, Kay J, Doyle MK, et al. 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. Lancet. 2009;374: Glass RJ, Shadick NA, Cui J, Mahere N, Weinblatt M. Clinical outcomes in patients after one or multiple anti-tnf therapies in rheumatoid arthritis. Arthritis Rheum. 2008;58(9 suppl): Abstract van Vollenhoven RF, Ernestam S, Geborek P, et al. 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. Lancet. 2009;374: Unmet Needs in RA: The Role of Anti-TNF Therapy 7

8 Examining the Link Between RA and CVD Philip J. Mease, MD Head, Seattle Rheumatology Associates Clinical Professor, University of Washington School of Medicine Seattle, Washington O ne of the key issues that has emerged in the field of rheumatoid arthritis (RA) over the last several years has come from the recognition that RA is associated with a significant increase in cardiovascular risk, including early morbidity and mortality from myocardial infarction (MI) and stroke. 1-3 Inflammation is a common etiologic thread that links cardiovascular disease (CVD) and RA. Premature development of atherosclerotic plaque is driven by many of the same cells and cytokines that drive inflammation in RA, including activated T lymphocytes, macrophages, dendritic cells, and the proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukins 1 and 6. Moreover, therapies that target and reduce inflammation appear to reduce the risk of CVD in patients with RA, just as the therapies reduce RA disease activity by anti-inflammatory mechanisms. 4 The association between CVD and RA has attracted considerable interest among clinicians and researchers. Recent studies have added to the knowledge base related to the association and provided new insights. Table 1. RA and Risk of CVD Events 7,653 Patients with RA 37,837 Non-RA Controls Mean follow-up: 4.5 years Overall Risk MI Risk Increases Within a Year of RA Diagnosis Data from a large Swedish registry of patients with RA provided strong confirmation of the association between RA and CVD. 5 Investigators compared 7,653 patients with newly diagnosed RA (symptom duration <18 months) and 37,837 individuals from the general population, matched for age, sex, calendar year, residential area, and marital status. The primary objective was to determine the relative risk of MI, death from MI, and all-cause mortality at diagnosis of RA, as a function of time since diagnosis. The authors obtained information on incident MI hospitalization, death from MI, and all-cause mortality from various national registries with follow-up from Mean age at the start of follow-up was 57 years, and 71% of study participants were women. Mean follow-up was 4.5 years, resulting in a total follow-up of 33,040 person-years among patients with RA and 164,820 person-years for the general-population cohort. At the time of RA diagnosis, the patients did not have an increased prevalence of MI compared with that of the control group <1 Year Since RA Diagnosis 1-4 Years Since RA Diagnosis 5-10 Years Since RA Diagnosis Outcome RR RR RR RR Hospitalization for acute MI All-cause mortality Fatal MI RA = rheumatoid arthritis; RR = relative risk; MI = myocardial infarction; CVD = cardiovascular disease. Source: Gunnarsson et al. 5 (odds ratio [OR], 1.0). Moving forward from the diagnosis, the risk of hospitalization for acute MI increased over time in patients with RA, beginning with an OR of 1.4 in the first year after diagnosis and increasing to 1.7 in patients followed for 5 to 10 years after diagnosis of RA. Overall, patients with RA had a 60% greater risk of hospitalization for acute MI than that of the general-population cohort (OR, 1.6; 95% confidence interval [CI], ) (Table 1). The risk of death from MI ranged from 1.0 to 1.3 in patients with RA, but the difference did not achieve statistical significance at any point in follow-up. All-cause mortality was similar among the two groups (Table 1). The Swedish study provided further documentation that the presence of RA, in and of itself, increases the risk of heart attack. Notably, the study showed that the risk of MI begins to increase within the first year after diagnosis of RA. The findings of this study underscore the value of aggressive treatment of RA early in the course of the disease. Aggressive treatment should aim not only to control disease activity, inhibit radiographic progression of RA, and preserve function but also to diminish the role that inflammation plays in the elevated cardiovascular risk conferred by RA. PJM RA, Diabetes Impose Similar CVD Risk The CVD risk associated with RA has appeared to be similar in magnitude to the risk conferred by type 2 diabetes. However, most of the supporting data have come from cross-sectional studies. In particular, evidence from longitudinal studies has been lacking. 8 Unmet Needs in RA: The Role of Anti-TNF Therapy

9 Investigators from the Netherlands sought to clarify the magnitude of CVD risk imparted by RA. 6 They analyzed data from a prospective cohort study that included 335 outpatients with RA. The authors compared the 3-year incidence of CVD in the patients with RA with that of a general population of 1,852 individuals, including 155 patients with type 2 diabetes. Patients with RA had a 9% incidence of CVD during the 3-year follow-up period compared with 4.3% of the general population. The percentage translated into an incidence of 3.30 cases per 100 patient-years for patients with RA, double the rate for the general population (1.51 cases per 100 patient-years). As compared with the general population, patients with RA had an age- and sex-adjusted relative risk (RR) of 1.94 for CVD (95% CI, ; P=0.004). Adjustment for cardiovascular risk factors did not alter the results. Comparing data on patients with type 2 diabetes, investigators found a twofold greater risk of CVD than that among healthy individuals (RR, 2.04; 95% CI, ; P=0.019). A similar