Rheumatology News Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects

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1 A SUPPLEMENT TO Rheumatology News Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects HIGHLIGHTS OF A ROUNDTABLE FACULTY Arthur L. Weaver, MD, MS, FACP, MACR Chairperson/Editor Clinical Professor of Medicine, Emeritus Department of Medicine, Section of Rheumatology University of Nebraska Medical Center Omaha, Nebraska Mark C. Genovese, MD Associate Professor of Medicine Stanford University School of Medicine Co-Chief, Division of Immunology and Rheumatology Stanford Hospital Palo Alto, California Joel M. Kremer, MD Pfaff Family Professor of Medicine Albany Medical College Director of Research The Center for Rheumatology Albany, New York Eric M. Ruderman, MD Associate Professor of Medicine Division of Rheumatology Northwestern University Feinberg School of Medicine Attending Staff Physician Department of Medicine Northwestern Memorial Hospital Chicago, Illinois Immune Targets in Rheumatoid Arthritis 3 Conventional and Novel Therapies in Rheumatoid Arthritis 5 Defining Rheumatoid Arthritis Treatment Success or Failure 7 Strategies for Selecting Treatment in Rheumatoid Arthritis 8 Case Presentation: Patient With Incomplete Response to TNF Inhibitor Therapy 10 CME Posttest 12 TARGET AUDIENCE: The target audience for this educational activity includes RA community-based treatment teams: rheumatologists and rheumatology nurses. ACCREDITATION STATEMENT: This CME activity was planned and produced in accordance with the ACCME Essential Areas and Policies. DIME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. DESIGNATION STATEMENT: DIME designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. TERM OF OFFERING: September 2008 September 30, Sponsored by This activity is funded through an educational grant from Genentech/Biogen Idec.

2 Rheumatology News Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects This supplement is based on presentations at the Rheumatoid Arthritis Roundtable Meeting Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects, held on April 18, 2008, at the Westin O Hare in Rosemont, Illinois. In accordance with DIME policies regarding financial and off-label disclosure, the learner is advised that this CME activity may contain references to off-label or unapproved uses of drugs or devices. The use of these agents outside currently approved labeling is considered experimental, and participants are advised to consult prescribing information for these products. This CME activity was planned and produced in accordance with ACCME Essential Areas and Policies. This supplement was produced by the medical education department of Elsevier/ International Medical News Group. 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. The materials included in this activity have undergone peer review by the chairperson(s) or editor(s). All materials are included with the permission of the authors. All inquiries should be directed to: DIME 222 Merchandise Mart Plaza Suite Chicago, IL [email protected] This activity may be accessed on Copyright 2008 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. ACTIVITY PURPOSE: The purpose of this activity is to educate health care professionals on the latest developments in the treatment of patients with rheumatoid arthritis (RA), thereby improving clinical outcomes and patient quality of life. STATEMENT OF NEED: Although the pathogenesis of autoimmune disorders is complex, until recently, the role of T cells has dominated research in autoimmune diseases such as RA. The wellcharacterized role of T cells in the pathogenesis of RA has resulted in the approval of several therapies for RA, such as tumor necrosis factor- and interleukin-1 (IL-1) inhibitors. Despite the success of these agents, a significant minority of patients about one third remain unresponsive to biologic therapy. The role of B cells in RA is not as well defined as that of T cells, but our understanding of their role has been remarkably expanded in the past few years. A B-cell depleting antibody, rituximab, is available for the treatment of RA and other B-cell targets that have been identified. The unprecedented number of randomized clinical trials (RCTs) in rheumatology in the past decade poses a challenge in applying the mass of clinical data to practical clinical utility in the community. It is useful from time to time for those involved in clinical research to provide a high-level review of the significance of clinical research over the past few years, and to identify clinical questions that need to be answered by RCTs. LEARNING OBJECTIVES: On completion of this activity, participants should be able to: Compare and contrast targeted therapies with regard to their adverse effects and clinical outcomes in patients with RA Evaluate clinical measures for defining response in patients receiving treatment for RA Recognize the broad implications of clinical studies over the past 10 years on clinical practice for patients with RA. DISCLOSURES: DIME requires that all persons who were in a position to control or influence the content of this CME activity disclose all relevant financial relationships with any commercial interest. This information is used to: (1) determine whether a conflict exists, (2) resolve the conflict by initiating a content validation process, and (3) advise learners of this information. Arthur L. Weaver, MD, MS, FACP, MACR: Consulting Agreements: Abbott Laboratories; Alpharma Inc.; Amgen Inc.; Astellas Pharma US, Inc.; Aventis Pharmaceuticals Inc.; Azano Pharmaceuticals Inc.; Biogen Idec; Biovail Corporation; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Centocor, Inc.; Cypress Bioscience Inc.; Fujisawa Healthcare, Inc.; Genentech, Inc.; Helsinn Birex Therapeutics Ltd; Horizon Therapeutics; Human Genome Sciences, Inc.; Lilly ICOS; MEDecision; Merck & Co., Inc.; Merckel; Mylan; Novartis Pharmaceuticals Corp; Ortho-McNeil Pharmaceutical, Inc.; Pfizer Inc; Primus Pharmaceuticals, Inc.; Prometheus Laboratories Inc.; Proprius Pharmaceuticals; Savient Pharmaceuticals, Inc.; Schwarz Pharma AG; Takeda Pharmaceutical Company Limited; TAP Pharmaceutical Products Inc.; TheraQuest Biosciences; Wyeth Pharmaceuticals. Financial Interests/Stock Ownership: Azano Pharmaceuticals Inc.; MGI PHARMA, INC. Speakers Bureau/Honorarium Agreements: Abbott Laboratories; Alpharma Inc.; Amgen Inc.; Biogen Idec; Genentech, Inc.; Pfizer Inc; Savient Pharmaceuticals, Inc.; TAP Pharmaceutical Products Inc.; UCB; Wyeth Pharmaceuticals. Mark C. Genovese, MD: Sources of Funding for Research: Abbott Laboratories; Biogen Idec; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; EMD Serono, Inc.; Genentech, Inc.; Pfizer Inc; Wyeth Pharmaceuticals. Consulting Agreements: Abbott Laboratories; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Biogen Idec; EMD Serono, Inc.; Genentech, Inc.; Pfizer Inc; Wyeth Pharmaceuticals. Speakers Bureau/Honorarium Agreements: Abbott Laboratories; Amgen Inc.; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Genentech, Inc. Joel M. Kremer, MD: Sources of Funding for Research: Abbott Laboratories; Amgen Inc.; Biogen Idec; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Centocor, Inc.; Genentech, Inc.; Human Genome Sciences, Inc.; Roche. Consulting Agreements: Abbott Laboratories; Amgen Inc.; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Centocor, Inc.; Genentech, Inc.; Roche. Speakers Bureau/Honorarium Agreements: Amgen Inc.; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Eric M. Ruderman, MD: Sources of Funding for Research: Abbott Laboratories; Amgen Inc.; Biogen Idec; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Genentech, Inc.; Pfizer Inc. Consulting Agreements: Abbott Laboratories; Amgen Inc.; Biogen Idec; Bristol-Myers Squibb/ Sanofi Pharmaceuticals Partnership; Genentech, Inc.; Wyeth Pharmaceuticals. Denise M. Erkkila, RPh, Editor: Nothing to disclose. Natasha A. Mitchner, PhD, Editor: Financial Interests/Stock Ownership: Pfizer Inc.

