Biologic Agents: Practice Implications and Improved Patient Outcomes

Transcription

1 A CME-CERTIFIED SUPPLEMENT TO Biologic Agents: Practice Implications and Improved Patient Outcomes Examining the Role of IL-6 in the Pathophysiology of RA Ernest H. S. Choy, MD, FRCP Consultant and Clinical Reader in Rheumatology King s College London, England Correlation Between IL-6 Inhibition and Anti IL-6 Observed Efficacy and Safety Outcomes Mark C. Genovese, MD Professor of Medicine Co-Chief, Division of Immunology and Rheumatology Stanford University Medical Center Palo Alto, California Disease Remission in RA: What Does It Mean? What Is Its Relevance? Josef S. Smolen, MD Professor of Medicine Chairman, Department of Internal Medicine Division of Rheumatology Medical University of Vienna Vienna, Austria Can I Translate Clinical Guidelines Into Daily Practice? Roy M. Fleischmann, MD Clinical Professor Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas Release date: March 11, 2010 Expiration date: March 10, 2011 Estimated time to complete activity: 1.25 hours Jointly sponsored by Supported by an independent educational grant from

2 A SUPPLEMENT TO Biologic Agents: Practice Implications and Improved Patient Outcomes This activity is developed from scientific information presented at the 2009 American College of Rheumatology (ACR) annual meeting, convened in Philadelphia, Pennsylvania, on October 20, This educational supplement is neither sanctioned by nor part of ACR. This CME supplement was authored by Bret Fulton, RPh, and Mindy Tanzola, PhD, medical writers, and reviewed and approved by Arthur Kavanaugh, MD; Ernest H. S. Choy, MD; Roy M. Fleischmann, MD; Mark C. Genovese, MD; and Josef S. Smolen, MD. This CME supplement has been reviewed for content validity and fair balance by an independent clinical peer reviewer, Rodolfo V. Curiel, MD, Assistant Professor of Medicine, Rheumatology Fellowship, Program Director, The George Washington University, Washington, DC. This supplement was produced by the medical education department of Elsevier/ International Medical News Group in conjunction with the American Academy of CME and Alliance Medical Communications. 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 2010 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. 4 Examining the Role of IL-6 in the Pathophysiology of RA Ernest H. S. Choy, MD, FRCP Consultant and Clinical Reader in Rheumatology King s College London, England 7 Correlation Between IL-6 Inhibition and Anti IL-6 Observed Efficacy and Safety Outcomes Mark C. Genovese, MD Professor of Medicine Co-Chief, Division of Immunology and Rheumatology Stanford University Medical Center Palo Alto, California 10 Disease Remission in RA: What Does It Mean? What Is Its Relevance? Josef S. Smolen, MD Professor of Medicine Chairman, Department of Internal Medicine Division of Rheumatology Medical University of Vienna Vienna, Austria 13 Can I Translate Clinical Guidelines Into Daily Practice? Roy M. Fleischmann, MD Clinical Professor Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas 16 Post-Test and Evaluation Form TARGET AUDIENCE This activity has been designed for rheumatologists. Other health care professionals who provide care and support to patients with rheumatoid arthritis may also participate. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of CME and Alliance Medical Communications. The American Academy of CME is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION The American Academy of CME designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. STATEMENT OF NEED There has been substantial progress in the understanding and treatment of rheumatoid arthritis (RA) in recent years, particularly an increased appreciation of the cytokines involved in disease etiology. Interleukin-6 (IL-6) plays a pivotal role in the pathogenesis of RA that includes local effects on joints and bones, a generalized effect on the immune system (both B-cell and T-cell mediated effects), and multiple systemic effects (ie, acute-phase protein production, increased cardiovascular risk, osteoporosis, anemia). Reduction in IL-6 levels has been shown to closely correlate with improvement of disease activity. The IL-6 receptor inhibitor tocilizumab is effective in a variety of patient populations with RA including superiority to methotrexate as monotherapy. Monitoring of disease activity is crucial for optimizing outcomes because there is a close relationship between disease activity, joint damage, and disability. Even patients who 2 Biologic Agents: Practice Implications and Improved Patient Outcomes