difference emerged from a comparison of patients with RA and healthy individuals (RR, 2.16; 95% CI, ; P=0.004) (Table 2). Given that the increased risk of CVD in patients with RA could not be explained by traditional cardiovascular risk factors, the authors concluded that RA itself should be considered an important cardiovascular risk factor. Table 2. Risk for CVD: RA vs Type 2 Diabetes 3-Year Incident CVD 335 outpatients with RA 1,852 non-ra controls 155 diabetic patients Relative Risk General population 1.0 P-value Type 2 diabetes RA CVD = cardiovascular disease; RA = rheumatoid arthritis Source: Peters et al. 6 Results of this study have implications for management of RA. Historically, tight glycemic control has been encouraged as a means to reduce the excess cardiovascular risk seen in patients with type 2 diabetes versus that of the general population. By analogy, tight control of RA activity might also mitigate the inflammationdriven excess CVD risk, in addition to control of traditional risk factors, such as hyperlipidemia, hypertension, and obesity, just as it is with patients with type 2 diabetes. PJM Therapy for RA May Reduce CVD Risk The large volume of evidence linking RA to increased CVD risk begs the question of whether aggressively treating RA will reduce the associated cardiovascular risk. Data from patient registries in Sweden, the United Kingdom, and the United States have suggested that treatment of RA with an oral disease-modifying antirheumatic drug (DMARD), such as methotrexate (MTX), can help mitigate cardiovascular risk. More compelling data for reduced CVD risk have emerged from studies of biologic agents, particularly TNF inhibitors. Some of the most recent contributions to the knowledge base in this field have come from the Consortium of Rheumatology Researchers of North America (CORRONA). At the 2008 meeting of the American College of Rheumatology, CORRONA investigators presented new evidence that effective treatment of RA reduces cardiovascular risk. 7 The evidence came from an examination of the risk of MI, stroke, and transient ischemic attack (TIA) in patients treated with conventional and biologic DMARDs. Rheumatologists medication reports formed the basis for developing a longitudinal time-varying exposure record. The analysis included 10,870 patients with a median follow-up of 24 months in CORRONA and a median RA duration of 7 years. Three fourths of the patients tested positive for rheumatoid factor (RF). CORRONA investigators identified 71 patients who had confirmed cardiovascular events: 26 MIs and 45 strokes and TIAs. Adjusted models for cardiovascular events showed that treatment with a TNF inhibitor reduced the hazard ratio (HR) by 70% (HR, 0.3; 95% CI, ) compared with nonbiologic DMARDs exclusive of MTX. Treatment with MTX reduced the risk of cardiovascular events by approximately 40%, but the effect did not achieve statistical significance (HR, 0.6; 95% CI, ). Separate analysis of MI and stroke/tia revealed similar trends toward reduced risk. Variables associated with trends toward increased risk of cardiovascular events included older age (45 to 64 years: HR, 4.4; 65 years: HR, 13.9, versus <45 years), male sex (HR, 1.6), modified Health Assessment Questionnaire score (HR, 1.4), Disease Activity Score 28 (HR, 1.2 per point), nodules (HR, 1.3), hyperlipidemia (HR, 2.3), current smoker (HR, 1.6), and current prednisone dose (HR, 1.2 per mg). Treatment with TNF inhibitors was associated with a significantly reduced risk of cardiovascular events, whereas treatment with MTX resulted in a trend toward lower risk. This analysis is consistent with results from other registries. The principal theory to explain RA therapy s effect on cardiovascular risk centers on the drugs ability to reduce systemic inflammation by targeting specific proteins and cytokines, such as TNF. Studies have shown that anti- TNF agents also improve endothelial function and help counter insulin resistance, two factors that contribute to atherosclerosis associated with most MIs and strokes. The findings support the view that use of TNF inhibitors and to a lesser extent, use of MTX can reduce cardiovascular risk in patients with RA. PJM Unmet Needs in RA: The Role of Anti-TNF Therapy 9

10 EULAR Offers Strategy to Lower Cardiovascular Risk in Patients With RA Recognizing the cardiovascular risk imparted by RA, the European League Against Rheumatism (EULAR) has recommended a nine-point strategy to reduce the risk associated with RA and other inflammatory arthritides. 8 The recommendations followed deliberations by an 18-member multidisciplinary task force representing nine European countries. As presented at the 2009 EULAR congress, the recommendations reflect a combination of best-available evidence and expert opinion. The task force offered the following recommendations and opinions: 1. RA should be considered a high-risk condition for CVD. The recommendation also applies to ankylosing spondylitis and psoriatic arthritis, although the evidence is more limited. The increased risk appears to emerge from the combination of a high prevalence of traditional cardiovascular risk factors and a high burden of systemic inflammation. 2. Adequate control of RA disease activity is necessary to lower cardiovascular risk. Anti-TNF agents and MTX have the best evidence. 3. Annual assessment of cardiovascular risk (by means of national guidelines or the Systematic Coronary Risk Evaluation [SCORE] model) is recommended for all patients with RA and should be considered for patients with ankylosing spondylitis and psoriatic arthritis. Risk assessment should be repeated when antirheumatic treatment changes. 4. Risk score models should be adapted for patients with RA by use of a 1.5 multiplication factor for patients who meet two of the following three criteria: disease duration >10 years, positivity for RF or anticyclic citrullinated antibodies, and presence of certain extra-articular manifestations. 