3 INTRODUCTION Arthur L. Weaver, MD, MS, FACP, MACR The introduction of early aggressive combination therapy with traditional disease-modifying antirheumatic drugs (DMARDs) and/or biologic DMARDs has significantly altered our treatment approaches for rheumatoid arthritis (RA). The goals of therapy have evolved from merely providing symptomatic relief to preventing long-term joint damage and disability and minimizing the impact of systemic manifestations and comorbidities. Recognition of the role of B cells and identification of additional T-cell related targets in the pathophysiology of RA have resulted in the availability of biologic agents with varying mechanisms of action that are safe and effective in patients with an inadequate response to conventional therapies or tumor necrosis factor inhibitors. Novel immune pathways, including T-cell, B-cell, and cytokine targets, are also under investigation for use in RA, and preliminary data support their efficacy. Although recent clinical trial data provide guidance on the importance of intensive management and the efficacy and safety of switching biologic agents, additional data are needed. It is expected that data from patient registries will increasingly be available to guide clinical decisions. Furthermore, a number of clinical assessment tools and imaging techniques are available to monitor disease activity and guide treatment decisions, yet validation of these tools is needed to determine appropriate techniques and optimal intervals of use. It is important for clinicians to remain abreast of clinical trial data and emerging therapies, as it is anticipated that the treatment of RA will continue to evolve, with improved patient outcomes. IMMUNE TARGETS IN RHEUMATOID ARTHRITIS Mark C. Genovese, MD A n integrated immune response of cytokine signaling pathways and cell-cell interactions underlies the pathophysiology of rheumatoid arthritis (RA). Although the initial antigen is unknown, antigen is presented in the context of a major histocompatability complex on an antigen-presenting cell, such as a dendritic, B, T, or other innate immune cell. Ultimately, the antigen is recognized by a T cell via activation of the T-cell receptor. A redundant network of pro- and anti-inflammatory cytokines becomes involved and B cells are engaged, followed by plasma cell and autoantibody formation (Figure 1). 1 These processes culminate in production of immune complexes and complement fixation. Activation of the innate immune system, including macrophages and monocytes, leads to the local and systemic inflammation characteristic of RA. Interactions with chondrocytes, osteoclasts, and fibroblast-like synoviocytes lead to the production of metalloproteinases and other effector molecules which ultimately erode bone and cartilage. In contrast to the normal synovium, synovial tissue from patients with RA has thick hypertrophic layers of fibroblast-like synoviocytes, angiogenic development, cellular infiltrates, and inflammatory markers. Increased understanding of the cytokine pathways and cell lineages that damage the synovium in RA has elucidated a number of immune targets with potential for therapeutic intervention in RA. This paper will review T-cell, B-cell, cytokine, bone remodeling, and intracellular enzyme targets, and their status in the treatment of RA. T-Cell Targets Subsequent to antigen presentation to the T cell receptor, a secondary signalling process dictates whether the T cell undergoes activation, anergy, or apoptosis. Engagement between costimulatory molecules CD80/CD86 on dendritic cells and CD28 on the T cell results in T-cell activation. Attenuation of the activated T cell is mediated by cytotoxic T- Figure 1. Targeted Approaches in RA Activates Inflammation Joint Damage Activates Activates RF Autoantibodies B=B cell; DC=dendritic cell; FLS=fibroblast-like synoviocyte; M =macrophage; RF=rheumatoid factor; T=T cell. Adapted from Choy EH, Panayi GS. N Engl J Med. 2001; 344: lymphocyte associated antigen-4 (CTLA4), which is expressed on T cells 24 to 72 hours after activation. Abatacept, a fusion protein of the CTLA4 extracellular domain and the Fc region of an immunoglobulin, targets CD28 mediated T-cell activation and is approved for treatment of RA. A number of costimulatory pathways with positive and negative effects on T-cell activity, such as inducible costimulator (ICOS) and programmed death 1 (PD-1), are potential targets for therapeutic intervention in RA and other autoimmune diseases. 2 B-Cell Targets The importance of B-cell activation, proliferation, and development of plasma and autoreactive B cells has been increasingly recognized and studied as a target in autoimmune diseases. Rituximab, a chimeric monoclonal antibody (mab), depletes B cells via binding to cell surface CD20 and is approved for use in RA. 3 A number of factors involved in B-cell lineage and activation are under investigation as immune targets for inhibiting B-cell function. These include the stimulatory factors facilitating transition from immature B cells to transitional and mature B cells, and ultimately, an antibodyproducing plasma cell or an autoreactive B cell producing autoantibodies. For example, B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) bind to one of three cell-surface receptors (TACI, BCMA, or BLyS-R3) to promote B-cell survival and maturation. Belimumab, an mab against BLyS, and atacicept, a fusion protein that inhibits both BLyS and APRIL, have Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects 3

4 been studied in RA and autoimmune diseases. A number of other BLyS and APRIL inhibitors, and fusion proteins against the cellsurface receptors, are also in development. 4 Anti-Cytokine Targets It is well established that blockade of the tumor necrosis factor (TNF) and interleukin (IL) 1 cytokines improves outcomes in RA. A number of novel cytokine targets are under evaluation in RA. For example, IL-6 plays a role in RA and other inflammatory diseases via T-cell activation and B-cell proliferation and activation. Tocilizumab, a humanized anti-il-6 receptor mab that binds the cell surface and soluble IL-6 receptors, is under investigation. 5 Another proinflammatory cytokine target, IL-17, has effects on osteoclastogenesis, chondrocytes, and synoviocytes, suggesting the potential for targeting inflammation and joint destruction. An mab against the p40 subunit of the IL-12/IL-23 family of heterodimeric cytokines is effective in psoriasis and may be a potential target for RA. The lymphotoxin beta system, a member of the TNF superfamily, has also been investigated as a means of down-regulating inflammation in RA. A heterotrimer of two lymphotoxin beta subunits and lymphotoxin alpha binds to a cell-surface receptor to control lymphoid microenvironments and leukocyte trafficking. Bone Remodeling Targets Increased advances in the ability to interfere with osteoclastogenesis and bone destruction elucidated novel bone remodeling targets such as RANK ligand, a receptor activator of the NF kappa B signalling system. 6 In addition to their effects on T cells, inflammatory cytokines such as TNF, IL-1, and IL-6 drive osteoblasts/stromal cells to activate osteoclast precursors via release of RANK ligand. Denosumab, an mab against RANK ligand, is being studied for its ability to decrease the risk of osteoporosis and bone erosion associated with RA. Intracellular Enzyme Inhibition Intracellular targets also have significant potential as immune therapeutic approaches in RA. For example, the p38 mitogen activated protein (MAP) kinase pathway is inducibly expressed after tissue injury (ischemia or oxidation), resulting in release of a number of inflammatory mediators, tissue inflammation, and disease progression. 7 Janus kinase (JAK), a tyrosine kinase responsible for intracellular signalling in response to inflammatory stimuli, is involved in many cytokine signalling pathways. 