5. The total cholesterol/high-density lipoprotein cholesterol ratio should be used with the SCORE model. 6. Intervention with lipid-lowering agents and/or antihypertensive drugs should be initiated in accordance with national guidelines. 7. Statins, angiotensin-converting enzyme inhibitors, and/or angiotensin receptor blockers are preferred because of their pleiotropic effects. 8. The role of cyclooxygenase-2 inhibitors and most nonsteroidal anti-inflammatory drugs in managing cardiovascular risk is not well established and requires further study. Hence, the agents should be prescribed cautiously. 9. Use the lowest possible dose of corticosteroids. The management of traditional risk factors, such as hyperlipidemia, warrants singling out for elaboration. Growing recognition of the increased cardiovascular risk associated with RA has raised questions about rheumatologists role in prescribing lipid-lowering drugs and antihypertensive agents. Some observers support a leadership role for rheumatologists in managing cardiovascular risk in patients with RA. Others favor a team approach, with rheumatologists, cardiologists, and primary care physicians sharing responsibility for cardiovascular risk management. In reality, the approach to managing cardiovascular risk in patients with RA will vary on a case-bycase basis, depending on other providers diligence in addressing the issues. Rheumatologists should have a leadership role in educating patients with RA about the importance of managing cardiovascular risk and evaluating patients risk in the clinic. In some instances, a collaborative approach will help ensure proper management of cardiovascular risk. In other cases, patients might not have other providers or might have providers who do not regularly address patients cardiovascular risk. In the latter example, rheumatologists should take the lead to ensure that the risk is evaluated regularly and managed accordingly. PJM REFERENCES 1. Warrington KJ, Kent PD, Frye RL, et al. Rheumatoid arthritis is an independent risk factor for multivessel coronary artery disease: A case control study. Arthritis Res Ther. 2005;7:R984-R Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: A populationbased study over 46 years. Arthritis Rheum. 2005;52: Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population-based cohort study. Arthritis Rheum. 2005;52: Wolfe F, Michaud K. The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: A cohort and nested casecontrol analysis. Arthritis Rheum. 2008;58: Gunnarsson M, Wedrén S, Jacobsson L, et al. Morbidity and mortality from myocardial infarction in rheumatoid arthritis: Increased risk of myocardial infarction already within a year of diagnosis. Ann Rheum Dis. 2009;68(suppl):Abstract OP Peters MJ, van Halm VP, Voskuyl AE, et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum. 2009;61: Solomon DH, Curtis J, Kremer JM, et al. TNF blocker use and cardiovascular outcomes. Arthritis Rheum. 2008;68 (9 suppl):abstract Peters MJL, Symmons DPM, McCaery DW, Nurmohamed MT. EULAR recommendations: Cardiovascular risk management in patients with rheumatoid arthritis and other types of inflammatory arthritis A EULAR task force. Ann Rheum Dis. 2009;68(suppl):Abstract OP Unmet Needs in RA: The Role of Anti-TNF Therapy

11 Emphasis on Early Diagnosis and Treatment in RA Ronald F. van Vollenhoven, MD, PhD Associate Professor of Rheumatology Rheumatology Clinic, Karolinska University Hospital Stockholm, Sweden T he conceptualization of rheumatoid arthritis (RA) has changed dramatically in recent years. Once considered an insidious disease that progresses slowly, RA has become recognized as a condition that can progress rapidly, resulting in joint damage and debilitation within the first year after diagnosis and possibly within 6 months. 1,2 Researchers and clinicians increased awareness of RA s potential for rapid progression has led to greater emphasis on early diagnosis and treatment. 3 Recognition of aggressive forms of RA remains a challenge, but a growing list of potential biomarkers may improve capabilities for early recognition in the foreseeable future. In clinical practice, physicians already have a variety of clinical as well as laboratory and imaging markers to aid in recognizing RA that is likely to have an aggressive, rapidly progressing clinical course. 4 Aggressive disease warrants equally aggressive treatment. Biologic agents, particularly inhibitors of tumor necrosis factor (TNF), offer the greatest potential for slowing, and perhaps reversing, progression of RA. Several studies have shown that early use of a TNF inhibitor, particularly in combination with methotrexate (MTX), can reduce levels of biomarkers associated with aggressive disease, suppress inflammation, and slow or inhibit radiographic progression. 5 The following summaries of data presented at recent rheumatologic congresses reinforce the importance of recognition and aggressive treatment of early RA. Combined Therapy Proves Superior to MTX Alone in Early RA MTX remains the cornerstone of therapy for early and active RA. However, some patients have persistently active disease despite use of MTX or another disease-modifying antirheumatic drug. For those patients, the addition of a TNF inhibitor to MTX is often recommended. Several earlier randomized trials have clearly established that the combination of MTX and a TNF inhibitor as initial therapy offers superior results, at the group level, to MTX alone, both in terms of the clinical course and radiographically. However, because some patients will do well with MTX alone, the exact role for such combination therapy has not been completely clarified. French investigators aimed to shed more light on this issue in the GUÉPARD trial, a prospective, randomized multicenter trial in patients with RA duration of less than 6 months and moderate or high disease activity as demonstrated by the Disease Activity Score based on a 28-joint count (DAS28). 