8 A JAK3 inhibitor with immunosuppressive properties is under investigation for a number of inflammatory diseases, including RA. Data to date also support blockade of another tyrosine kinase pathway, spleen tyrosine kinase (Syk), to inhibit degranulation, cytokine production, and other intracellular enzymes. Summary It is unknown which of the novel targets will result in pharmacotherapies that are efficacious and safe. Furthermore, it is unknown whether combination therapies with existing and novel agents will have synergistic or additive effects without toxicity. Accumulating data indicate that genetic and proteomic profiling may eventually be used to predict response and potential safety issues, thereby guiding treatment decisions. Regardless of the target, novel therapies must have improved efficacy, safety, tolerability, convenience, cost, and perhaps long-term safety compared with existing agents in order to gain acceptance in the treatment of RA. Discussion Question Is it feasible to target more than one immune pathway in clinical practice? Current clinical practice successfully utilizes combination therapy with conventional disease-modifying antirheumatic drugs (DMARDs), such as sulfasalazine or methotrexate, or a combination of a conventional DMARD and a biologic; however, therapy with multiple biologics has not been successful because of toxicities. Increased infection rates have been observed with combination therapy of TNF and IL-1 inhibitors or a TNF inhibitor and abatacept. Dual or triple blockade of immune targets may be necessary to improve patient outcomes and increase remission rates compared with current monotherapies. Unfortunately, it is currently not possible to predict which new therapies will have additive or synergistic properties, which will be efficacious yet safe, or which patients will elicit a response without toxicity. It is hypothesized that advances in the use of proteomic and genomic signatures and other biomarkers will guide treatment decisions with current and novel immune targets. References 1. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344: Stuart RW, Racke MK. Targeting T cell costimulation in autoimmune disease. Expert Opin Ther Targets. 2002;6: Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: Prospects for anti-b cell therapy. Arthritis Rheum. 2003;48: Dorner T, Burmester GR. New approaches of B-celldirected therapy: Beyond rituximab. Curr Opin Rheumatol. 2008;20: Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2: Romas E, Gillespie MT. Inflammation-induced bone loss: Can it be prevented? Rheum Dis Clin North Am. 2006;32: Thalhamer T, McGrath MA, Harnett MM. MAPKs and their relevance to arthritis and inflammation. Rheumatology (Oxford). 2008;47: Borie DC, Si MS, Morris RE, Reitz BA, Changelian PS. JAK3 inhibition as a new concept for immune suppression. Curr Opin Investig Drugs. 2003;4: Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects

5 CONVENTIONAL AND NOVEL THERAPIES IN RHEUMATOID ARTHRITIS Joel M. Kremer, MD T he ability to improve the course of rheumatoid arthritis (RA) by early use of disease-modifying anti-rheumatic drugs (DMARDs) revolutionized RA treatment. Conventional and novel therapies are available to significantly lessen the impact of RA. Intensive Therapy The TICORA study sought to determine the effect of intensive treatment, meaning sustained and tight control, compared to the routine care of RA. An algorithm defined response and predetermined steps for aggressive therapy. This approach significantly improved the numbers of ACR20, 50, or 70 responders. 1 Objective measures of response and predefined steps in disease management facilitated clinical judgment in treating RA. Newer Biologics Patients with poor response to methotrexate or tumor necrosis factor (TNF) inhibitors show response to abatacept or rituximab. The overall rates of serious infectious events (SIEs) and malignancies appear to be similar among the biologic DMARDs. All of the biologic DMARDs are associated with a risk of infection because of their immunosuppressive activity. ABATACEPT The AIM study (methotrexate failures) and the ATTAIN trial (TNF inhibitor failures) each showed that patients will stay on an abatacept regimen maintaining their initial level of ACR response after 3 years of follow-up. 2 In comparative safety analyses, patients in an abatacept clinical trial had a similar incident rate of SIEs or malignancies compared to patients in various RA registries. 3,4 Proximity of prior TNF inhibitor use did not affect the rate of SIEs, adverse events, infection, or malignancies in patients in abatacept clinical trials. 5 RITUXIMAB Patients who failed TNF inhibitors sustained their initial level of response to rituximab over a 6-month treatment course; one fourth were ACR70 responders at week An epidemiologic study of TNF inhibitor failures from a patient registry 7 showed better response to rituximab than to an alternative TNF inhibitor by both DAS28 and components of the DAS28 tender joints, swollen joints, and erythrocyte sedimentation rate. In these patients, B-cell depletion was an effective means of reducing RA disease activity following poor response to a TNF inhibitor. The rate at which SIEs occurred per 100 patient-years remained fairly constant in patients receiving up to four courses of rituximab. 8 In another study, the rate of SIEs per 100 patient-years increased as immunoglobulin levels decreased, specifically, IgM and IgG. 9 More study is needed to explore whether decreased immunoglobulin is an indicator for infection risk. Onset of Action TNF inhibitors appear to have the shortest onset of action; some patients respond during the first month of therapy. 10,11 Lack of response after 3 months indicates potential nonresponse to that TNF inhibitor and a switch in therapy should be considered. 12,13 Adalimumab and rituximab reportedly have a longer time to onset of action; 2 3 months may pass before a response is seen. 14,15 Alternative therapy may be advised if there is no improvement after 4 months with abatacept or 3 4 months with rituximab. 13 Over time the biologics appear to have a similar proportion of ACR20 responders. Even so, response varies patients should be assessed using objective measures of response so that there is a clear understanding of response over time. Emerging Therapies Tocilizumab is an IL-6 receptor antibody that disrupts the inflammatory response mediated by IL-6. A recent phase III study showed that tocilizumab and methotrexate resulted in ACR20, 50, and 70 responses at 24 weeks. The most common serious adverse event was infection; elevated serum lipids were seen in some patients. 16 Atacicept is a fusion protein that neutralizes two regulators of B-cell function. A phase Ib study showed that atacicept reduced RA disease activity and was well tolerated. Table 1. US Patient Registries Immunoglobulin levels, particularly IgM, decreased with atacicept treatment. 17 Certolizumab is a pegylated TNF inhibitor with sustained ACR responses when combined with methotrexate. At 52 weeks, 40% and about 21% of patients maintained an ACR50 and ACR70, respectively. 18 CP is an oral Janus kinase (JAK) 3 inhibitor that blocks cytokine signaling. In a 6-week dosefinding phase II study of patients who stopped all DMARDs, 81% of patients were ACR20 responders. 19 Patient Registries Patient registries provide insight into RA therapies outside of clinical trials by capturing data on real world patients. Clinical trial patients usually have more severe RA, and the profile of European patients appears to differ from that of patients in the US. Of the four main US registries (Table 1), three use patient-derived data and two retrieve data from rheumatologists. These registries will show how RA therapies are used in the clinic, and they may connect efficacy and toxicity data to biomarkers of response and genomic profiles Summary Both comparative trials and patient registry data provide insight about the relative outcomes of various RA therapies. This may inform discussions with the patient and also set up reasonable expectations regarding therapy. Even with the success of biologic therapies, new therapies are still needed for the many patients who fail to respond to current therapy. Registry Sponsor Patients Physician-Derived Patient-Derived Frequency (No.) Data Data of Collection Administrative 20 NIH, Arthritis 3500 No No Foundation 15,000 National Pharma 19,562 No HAQ, Every 6 mos Databank 20 demographics CORRONA 20 Pharma 17,000 ACR, DAS28, dexa, mhaq Every 3 mos radiographs, extra-articular manifestations, comorbidities, swollen and tender joint count, CDAI, ESR, CRP, CCP, RF, RNA, DNA for genomic fingerprint demographics, ROS BRASS 21,22 Millennium 1000 ACR, DAS, dexa, radiographs, MDHAQ Every 6 mos Pharmaceuticals extra-articular manifestations, demographics, comorbidities, swollen and RADAI, current tender joint count, CDAI, ESR, meds CRP, CCP, RF, RNA, DNA for genomic fingerprint ACR=American College of Rheumatology; BRASS=The Brigham and Women s Hospital Rheumatoid Arthritis Sequential Study; CCP=anti-cyclic citrullinated peptide; CDAI=Clinical Disease Activity Index; CORRONA=Consortium of Rheumatology Researchers of North America; CRP=C-reactive protein; DAS=Disease Activity Score; ESR=erythrocyte sedimentation rate; HAQ=Health Assessment Questionnaire; MDHAQ=Multidimensional Health Assessment Questionnaire; mhaq=modified Health Assessment Questionnaire; NIH=National Institutes of Health; RADAI=Rheumatoid Arthritis Disease Activity Index; RF=rheumatoid factor; ROS=review of systems. Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects 5

6 Discussion Question Will the US registries and registries from Canada and Europe track efficacy and safety of RA drugs? These registries could provide this information, but they are challenged by the lack of both baseline and consistent follow-up data provided by rheumatology practices. Barriers include time constraints for busy rheumatologists who may not always use metrics for evaluating RA disease activity during patient visits. While the European system requires objective documentation of patient response in order for patients to obtain RA medications, no similar system exists in the United States. Rheumatologists are encouraged to participate in a patient registry so that US-specific cost-effectiveness data will be available to guide decision making regarding the expanding choices in RA therapy. References 1. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial. Lancet. 2004;364: Kremer J, Westhovens R, Luggen M, et al. Long-term efficacy and safety of abatacept through 3 years of treatment in rheumatoid arthritis patients in the AIM and ATTAIN trials. Presented at: 71st Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals; November 8, 2007; Boston, MA. 3. Simon TA, Smitten A, Meng M, et al. Serious infections in the rheumatoid arthritis abatacept clinical development program: An updated epidemiological assessment. Ann Rheum Dis. 2007;66: Simon TA, Smitten A, Meng M, et al. Malignancies in the rheumatoid arthritis (RA) abatacept clinical development program: An updated epidemiological assessment. Ann Rheum Dis. 2007;66: Schiff M, Pritchard C, Teng J, Bahrt K, Genovese M. The safety of abatacept in patients with active rheumatoid arthritis and an inadequate response to anti-tnf therapy: Results from the ARRIVE trial. Ann Rheum Dis. 2007;66: Keystone EC, Fleischmann RM, Emery P, et al. Repeated treatment courses of rituximab produce sustained efficacy in patients with rheumatoid arthritis and an inadequate response or intolerance to one or more TNF inhibitors. Presented at: 71st Annual Scientific Meeting of the American College of Rheumatology/ Association of Rheumatology Health Professionals; November 10, 2007; Boston, MA. 7. Finckh A, Ciurea A, Brulhart L, et al. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum. 2007;56: van Vollenhoven RF, Emery P, Bingham COI, et al. Extended follow-up of the long-term safety of rituximab in rheumatoid arthritis. Presented at: 71st Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals; November 8, 2007; Boston, MA. 9. Genovese M, Emery P, Ruderman E, et al. Immunoglobulin levels and infection rates in patients with rheumatoid arthritis (RA) treated with repeated courses of rituximab. Presented at: 71st Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals; November 8, 2007; Boston, MA. 10. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: A randomized, controlled trial. Ann Intern Med. 1999;130: Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50: Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002;46: Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, Ann Rheum Dis. 2006;65: Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med. 2006;144: Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54: Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): A double-blind, placebo-controlled, randomised trial. Lancet. 2008;371: Tak PP, Thurlings RM, Rossier C, et al. Atacicept in patients with rheumatoid arthritis: Results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study. Arthritis Rheum. 2008;58: Keystone E, Mason D, Combe B. The anti-tnf certolizumab pegol in combination with methotrexate is significantly more effective than methotrexate alone in the treatment of patients with active rheumatoid arthritis: 1-year results from the RAPID 1 study. Presented at: 71st Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals; November 8, 2007; Boston, MA. 19. Kremer JM, Bloom BJ, Breedveld FC, et al. A randomized, double-blind, placebo-controlled trial of 3 dose levels of CP-690,550 versus placebo in the treatment of active rheumatoid arthritis. Presented at: 70th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals; November 10, 2006; Washington, DC. 20. Kremer JM, Gibofsky A, Greenberg JD. The role of drug and disease registries in rheumatic disease epidemiology. Curr Opin Rheumatol. 2008;20: BRASS: a groundbreaking longitudinal study of rheumatoid arthritis. Available at: hamandwomens.org/rheumatology/medical/rheumup date/brass.aspx. Accessed May 28, Karlson EW, Chibnik LB, Cui J, et al. Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study. Ann Rheum Dis. 2008;67: Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects

7 DEFINING RHEUMATOID ARTHRITIS TREATMENT SUCCESS OR FAILURE Arthur L. Weaver, MD, MS, FACP, MACR E arly, aggressive treatment of rheumatoid arthritis (RA) with combination disease-modifying antirheumatic drugs (DMARDs) and biologic therapy dramatically improves patient outcomes, with up to 40% of patients achieving remission in clinical trials. 1 However, observations in standard clinical practice differ from clinical trial results. Registry data indicate that clinical response and remission rates with traditional DMARDs and biologic therapy in clinical practice are attenuated compared with clinical trials. Furthermore, registry data reveal residual disease activity despite treatment and also that approximately 30% of patients discontinue DMARDs or biologic therapy after 1 year, presumably because of lack of response or toxicity. 2,3 Primary inadequate response, defined as a poor or lack of response to an agent, is relatively rare. Secondary inadequate response in which patients demonstrate an early response, but subsequently experience a lack of response, is more common. It is important to note that response as defined by clinical measures may not correlate with other methods of assessment. A number of clinical measurement tools, imaging techniques, and biomarkers are available for use in the evaluation of disease activity and treatment response in patients with RA (Table 2). Clinical Measurement Tools The American College of Rheumatology (ACR) criteria for assessing treatment response were developed for clinical trials and are not appropriate for standard clinical care, although they are used by some practitioners. A number of clinical assessment tools have been designed to classify disease activity and define remission, visit to visit, in patients with RA. The Disease Activity Score (DAS), a computerized measure using patient global scores, tender and swollen joint counts, and either erythrocyte sedimentation rate or C-reactive protein values, is widely used in clinical practice, particularly in the European Union, but may not be feasible in some situations as it requires a laboratory value. The Simplified Disease Activity Index requires a laboratory value, but is an additive measure, making it easier to use in clinical practice. The Clinical Disease Activity Index, Global Arthritis Score, Easy Rheumatoid Arthritis Measure, and Routine Assessment of Patient Index Data (RAPID) assessments encompass a variety of patient and physician observations, and do not require a laboratory value. These clinical assessment tools have been validated against the DAS in a significant number of patients. For example, RAPID3, an index of patient-reported outcomes, distinguished placebo from abatacept at levels comparable to DAS28 in two randomized clinical trials. 