6 Patients were randomized to MTX up to 20 mg/week, alone or in combination with adalimumab at a dosage of 40 mg subcutaneously every other week. Disease status was assessed at 3-month intervals, and treatment was modified as necessary to achieve and maintain a low disease-activity state, defined as DAS28 <3.2. This study clearly confirmed that the combination of MTX plus an anti-tnf agent leads to a more rapid response than does MTX monotherapy and that the aggressive therapy approach used in this study leads to overall good results in a majority of patients. However, the results probably did not meet the authors expectations. In all likelihood, they hoped to demonstrate that the early use of anti-tnf therapy which could then be stopped when patients have a good response and continuing treatment with MTX alone to maintain the response would result in a long-term advantage. This At the 3-month visit, patients who achieved low disease activity with MTX monotherapy continued treatment, but the dose was gradually tapered. Patients who achieved a low disease-activity state after 3 months with the combination therapy continued treatment, but the adalimumab dose was decreased and then discontinued at 9 months. The primary outcome was the 1-year area under the curve (AUC) of the DAS28. The study involved 65 patients who had a mean baseline DAS28 of The 1-year DAS28 AUC was 164 with initial combination therapy versus 186 with initial MTX monotherapy (P<0.05). The difference was attributable to a better response during the first 12 weeks in the combination arm than in the MTX monotherapy arm (the AUC over 12 weeks was 49 vs 62, P<0.0001). The proportion of patients with low disease activity at 12 weeks was 25% with monotherapy vs 64% with the combination, a clear and highly significant difference (P=0.001). However, at 1 year, 65% of the monotherapy group and 64% of the combination arm had low disease activity the groups had achieved equal results. possibility has been referred to as the window of opportunity, and such a possibility was suggested by the T20 and BeSt trials using infliximab. However, those trials did not either, in the end, demonstrate that the clinical (as opposed to radiographic) results were better with the early treatment, and the main gain in those trials, as well as here in the GUÉPARD study, was the more rapid achievement of a satisfactory low diseaseactivity state in the majority of patients. Thus, this new trial adds to the evidence that MTX plus anti-tnf in early RA achieves rapid clinical improvements in a majority of patients. RFvV Unmet Needs in RA: The Role of Anti-TNF Therapy 11

12 TNF Inhibition Before MTX Thus, although MTX may still be considered the standard for initial treatment of many patients with RA, trials with adalimumab, etanercept, and infliximab have demonstrated that for some patients starting treatment with MTX plus a TNF inhibitor will lead to better clinical outcomes in early disease. There are relatively few data on the use of TNF inhibitor monotherapy in early RA. Golimumab is a new anti-tnf agent that was recently approved in the United States and Europe. The GO-BEFORE trial, a large multicenter, randomized, placebocontrolled clinical trial, investigated the efficacy of MTX, golimumab, or the combination of the two in early RA. 7 Investigators randomized 637 patients to four treatment groups: MTX 20 mg/week plus placebo, subcutaneous golimumab 100 mg every 4 weeks plus placebo, or golimumab 50 or 100 mg every 4 weeks plus MTX 20 mg/week. The primary end point was the proportion of patients who met the American College of Rheumatology (ACR) 50 criterion after 24 weeks. At the end of the study, 29.4% of patients on MTX alone had an ACR50 response, as did 32.7% of patients on golimumab 100 mg alone, 40.3% of patients treated with golimumab 50 mg plus MTX (P=0.042 vs MTX alone), and 36.5% of patients treated with golimumab 100 mg plus MTX. Combining both combination therapy arms resulted in an ACR50 of 38.4%, which represented a trend toward superiority, but not a significant difference from MTX alone (P=0.053). A post hoc analysis that excluded three patients who dropped out before receiving any therapy resulted in an overall ACR50 response This study evaluated golimumab as firstline antirheumatic therapy for RA. The TNF inhibitor was compared to first-line MTX, which most clinicians consider the standard of care for RA. The study was designed to answer a key therapeutic question: Can you improve outcomes in RA by giving a biologic agent right from the start? In the intention-to-treat analysis, the study did not meet the primary end point, but it is fair to say that the results showed rate of 38.5% for the two combination arms combined (P=0.049). The modified analysis also strengthened the difference between the MTX-only arm and the golimumab 50 mg plus MTX arm (P=0.038). TNF Inhibition After MTX Failure Although MTX remains a cornerstone of therapy for RA, many patients do not achieve adequate disease control with the drug. Given the evidence that RA can cause radiographic damage even in the very early stage and may progress rapidly, attaining disease control as soon as possible is a paramount therapeutic consideration. The advent of biologic therapy has given clinicians new options for management of patients whose RA does not respond sufficiently to MTX. Whereas, golimumab has been investigated mostly as a subcutaneous medication (and was, indeed, approved on that basis in the United States), a new study evaluated the safety and efficacy of intravenous golimumab in a randomized clinical trial involving 643 patients who had persistent disease activity despite treatment with MTX. 8 Patients received intravenous golimumab administered at a dosage of 2 or 4 mg/kg every 12 weeks, intravenous golimumab plus MTX 15 to 25 mg/week, or MTX and a placebo infusion. The primary end point was the ACR50 response rate after 14 weeks, with a principal secondary end point the ACR50 response rate at 24 weeks. Patients who had less than 20% improvement in joint counts could enter early escape from the protocol and receive additional therapy at 16 weeks or an increased dose of existing therapy at 24 weeks. a clear trend in favor of first-line therapy that included a TNF inhibitor. As has been seen for other anti-tnf agents, the combination with MTX provides superior results to those achieved with monotherapy. The data consistently favored more aggressive treatment, and many of the secondary end points were significantly improved with the addition of a biologic agent to first-line therapy. RFvV At week 14, the ACR50 response rate was 21.4% with the golimumab-mtx combinations, 21.7% with golimumab 2 mg/kg, and 21.1% with golimumab 4 mg/kg. None of the results differed significantly from the 13.2% ACR50 response rate with MTX-placebo. By week 24, significantly greater percentages of patients treated with golimumab had achieved ACR50 responses than did patients receiving placebo (9.3%): all golimumab- MTX groups combined (21.8%, P=0.002); golimumab 2 mg/kg (18.6%, P=0.032); and golimumab 4 mg/kg (25%, P<0.001). Significant differences in other secondary end points emerged in favor of golimumab- MTX combination therapy vs MTX-placebo: ACR20 response (53.3% vs 27.9%, P<0.001); European League Against Rheumatism (EULAR) good or moderate response (71.4% vs 44.2%, P<0.001); and the physical component of the Short Form (SF)-36 health status assessment (6.8 vs 4.2, P=0.005). Through week 16, adverse event rates were similar with golimumab (66.1%) and placebo (67.4%). To my knowledge, this is the first phase III clinical trial to evaluate intravenous golimumab. Given the agent s effectiveness with subcutaneous administration, one could reasonably expect intravenous administration to be at least as good. Investigators in this trial sought to determine whether intravenous administration would lead to a more rapid improvement in disease activity. The trial had a very ambitious design. First, the investigators chose the ACR50 response rate as the primary end point: the ACR50 represents a rather large clinical improvement and may, therefore, be harder to achieve. Second, the primary end point was evaluated at 14 weeks. I can think of no other studies of biologic agents that have evaluated the primary end point so soon after the start of treatment. The study failed to meet the specified end point, but only by a small margin. The data revealed strong trends toward improved outcomes at the early time point of 14 weeks with intravenous golimumab. RFvV 12 Unmet Needs in RA: The Role of Anti-TNF Therapy

13 Early Results Predict Long-Term Outcomes The ability to predict long-term RA outcomes should make for more efficacious and cost-effective therapy. Results of a study reported at the 2009 EULAR suggested that response to treatment at 3 months predicted 2-year outcomes. 9 The findings came from a subgroup analysis of a randomized, multicenter clinical trial that compared adalimumab alone, MTX alone, and the combination of the two drugs in patients with early RA. 9 The overall results of the trial demonstrated the superiority of the combination compared with monotherapy. 10 The subgroup analysis included 540 patients who completed 2 years of randomized therapy. The principal objective was to determine whether clinical response at 3 and 6 months predicted radiographic results at 2 years. Clinical assessment included tender and swollen joint counts and the DAS28. The patients were grouped according to radiographic outcomes at 2 years (>0.5 incremental change in modified total Sharp Score [mtss]). The 3-month clinical results with combination therapy did not predict 2-year radiographic outcomes (Table 1). In the monotherapy groups, however, patients who had radiographic progression at 2 years had less improvement at 3 months with respect to swollen joint count (42% for MTX, 44% for adalimumab) than did patients without progression (59% and 67%, respectively). Radiographic progression in the monotherapy groups also was associated with less change in DAS28 at 3 months (1.8 and 1.9 for MTX and adalimumab, respectively, vs 2.4 and 2.3 for patients without radiographic progression). Moreover, lack of radiographic progression at 2 years was associated with better ACR response at 3 months. The change in tender joint count at 3 months did not correlate with 2-year radiographic findings. The authors concluded that patients treated with the combination of adalimumab and MTX had low rates of radiographic progression at 2 years regardless of clinical response at 3 months. However, they suggested that patients treated with monotherapy Table 1. Average Change in Sharp Score at 2 Years by Response at 3 Months should be evaluated at 3-month intervals for possible change in treatment, particularly patients with high disease activity. Data have consistently demonstrated the superiority of combination therapy with MTX plus a TNF inhibitor versus monotherapy with either MTX or a biologic agent. The findings of this study corroborate those of previous clinical investigations: patients who received combination therapy early in the disease course had minimal radiographic progression at 2 years. However, the key message of this subanalysis is that in patients whose RA is treated with a single antirheumatic agent, whether biologic or nonbiologic, the early results predict long-term outcomes. Therefore, such patients should be monitored closely (every 3 months), and if they fail to achieve good clinical results, therapy should be changed. RFvV