4 Thresholds have also been established for classifying patients as being in remission or having high, moderate, or low disease activity. Imaging Techniques Radiographic joint damage is positively correlated with disease activity and disability. 5 As such, radiographic imaging continues to be the standard for assessment of joint damage in RA. Ultrasound and power Doppler are rarely used in the United States despite their ability to detect early erosions, increased blood flow, and synovitis across multiple joints. Results are dependent on the experience and skill of the operator, and these technologies are untested in controlled trials. Traditional and three-dimensional magnetic resonance imaging (MRI) can be used to evaluate bone marrow edema, bone erosions, and synovitis. Although a scoring system and atlas have been developed, additional validation is needed to establish MRI as a measure of outcomes in RA. Cost is a concern with MRI, and there are a number of different types of machines available, complicating comparisons. Nonetheless, patients with continued low-grade synovitis despite normal radiographs may benefit from the use of MRI. Accumulating data indicate that radiologic assessment may not correlate with clinical measures of response. Signs of joint damage, including the appearance of new erosions, have been observed in patients with prolonged DAS defined clinical remission. 6 Similarly, patients with DMARD induced clinical remission exhibited synovitis and bone marrow edema with MRI or ultrasound evaluation. 7 These data underscore the importance of radiographic assessments in RA patients. Biomarkers A number of biomarkers for inflammation, joint and cartilage damage, and bone resorption and formation have been examined as predictors of disease activity and joint damage. For example, elevated serum levels of MMP-3 and IL-6 appear to be significantly associated with disease activity. 8 Although Table 2. Tools for Assessing Outcomes in RA Clinical Measurement Tools Imaging Techniques Biomarkers anti-ccp antibodies do not have clinical utility as a marker of disease activity, elevated levels are a strong predictor of incident RA and radiographic progression. 9,10 Interestingly, levels of IL-6 and TNF receptor may be elevated up to 12 years prior to a diagnosis of RA. 9 Joint and cartilage breakdown products, such as hyaluronic acid and cartilage oligomeric protein, and bone biochemical markers such as RANK ligand OPG ratio and bone morphologic proteins, have been investigated as markers, but are not currently available for standard clinical use. It is expected that advances in pharmacogenomics will significantly alter treatment approaches to RA. Genetic diagnostics may be used for risk profile determination, disease prediction, earlier diagnosis, and treatment selection, based on response and toxicity predictions. For instance, data on azathioprine toxicity and emerging data on methotrexate nonresponse and toxicity can be used to guide treatment. Summary Therapeutic decisions must be guided by clinical measures and imaging data to improve short- and long-term patient outcomes in RA. Although patients are increasingly educated about therapeutic interventions, education on the significance of radiographic damage and long-term outcomes is necessary. The most appropriate assessment tool and interval for screening in standard clinical practice must be identified in order to ensure that clinical and radiographic measures are met in patients with RA. Discussion Question What are the strategies for implementing clinical and radiographic assessment in community-based rheumatology practices? Clinical trial data underscore the importance of assessing radiographic progression and clinical measures in improving short- and long-term outcomes in patients with RA. DAS Radiography Inflammatory markers Continued on page 9 SDAI Ultrasound Joint and cartilage breakdown products CDAI Power Doppler Biochemical markers of bone resorption and formation GAS MRI (traditional and three-dimensional) ERAM RAPID CDAI=Clinical Disease Activity Index; DAS=Disease Activity Score; ERAM=Easy Rheumatoid Arthritis Measure; GAS=Global Arthritis Score; RAPID=Routine Assessment of Patient Index Data; SDAI=Simplified Disease Activity Index. Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects 7

8 STRATEGIES FOR SELECTING TREATMENT IN RHEUMATOID ARTHRITIS Eric M. Ruderman, MD W e now understand that disease-modifying therapy is a central part of the rheumatoid arthritis (RA) treatment plan and that active disease signifies a patient with inadequately treated disease. Goals of therapy include short-term symptomatic relief, long-term prevention of joint damage and disability, and minimizing the impact of systemic manifestations of RA. Therapeutic goals may also change according to disease duration and progressive disability. 1 Selecting Treatment in Early RA The first challenges are to accurately diagnose RA early, define disease activity upfront, and, if possible, also define the prognosis. Addressing comorbid conditions early is also important, as these may impact management and treatment choices for a patient. Rheumatologists should consider both treatment data and patient preference when choosing first-line therapy. Patients are inevitably concerned about treatment adverse effects, questioning the type and severity that are associated with RA therapy. While uncomplicated oral regimens are easiest to use, patients are also willing to consider parenteral therapies and more complex combination regimens. Patients have become more knowledgeable about RA therapies, but a trusting relationship with the physician remains a key factor in acceptance of a treatment plan. 2 Methotrexate is the recognized standard of care for initial therapy, supported by long experience and the fact that methotrexate is clinically effective in a significant proportion of patients. Methotrexate and tumor necrosis factor (TNF) antagonists result in similar clinical response in early disease, 3,4 and in a recent study, 29% of patients receiving a 3 4 month aggressive methotrexate regimen achieved low disease activity or remission measured by DAS28. 5 Another nonbiologic disease-modifying antirheumatic drug (DMARD) option is leflunomide, which has shown similar clinical response to methotrexate. 6 TNF antagonists are also effective in early disease, with or without methotrexate. Approximately 50% of patients on a TNF antagonist alone had an ACR50 after 1 year on treatment. 3,4,7 Response was improved by adding methotrexate, 4,7,8 with more ACR70 responders 7,8 or DAS28 remissions. 4 Similarly, almost 50% of patients on abatacept and methotrexate had an ACR50 after 1 year and almost 29% were ACR70 responders. 9 Combination rituximab and methotrexate resulted in an ACR50 in about one third of patients at 6 months; ACR20, 50, and 70 responses were still noted after 48 weeks. 10 Selecting Treatment in Advanced RA Disease activity should also be defined in advanced RA, in addition to defining disease-related damage, areas of inevitable progression, and the goals of therapy. While joint damage may be irreversible, patients should be informed about the benefits of reducing chronic inflammation. Patients with advanced RA can have a good response to biologics. In long-standing, advanced disease inadequately controlled with methotrexate, addition of a TNF antagonist for 6 months resulted in considerable response. 7,11 Switching Therapy Some patients who failed methotrexate and a TNF antagonist have responded to an alternate TNF antagonist. About one third of patients switching from infliximab to etanercept were ACR20 responders after 12 weeks, along with some ACR50 and 70 responses. 