Evidence of Joint Damage Emerges Early in RA Anti-TNF agents inhibit radiographic progression irrespective of their effects on disease activity. How soon the inhibition of progression can be detected had not been determined. The issue was evaluated in a A+M A M n DAS28 Response * to < * to < < ACR Response < * to < to < * to < to A = adalimumab; M = methotrexate; DAS = Disease Activity Score * P<0.05 vs A and M; P<0.05 vs. M; P<0.05 vs. A Source: Keystone et al. 9 subanalysis of data from two large phase III clinical trials of certolizumab pegol as add-on therapy to MTX in patients with early RA. 11 Lack of an ACR20 response at both 12 and 14 weeks was defined as treatment failure. Patients who dropped out at that point had radiographic assessments. The primary objective of the subanalysis was to determine whether evidence of radiographic progression manifested as early as 16 weeks. The analysis included 483 patients who withdrew from the trials because they did not meet response criteria. The patients had similar DAS values at baseline, and they continued to have clinically active RA at 16 weeks (Table 2). Radiographic assessments showed that, despite the lack of adequate clinical responses and the clinical similarity of the groups, those patients who were treated with the TNF inhibitor plus MTX had significantly less change from baseline in mtss, joint erosion, and joint space narrowing than did the patients treated with MTX alone (P 0.05 for all comparisons) (Table 2). The authors concluded that their data supported previous observations that radiographic response to treatment does not correlate consistently with clinical responses. The finding that combination therapy retards radiographic progression as early as week 16 provides support for shorter intervals between radiographic assessments. Unmet Needs in RA: The Role of Anti-TNF Therapy 13

14 Table 2. Changes at 16 Weeks PBO + MTX Historically, rheumatologists have assumed that radiographic changes in response to therapy for RA occur more gradually than do clinical responses. As a result, the use of annual imaging studies has been standard. The observation that anti-tnf therapy often induces rapid improvement in patients with RA has raised questions about the possible need to perform imaging studies at shorter intervals, such as 6 months. Results of this study suggest an even shorter interval might be appropriate for patients where the use of MTX and/or a TNF inhibitor is considered. These interesting findings, which should be confirmed in additional prospective studies, raise the possibility that differences in structural damage may be evident much sooner than has been assumed by most clinicians and rheumatology scientists. RFvV Disability and Quality of Life The clinical and physical manifestations of RA have a strong correlation with functional status, work performance, and quality of life. RA-associated debilitation emerges early in the disease process and progresses over time. 12 Similarly, work performance suffers early and progressively in patients with RA. Ten years after diagnosis, fewer than 60% of patients with RA continue to work. 13 CZP 200 mg + MTX PBO + MTX CZP 400 mg + MTX n Baseline DAS, median DAS at week 16, median Baseline mtss, mean RAPID 1 RAPID 2 mtss Joint erosion JSN CZP = Certolizumab pegol; PBO = Placebo; MTX = methotrexate; DAS = Disease Activity Score; mtss = modified total Sharp Score; RAPID = RA Prevention of Structural Damage; 16 = mean change at 16 weeks; JSN = joint space narrowing. Source: van der Heijde et al. 11 Early, aggressive treatment of RA can favorably affect functional status, ability to work and perform routine household activities, and maintenance of quality of life. Increasingly, evaluation of newer therapies, particularly the TNF inhibitors, has incorporated assessment of quality-of-life issues. The assessments have shown that anti-tnf agents help patients maintain functional capacity and lifestyle 14 and can do so in a cost-effective manner. 15 Anti-TNF Therapy and Physical Function Ritchlin et al 16 examined the impact of golimumab, one of the newest members of the TNF inhibitor class, on the physical function, health-related quality of life, and productivity of patients with RA who were enrolled in a clinical trial of the drug. The study included 643 patients who were randomly assigned to monotherapy with MTX or intravenous golimumab or to the combination of the two agents. Assessments occurred at baseline and after 14, 24, and 48 weeks of therapy and included the Health Assessment Questionnaire (HAQ), the physical and mental components of the SF-36 health status survey, health care resource use, and self-reported productivity. At weeks 14 and 24, the proportion of patients with 0.25 improvement in the HAQ was significantly greater in patients treated with the combination of golimumab and MTX than with monotherapy (P 0.005). Results were similar at 48 weeks. The change from baseline in the physical component of the SF-36 was greater with combination therapy at week 14 through week 48. Self-reported productivity had improved significantly more with combination therapy at 24 weeks than with monotherapy, and the advantage persisted to 48 weeks. Health resource use, employability, and time lost from work did not differ among treatment groups at 24 weeks. Resource use and employability had improved by 48 weeks in all patients who received golimumab. These results add to the growing body of evidence using patient-related outcomes as a complement to the more standard clinical ones such as ACR and EULAR responses. In the case of this trial, the new TNF antagonist golimumab was shown to be effective in achieving meaningful and consistent improvements in such outcomes. The expectation with this and other anti- TNF agents is that such improvements will translate, in the longer term, into decreased