12 After 16 weeks, 62% of patients switching from etanercept to infliximab had an ACR20 and 31% had an ACR50 and improved DAS28 and HAQ. 13 About one half of patients switching from a TNF antagonist to either abatacept 14 or rituximab 15 were ACR20 responders at 6 months, with fewer patients reaching an ACR50 or 70. While multiple options have been shown to be effective in patients with an inadequate response to current therapies, there are no controlled data comparing these options; further studies are needed to clarify the most beneficial sequencing of biologic therapies. TNF antagonists effectively reduce joint damage and inhibit radiographic progression regardless of baseline disease activity or joint damage. 16,17 However, one consideration when switching biologics is to weigh the importance of slowing radiographic progression against improvements in clinical signs and symptoms and disability. Both abatacept 9,18 and rituximab 15 reduce radiographic progression as well as improve clinical signs and symptoms, but studies are needed to clarify how the biologics compare in their ability to reduce joint damage for a majority of patients. Figure 2. Mortality in Patients With RA: Impact of Treatment Mortality Hazard Ratio* *Adjusted for severity, comorbidity, and demographic variables. Michaud K, Wolfe F. Ann Rheum Dis. 2005;64:87. Comorbid Conditions in RA Comorbid conditions may affect both the clinical outcome and treatment safety in RA. RA patients are at greater risk for atherosclerosis and cardiovascular disease (CVD). Extra-articular RA is also associated with CV morbidity and mortality. Recent investigations show that long-term use of both nonbiologic and biologic DMARDs can reduce the risk of CVD. 19 Registry data also suggest that methotrexate and TNF antagonists are associated with a reduction in mortality, primarily related to CVD (Figure 2). 20 Patients with underlying comorbidities such as lung disease or neurologic conditions could be at greater risk for infection. There is infection risk with all of the biologics and methotrexate, and RA patients should be screened for current infection or a history that might predispose to infection. In the absence of comparative studies, registry data will likely be the best source for understanding differences between the biologics. Genotyping studies may also help to define groups of patients at increased risk for infection with biologic and nonbiologic therapies. 21 Summary Without guidance from comparative studies, strategies for selecting RA therapy include identifying therapeutic targets and patient-specific issues. Available outcomes data and clinical experience may guide the clinician when choosing therapy, but prospective data are sorely needed. While the management of RA has benefited from the many treatment options currently available, further study is needed to clarify treatment decisions. Discussion Question What issues have not been adequately addressed by clinical trials of RA therapies? There is a need for direct comparative data between the RA drugs and a need for bio- N=19,580 Prednisone Methotrexate TNF Inhibitors 8 Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects

9 markers of response to guide treatment selection. Patients from clinical trials often have more severe RA, and these patients may respond differently than patients seen in most rheumatology practices. It has been suggested that most patients seen in practice would not qualify for clinical trials, making the extrapolation of clinical trial data to clinical practice both difficult and potentially misleading. References 1. Kirwan JR. Links between radiological change, disability, and pathology in rheumatoid arthritis. J Rheumatol. 2001;28: Martin RW, Head AJ, Rene J, et al. Patient decisionmaking related to antirheumatic drugs in rheumatoid arthritis: The importance of patient trust of physician. J Rheumatol. 2008;35: 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: Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, doubleblind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54: van Vollenhoven RF, Ernestam S, Coster L, et al. Methotrexate monotherapy is clinically adequate in 29% of patients with early RA-initial open-label phase of the SWEFOT multicenter clinical trial. Ann Rheum Dis. 2007;66: Arava [package insert]. Bridgewater, NJ: sanofiaventis; Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial. Lancet. 2004;363: 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: Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med. 2006;144: Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54: Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized, placebocontrolled, 52-week trial. Arthritis Rheum. 2004; 50: Buch MH, Bingham SJ, Bejarano V, et al. Therapy of patients with rheumatoid arthritis: Outcome of infliximab failures switched to etanercept. Arthritis Rheum. 2007;57: Furst DE, Gaylis N, Bray V, et al. Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: The opposite study. Ann Rheum Dis. 2007; 66: Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005; 353: Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54: Smolen JS, van der Heijde DM, St Clair EW, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: Results from the ASPIRE trial. Arthritis Rheum. 2006;54: Emery P, Genovese M, van Vollenhoven R, Patra K, Sasso E. Less progression of joint erosion (JE) and joint space narrowing (JSN) with adalimumab plus MTX vs. MTX monotherapy at all levels of clinical response: Subanalysis of PREMIER. Ann Rheum Dis. 2007;66: Genant HK, Peterfy CG, Westhovens R, et al. Abatacept inhibits structural damage progression in rheumatoid arthritis: Results from the long-term extension of the AIM trial Ann Rheum Dis. 2008;67: Naranjo A, Sokka T, Descalzo MA, et al. Cardiovascular disease in patients with rheumatoid arthritis: Results from the QUEST-RA study. Arthritis Res Ther. 2008;10:R Michaud K, Wolfe F. Reduced mortality among RA patients treated with anti-tnf therapy and methotrexate. Ann Rheum Dis. 2005;64: Hughes LB, Criswell LA, Beasley TM, et al. Genetic risk factors for infection in patients with early rheumatoid arthritis. Genes Immun. 2004;5: DEFINING RHEUMATOID ARTHRITIS TREATMENT SUCCESS OR FAILURE Continued from page 7 Arthur L. Weaver, MD, MS, FACP, MACR However, there is a lack of consensus on the most appropriate measure and frequency of use. For example, sequential radiographs should be used to monitor new and existing erosions, but there are few quantitative assessments for use in standard clinical practice and the frequency with which radiography should be performed is unclear. Most experts agree that x-rays of the hands and feet should be obtained every 6 to 12 months in patients with active disease. If there is uncertainty, ultrasound and/or MRI, which have increased specificity and sensitivity, may be useful. While DAS28 is used extensively in Europe and most clinical trials, this assessment requires acute-phase reactant data, which may not be practical in some clinical settings. This has led to the development of several validated clinical measures which do not require laboratory parameters. Because rheumatologists are data driven, clinical trial results are often used to guide clinical and radiographic assessments in standard clinical practice. There are also a number of societal and economic factors involved. Use of electronic medical records continues to expand, and patients are increasingly involved in health care decisions and monitoring disease activity. It is also important to note that RA is an individualized, heterogeneous disease such that there will be exceptions in the use of assessments. It is possible for a patient to be in DAS remission but continue to have a swollen and tender wrist. If the dominant wrist is involved and work function is severely compromised, this patient may require further treatment despite being in remission. References 1. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: Two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum. 2006;54: Weisman MH, Bombardier C, Massarotti EM, Gregersen PK, Fave GM, Kent JD. Analysis at 2 years of an inception cohort of early rheumatoid arthritis: The Study of North American Patients Diagnosed with New-Onset Rheumatoid Arthritis (SONORA) study. Ann Rheum Dis. 2004;63: Heiberg MS, Koldingsnes W, Mikkelsen K, et al. The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: Results from a longitudinal, observational, multicenter study. Arthritis Rheum. 2008;59: Pincus T, Bergman MJ, Yazici Y, Hines P, Raghupathi K, Maclean R. An index of only patient-reported outcome measures, routine assessment of patient index data 3 (RAPID3), in two abatacept clinical trials: Similar results to disease activity score (DAS28) and other RAPID indices that include physician-reported measures. Rheumatology (Oxford). 2008;47: Fuchs HA, Pincus T. Radiographic damage in rheumatoid arthritis: Description by nonlinear models. J Rheumatol. 1992;19: Cohen G, Gossec L, Dougados M, et al. Radiological damage in patients with rheumatoid arthritis on sustained remission. Ann Rheum Dis. 2007;66: Brown AK, Quinn MA, Karim Z, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: Evidence from an imaging study may explain structural progression. Arthritis Rheum. 2006;54: Izmailova ES, Pickard M, Paz N, et al. Biomarkers of rheumatoid arthritis disease activity: A translational approach. Presented at: American College of Rheumatology Annual Scientific Meeting. November 6-11, 2007; Boston, MA. 9. Karlson EW, Chibnik LB, Tworoger SS, Shadick NA, Manson JE, Costenbader KH. Biomarkers for pre-clinical rheumatoid arthritis in women from two cohort studies. Presented at: American College of Rheumatology Annual Scientific Meeting. November 6-11, 2007; Boston, MA. 10. Quinn MA, Gough AK, Green MJ, et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxford). 2006;45: Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects 9

10 CASE PRESENTATION: PATIENT WITH INCOMPLETE RESPONSE TO TNF INHIBITOR THERAPY Introduction This case reviews the treatment course of a 49-year-old woman who was diagnosed with rheumatoid arthritis (RA) 2 years previously. The perspectives of two rheumatologists are presented to compare and contrast assessment approaches and treatment decisions. Viewpoints from roundtable participants are included to show the relative merits and drawbacks of the clinical decisions in this scenario. Visit 1: Baseline Examination Visit 3 Rheumatologist A Rheumatologist B Rheumatologist A Rheumatologist B Hand and foot x-rays reveal no evidence of damage Anti-CCP positive RF positive CRP: 20 mg/l Hand and foot x-rays reveal no evidence of damage Anti-CCP positive RF positive CRP: 20 mg/l Multiple swollen and tender joints Swollen joints: 18 Tender joints: 14 Physician global: 70 Patient global: 75 DAS28: 6.39 (severe disease activity) CDAI: 46.5 SDAI: 48.5 Start oral methotrexate 15 mg/week Start oral methotrexate 15 mg/week and prednisone 5 mg/day and prednisone 5 mg/day Continued morning stiffness, tender and swollen joints despite 6 months of therapy with methotrexate and prednisone Minimal improvement CRP: 11 mg/l Continue current regimen Continued morning stiffness, tender and swollen joints despite 6 months of therapy with methotrexate and prednisone CRP: 11 mg/l Swollen joints: 6 Tender joints: 4 Physician global: 30 Patient global: 30 DAS28: 4.08 (moderate disease activity) CDAI: 16 SDAI: 17.1 Add etanercept 50 mg/week Visit 2 Visit 4 Rheumatologist A Rheumatologist B Rheumatologist A Rheumatologist B Continued morning stiffness, tender Continued morning stiffness, tender and swollen joints despite 3 months and swollen joints despite 3 months of therapy with oral methotrexate of therapy with oral methotrexate 15 mg/week and prednisone 5 mg/day 15 mg/week and prednisone 5 mg/day Signs of improvement CRP: 13 mg/l CRP: 13 mg/l Swollen joints: 8 Tender joints: 7 Physician global: 40 Patient global: 40 DAS28: 4.74 (moderate disease activity) CDAI: 22 SDAI: 23.3 MRI: signs of bone marrow edema Increase oral methotrexate to Increase oral methotrexate to 20 mg/week 20 mg/week Because increased doses of oral methotrexate are associated with variable bioavailability, parenteral methotrexate should be considered. 1 Continued morning stiffness, tender and swollen joints despite 9 months of therapy with methotrexate and prednisone Minimal improvement CRP: 11 mg/l Add etanercept 50 mg/week Continued morning stiffness, tender and swollen joints despite 9 months of therapy with methotrexate and prednisone 5 mg/day, and 3 months of etanercept 50 mg/week CRP: 11 mg/l Swollen joints: 4 Tender joints: 4 Physician global: 20 Patient global: 20 DAS28: 3.81 (moderate disease activity) CDAI: 12 SDAI: 13.1 Continue current regimen Although the patient has experienced some improvement, her DAS28 indicates that she continues to have moderate disease activity. Her current regimen is continued because data suggest that patients with an inadequate response to etanercept at 3 months may benefit from continuing therapy for up to 6 months Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects

11 Current Examination Rheumatologist A Continued morning stiffness, tender and swollen joints despite 12 months of therapy with methotrexate and prednisone 5 mg/day, and 3 months of etanercept 50 mg/week Hand x-rays reveal joint space narrowing in MCP and PIP joints with isolated cystic changes Some improvement CRP: 11 mg/l Rheumatologist B Continued morning stiffness, tender and swollen joints despite 12 months of therapy with methotrexate and prednisone, and 6 months of etanercept 50 mg/week Hand x-rays reveal joint space narrowing in MCP and PIP joints with isolated cystic changes Patient improved; not in remission CRP: 8 mg/l Swollen joints: 3 Tender joints: 2 Physician global: 15 Patient global: 15 DAS28: 3.24 CDAI: 8 SDAI: 9 Summary: In this scenario, the clinician relies on global assessment to guide treatment decisions. Despite 12 months of therapy with methotrexate and prednisone 5 mg/day and 3 months of etanercept 50 mg/week, the patient continues to experience morning stiffness and tender and swollen joints. Viewpoint: A change in therapy is warranted Clinical experience suggests that if a patient does not respond to biologic therapy within 3 6 weeks, response will not improve. Without clinical measurement, this rheumatologist is unable to determine if there has been improvement. An incomplete response to one TNF inhibitor does not indicate a similar response to a second agent in this class. The patient may benefit from a TNF inhibitor with a different mechanism of action. Her therapy could also be switched to an agent with a different mechanism of action such as abatacept, rituximab, or anakinra. Summary: In this scenario, the clinician uses laboratory tests, formal joint counts, and clinical assessment tools to monitor disease activity and response to treatment. However, after 12 months of therapy with methotrexate and prednisone and 6 months of etanercept 50 mg/week, the patient continues to experience morning stiffness and tender and swollen joints. Since initiating etanercept therapy, the magnitude in DAS28 improvement is minimal, from 4.0 to 3.2. Viewpoint: Continue current therapy The DAS28 continues to improve, suggesting partial response to etanercept. An adequate trial of etanercept has occurred (ie, 6 months), but the patient is not in remission. 2 However, if the patient feels better, she may be reluctant to change therapy. Viewpoint: A change in therapy is warranted Viewpoint: Switch to a second TNF inhibitor In this rheumatologist s opinion, the patient has improved, suggesting some An incomplete response to one TNF inhibitor does not predict a similar response to etanercept. Etanercept therapy should be continued for up to response to a second agent in this class. The patient may benefit from a 6 months to allow for an adequate response. TNF inhibitor with a different mechanism of action. Viewpoint: Change to another biologic class The patient s magnitude of response may not increase with either further exposure to etanercept or a switch to an alternative TNF antagonist. Therefore, her therapy could also be switched to an agent with a different mechanism of action, such as abatacept, rituximab, or anakinra. Conclusions This case is a classic scenario of a good but incomplete response to therapy in a patient with RA. To justify continuing the current therapeutic regimen, the clinician needs to determine if the patient has exhibited adequate response. If the patient has failed to achieve sufficient response, the clinician needs to decide if a change in treatment is warranted. Rheumatologist A based treatment on clinical judgment rather than clinical measures, resulting in prolonged traditional