direct and indirect costs associated with the rheumatic disease. The 48-week data in this trial suggest that this is, indeed, the case. RFvV MTX-Resistant Disease Genovese et al 17 analyzed the effect of subcutaneous golimumab as add-on therapy for patients who had achieved inadequate responses with MTX alone. The analysis comprised 444 patients randomized to two doses of golimumab plus MTX, MTX plus subcutaneous placebo, or golimumab alone. The primary outcomes were change in HAQ score, mental and physical components of the SF-36, and fatigue score at 24 weeks. Compared with MTX plus placebo, patients treated with golimumab-mtx combination therapy had significantly greater mean improvement in HAQ, physical and mental components of the SF-36, and fatigue (P<0.05 to P<0.0001). Additionally, patients who received 100 mg of golimumab plus placebo improved significantly more than did patients treated with MTX plus placebo with respect to the mental component of the SF-36 and fatigue score (P<0.05). 14 Unmet Needs in RA: The Role of Anti-TNF Therapy

15 As indicated in this study, patientrelated outcomes are increasingly seen as important pieces of information on the overall efficacy of antirheumatic therapy. In this trial, golimumab achieved significant improvements in this respect. RFvV Sustained Improvement Over Time Strand et al 18 evaluated the quality-of-life benefits of adding certolizumab pegol to MTX for patients with active RA. The analysis included 1,600 patients from two clinical trials. Patients in both trials were randomized to two different doses of certolizumab pegol plus MTX or to placebo plus MTX. Follow-up continued for 52 weeks in 982 patients and for 24 weeks in the remaining patients. In both trials, mean changes in HAQ scores were significantly greater in patients treated with certolizumab pegol than in those receiving placebo plus MTX, and the advantages were maintained through the entire follow-up period (P<0.001). In the trial with 52 weeks of follow-up, more than 80% of patients still on therapy at the end of the study had improvement in HAQ that exceeded the 0.22 definition of minimum clinically important difference (MCID). In the 24-week study, 80% to 90% of patients treated with certolizumab pegol exceeded the MCID threshold. In both studies, certolizumab pegoltreated patients exhibited significantly greater The use of patient-related outcomes to define more accurately the efficacies of anti-tnf agents has recently received much-needed attention. In this trial, the new TNF antagonist certolizumab pegol, which was recently approved in the United States and Europe was shown to achieve meaningful and highly signficant improvements in a variety of patient-related outcomes. These results, therefore, complement previously published more standard clinical data on this new agent. RFvV improvement in the physical and mental components of the SF-36 from week 12 until the end of follow-up (P<0.001 vs placebo). Additionally, the MCID threshold was exceeded from week 12 onward. REFERENCES 1. van der Heijde D, Landewé R, van Vollenhoven R, Fatenejad S, Klareskog L. Level of radiographic damage and radiographic progression are determinants of physical function: A longitudinal analysis of the TEMPO trial. Ann Rheum Dis. 2008; 67: Østergaard M, Ejbjerb B, Szkudlarek M. Imaging in early rheumatoid arthritis: Roles of magnetic resonance imaging, ultrasonography, conventional radiography, and computed tomography. Best Pract Res Clin Rheumatol. 2005;19: Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59: Emery P, McInnes IB, van Vollenhoven R, Kraan MC. Clinical identification and treatment of a rapidly progressing disease state in patients with rheumatoid arthritis. Rheumatology (Oxford). 2008;47: van der Bijl AE, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis. Arthritis Rheum. 2007;56: Soubrier M, Puéchal X, Sibilia J, et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD Trial. Rheumatology. 2009;48: Emery P, Fleischmann RM, Moreland LW, et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twentyfour-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. Arthritis Rheum. 2009;60: Kremer J, Ritchlin C, Mendelsohn A, et al. Golimumab, a new human anti-tnfa antibody, administered intravenously in patients with active rheumatoid arthritis: 24-week efficacy and safety results of a phase 3, randomized, double-blind, placebo-controlled study. Ann Rheum Dis. 2009;68(suppl): Abstract OP Keystone EC, Genovese M, Guérette B, Patra K, Lavie F. Can clinical response at 3 and 6 months predict radiographic progression for patients with rheumatoid arthritis? A subanalysis of PREMIER. Ann Rheum Dis. 2009;68(suppl): Abstract OP Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate vs methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Ann Rheum. 2006; 54: van der Heijde D, Weinblatt M, Landewé R, Goel N, Wells AF, Fleischmann RM. Early inhibition of progression of structural damage in certolizumab pegol-treated patients: 16-week efficacy results from RAPID. Ann Rheum Dis. 2008;67(suppl): Abstract OP Scott DL, Symmons DP, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid arthritis: Results after 20 years. Lancet. 1987;1: Young A, Norton S, Stafford S, et al. Which patients stop working because of RA? Results from an inception cohort with 10 yr follow up. Ann Rheum Dis. 2008;67(suppl): Abstract OP Emery P, Smolen J, Kavanaugh A, Richard L, Purcaru O. Combination therapy with certolizumab pegol plus methotrexate improves household productivity and daily activities in patients with active rheumatoid arthritis. Arthritis Rheum. 2008;58(suppl):Abstract Russell AS. Quality-of-life assessment in rheumatoid arthritis. Pharmacoeconomics. 2008;26: Ritchlin C, Kremer J, Buchanan J, et al. Golimumab, a new human anti-tnfa antibody, administered intravenously in patients with active rheumatoid arthritis: 48-week physical function, health-related quality of life and self-reported productivity results of the phase 3, GO-LIVE Study. Ann Rheum Dis.2009;68(suppl):Abstract THU Genovese MC, Keystone EC, Hsia EC, et al. Golimumab significantly improves physical function, health-related quality of life, and fatigue in patients with active rheumatoid arthritis despite methotrexate: Results from the GO-FORWARD Study. Ann Rheum Dis. 2009;68(suppl):Abstract FRI Strand V, Keininger D, Kavanaugh A. Certolizumab pegol (CZP) induces rapid and sustained clinically meaningful improvements in physical function and health-related quality of life (HRQOL) in patients with rheumatoid arthritis (RA): The RAPID 1 and 2 randomised clinical trials (RCTs). Ann Rheum Dis. 2008;67(suppl):Abstract FRI0141. Unmet Needs in RA: The Role of Anti-TNF Therapy 15