DMARD therapy, delayed initiation of biologic therapy, and uncertainty about the degree of success of etanercept. The goal of therapy is to treat to remission; this patient was clearly not in remission. Her marginal response should not be considered therapeutic success. Rheumatologist B relied on quantitative measures, and while improvement was observed, the magnitude of change was not acceptable. Although rheumatologist B also faced a number of clinical decisions, the choices were more clearly defined compared with the treatment course of rheumatologist A. In selecting subsequent treatments for this patient, a number of factors should be considered, including physical function and ability to work and complete daily activities. For example, if a patient has 3 swollen joints after treatment, but is able to work and participate in recreational sports, a change in therapy may not be warranted, particularly if biologic DMARD therapy has already been initiated. However, if the remaining 3 swollen joints include the patient s dominant wrist and work ability is comprised, a change in therapy may be necessary. Treatmentrelated adverse effects, patient preferences, and costs should always be considered in the selection of therapy. References 1. Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol. 2004;31: Kavanaugh A, Klareskog L, van der Heijde D, et al. Patients with rheumatoid arthritis who are non-responders to etanercept plus methotrexate therapy at week 12 achieve a response at week 24 and sustain the gain in response. Presented at: American College of Rheumatology Annual Scientific Meeting. November 6-11, 2007; Boston, MA. Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects 11

12 Rheumatology News Option 1: The DIME online credit system A. Please visit B. Select Register to the right of the title, Biologics in RA: Latest Developments and Practical Aspects. C. Complete the enrollment form, posttest, and evaluation form. D. If you receive a passing score of at least 70% on the posttest, your electronic statement of credit will be made available to you immediately. If you have difficulty accessing the link, please contact DIME at or [email protected]. Option 2: Complete this enrollment form, posttest, and evaluation form and mail them to: DIME Merchandise Mart Plaza Suite Chicago, IL You will receive a statement of credit within 4 6 weeks. Biologics in Rheumatoid Arthritis: Latest Developments and Practical Aspects Please print clearly* Name (Last) (First) (Initial) Degree Specialty Street or PO Box City State ZIP Code Phone Fax *To receive the information you are requesting, please make certain your contact information is legible. Evaluation Questions Overall Enduring Material Evaluation 5=Excellent 4=Good 3=Satisfactory 2=Fair 1=Poor Using the above scale, please evaluate this activity by marking the appropriate response Objectivity and balance Did you perceive any bias or commercialism in this activity (towards any product or drug)? Yes No If Yes, please explain: 3. Scientific rigor Amount of information presented Level of instruction Learning Objectives 5=Strongly agree 4=Agree 3=Neutral 2=Disagree 1=Strongly disagree Using the above scale, indicate whether after completing this activity you are better able to: 6. Compare and contrast targeted therapies with regard to their AEs and clinical outcomes in patients with RA Evaluate clinical measures for defining response in patients receiving treatment for RA Recognize the broad implications of clinical studies over the past 10 years on clinical practice for patients with RA Reason for Participation 5=Extremely 4=Very 3=Somewhat 2=Not very 1=Not at all Using the above scale, indicate how important the following reasons are for your participation in educational activities: 9. Topics Faculty/Editor s reputation CME/CE credit As a result of participating in this activity, did you learn anything that would cause you to make a change in your clinical practice? (choose only one) 1=Yes, I am going to try to incorporate some of the information presented into my clinical practice. 2= No, I am not going to incorporate the information into my clinical practice. 13. If Yes, how soon do you intend to incorporate changes in your practice as a result of this CME activity? 1=Immediately 2=In 1 month 3=In 3 months 4=In 6 months 5=I do not know 14. If No, why not? 1=I learned some new information, but the information presented is not applicable to my clinical practice. 2=The information presented confirmed my current clinical practice. 3=I did not find the information useful and I will not change my current clinical practice. 4=I do not know. Indicate your level of confidence in the following after completing this activity: 0 = Not at all confident 7 = Completely confident 15. Selecting a selective costimulatory modulator as treatment for RA Selecting a B-cell depletion therapy as treatment for RA Selecting a TNF antagonist as treatment for RA Selecting an alternative biologic agent for a patient with RA who responded poorly to another biologic agent Indicate whether you would recommend this activity to others: 1=Yes 2=No Please rate your interest in the following RA educational topics from 5 (highest interest) to 1 (lowest interest): Pathophysiology of RA Monitoring treatment response Pharmacoeconomic data MOA of emerging agents Clinical trial efficacy data Quality of life issues Inadequate response to therapy Clinical trial safety data Comorbid conditions 20. Additional Comments: Posttest 1. All of the following statements are true except: A. A redundant network of pro- and anti-inflammatory cytokines contributes to the pathogenesis of RA B. Production of metalloproteinases and other effector molecules ultimately erodes bone and cartilage C. The antigen that initiates the inflammatory cascade is well characterized D. Activation of B cells results in formation of plasma cells and autoantibodies 2. Which of the following best describes the mechanism of action of the investigational agent tocilizumab? A. Inhibition of IL-6 via binding to cell-surface IL-6 receptors B. Inhibition of IL-17 via binding to cell-surface IL-17 receptors C. Inhibition of IL-6 via binding to cell-surface and soluble IL-6 receptors D. None of the above 3. Patient registries provide insight into the treatment of RA by collecting patient data from clinical trials and patients seen in clinical practice. A. True B. False 4. Which of the following is (are) true regarding the TICORA study? A. TICORA compared routine care of RA to sustained and tight control of RA B. An algorithm designed to establish tight control outlines steps for the RA regimen C. Treatment designed to achieve tight control of RA yields a higher proportion of patients with a more robust ACR response D. All of the above 5. Which of the following is (are) a therapeutic option(s) for patients who respond poorly to TNF inhibitors? A. Rituximab D. Certolizumab B. Tocilizumab E. A and C C. Abatacept 6. Elevated levels of which of the following biomarkers have been observed up to 12 years prior to a diagnosis of RA? A. TNF receptor C. IL-6 B. Hyaluronic acid D. A and C 7. Which clinical measurement tool does not require a laboratory test? A. Simplified Disease Activity Index (SDAI) B. Disease Activity Score (DAS) C. Routine Assessment of Patient Index Data (RAPID) D. All of the above 8. Strategies for selecting therapy for a patient with early RA include: A. Encouraging communication with the patient to ascertain patient preferences and build a trusting relationship B. Defining disease activity and prognosis C. Evaluating comorbidities that might affect the course of RA D. All of the above 9. Patients with RA are at greater risk of cardiovascular disease, which in turn may impact treatment efficacy and safety. A. True B. False 10. All of the following statements are true except: A. Patients who respond poorly to one TNF inhibitor may respond to an alternative TNF inhibitor B. After switching to another biologic therapy, the best reported response a patient can achieve is ACR20 C. Further studies are needed to establish the optimal sequencing of biologic therapies D. TNF inhibitors are shown to reduce joint damage regardless of baseline RA activity or preexisting joint damage