16 A SUPPLEMENT TO Rheumatology News CME POST-TEST ANSWER SHEET AND EVALUATION FORM Unmet Needs in RA: The Role of Anti-TNF Therapy Release Date of Activity: November 2009 Expiration Date of Activity for AMA PRA Category 1 Credit : October 31, 2010 Estimated Time to Complete This Activity: 2 hours Instructions Review the learning objectives for this activity and read the supplement carefully. Read each question and circle the correct answer. Retain a copy of your answers for your records. Complete and submit your answer sheet as directed online at You will receive your statement of credit immediately upon successful completion (correctly answering 70% of the questions). 1. The data reported in this educational activity support the concept that TNF inhibitors: A. Can be used sequentially B. Are ineffective when used in sequence C. Pose a significant risk of infection when used sequentially D. Are less effective than methotrexate 2. Adding a TNF inhibitor to MTX: A. Does not improve RA disease compared with a TNF inhibitor alone B. Causes unacceptable toxicity C. Has not been evaluated in a clinical trial D. None of the above 3. The risk of MI in patients with RA is: A. No greater than in the general population B. Increased within the first year after diagnosis of RA C. Increased within 5 years after diagnosis of RA D. Undetermined 4. What is presumed to be the common link between RA and CVD? A. Fatty diet B. Abnormal intracellular calcium flux C. Inadequate physical activity D. Systemic inflammation 5. Data from the CORRONA Registry suggest that effective treatment of RA: A. May reduce cardiovascular risk B. Helps control blood pressure and cholesterol levels C. Has no effect on cardiovascular risk D. Is of greater importance than controlling conventional cardiovascular risk factors 6. TNF, interleukin 1, and dendritic cells are examples of: A. Targets of the newest agents available for treatment of RA B. Anti-inflammatory proteins activated by RA therapy C. Factors that have an uncertain role in RA D. Factors involved in the inflammatory cascade associated with RA 7. Current clinical guidelines recommend TNF inhibitors: A. As first-line therapy for RA B. As an option after an initial trial of methotrexate C. Only as salvage therapy for RA D. For use as first-line therapy in combination with methotrexate 8. In a randomized clinical trial comparing all of the currently available TNF inhibitors, which agent demonstrated superiority over all the others? A. Infliximab C. Golimumab B. Etanercept D. No such trial has been conducted 9. According to data presented in this educational activity, how soon can radiographic changes in patients with RA be observed? A. 1 year C. 16 weeks B. 6 months D. 4 weeks 10. The durability of clinical remission in RA is significantly influenced by: A. The type of therapy used B. The time required to achieve remission C. How soon methotrexate therapy begins D. Clinical remission is a theoretical concept that has not been demonstrated Please print Name: Specialty: Degree: MD DO PharmD RPh NP RN BS PA Other Affiliation: Address: City: State: ZIP: Telephone: Fax: Signature: (All information is confidential.) CME Credit Verification I verify that I have spent hour(s)/ minutes of actual time working on this CME activity. No more than 2.0 CME credit(s) will be issued for this activity. PRE-TEST ASSESSMENT: Please rate your current knowledge of rheumatoid arthritis on a scale of 1 to 4, with 1 being the lowest and 4 the highest POST-TEST ASSESSMENT: Please rate your current knowledge of rheumatoid arthritis on a scale of 1 to 4, with 1 being the lowest and 4 the highest COURSE EVALUATION: Please evaluate the effectiveness of this activity by circling your choice on a scale of 1 to 4, with 1 being the lowest and 4 the highest Learning Objectives Recognize the potential benefits of early diagnosis and treatment of RA Assess principles of aggressive therapy Describe relationships between RA and cardiovascular disease Appreciate the impact of RA on patient productivity and quality of life and the effects of therapy on those outcomes How do you rate the overall quality of this activity? How do you rate the educational content of this activity? After participation in this activity, have you decided to change one or more aspects in the treatment of your patients? Yes No If yes, what change(s) will you make? If no, why not? 4. Was the presented information fair, objective, balanced, and free of bias in the discussion of any commercial product or service? Yes No If no, please comment: 5. Suggested topics for future activities: 6. Suggested authors for future activities: 7. Would you be willing to participate in postactivity follow-up surveys? Yes No 8. Would you be willing to participate in a phone, , or in-person discussion exploring ways to improve our CME activities? Yes No CEC thanks you for your participation in this CME activity. All information provided improves the scope and purpose of our programs and your patients care. Copyright 2009 Elsevier Inc.