3 achieve a low level of disease activity have continued progression of joint damage. Thus, remission (ie, a state of minimal or no inflammatory disease activity) is the ultimate goal of therapy. Several studies have demonstrated that achievement of remission, including sustained remission, is possible with current treatment regimens and that treating to a disease activity target is possible. For example, in the Behandel Strategieën (BeSt) trial, Disease Activity Score (DAS)-guided treatment was associated with more rapid improvement, less radiologic damage, and less need for treatment adjustment than was sequential monotherapy or combination therapy. This underscores the need for appropriate disease activity reporting. There are several validated composite indices for the assessment of disease activity, including the American College of Rheumatology (ACR) criteria, DAS, Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). The SDAI and CDAI are particularly appropriate for use in routine clinical practice because they are simple to calculate and execute, and they perform at least as well as do the more complicated indices. The routine and consistent use of such disease activity assessments is vital to maximize clinical outcomes by preventing structural damage and long-term disability. EDUCATIONAL OBJECTIVES Upon completion of this activity, participants will be better able to: RA, including the role of proinflammatory cytokines of action of anti IL-6 receptor antibody with observed efficacy and safety outcomes monitoring disease remission with appropriate criteria such that structural and functional declines are prevented in patients with RA results of clinical trials to the management of patients with RA in the community setting. CONFLICT OF INTEREST According to the disclosure policy of the Academy, all faculty, planning committee members, editors, managers, and other individuals who are in a position to control content are required to disclose any relevant relationships with any commercial interests related to this activity. The existence of these interests or relationships is not viewed as implying bias or decreasing the value of the presentation. All educational materials are reviewed for fair balance, scientific objectivity, and levels of evidence. Disclosures are as follows: Dr Choy has been on the advisory board for marketing purposes for F. Hoffmann-La Roche Ltd, Pfizer Inc., and UCB Celltech Ltd. He has also served on the advisory board for scientific information for Chelsea Therapeutics, Inc., Eli Lilly and Company, F. Hoffmann-La Roche Ltd., GlaxoSmithKline plc, Jazz Pharmaceuticals, Inc., Merrimack Pharmaceuticals, Pfizer Inc., Pierre Fabre Medicament, Schering-Plough Corporation, Wyeth, and UCB Celltech Ltd. He has served as a consultant for marketing purposes for F. Hoffmann-La Roche Ltd., Pfizer Inc., and UCB Celltech Ltd. and as a consultant for clinical trial design for Chelsea Therapeutics, Inc., Eli Lilly and Company, F. Hoffmann- La Roche Ltd., GlaxoSmithKline plc, Jazz Pharmaceuticals, Merrimack Pharmaceuticals, Pfizer Inc., Pierre Fabre Medicament, Schering- Plough Corporation, and UCB Celltech Ltd. Dr Choy has also received grant/research support from Abbott Laboratories, Allergan, Inc., Chelsea Therapeutics, F. Hoffmann-La Roche Ltd., GlaxoSmithKline plc, Jazz Pharmaceuticals, Merck, Sharp, and Dohme, Pierre Fabre Medicament, UCB Celltech Ltd., and Wyeth. He has served on the promotional speakers bureau for Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Pfizer Inc., and UCB Celltech Ltd. Dr Fleischmann has served on the advisory board for scientific information for Abbott Laboratories, Amgen Inc., Centocor, Inc., Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, Inc., GlaxoSmithKline plc, Lexicon Pharmaceuticals, Inc., Pfizer Inc., UCB S.A., and Wyeth. He has also been a consultant for clinical trial design for Abbott Laboratories, Amgen Inc., Centocor, Inc., Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, Inc., GlaxoSmithKline plc, Lexicon Pharmaceuticals, Inc., Pfizer Inc., UCB S.A., and Wyeth. He has been a shareholder of Abbott Laboratories, Genentech, Inc., and Johnson and Johnson Services, Inc. Dr Fleischmann has received grant/research support from Abbott Laboratories, Amgen Inc., Celgene Corporation, Centocor, Inc., Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, Inc., GlaxoSmithKline plc, Lexicon Pharmaceuticals, Inc., MedImmune, LLC, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Inc., UCB S.A., and Wyeth. Dr Genovese has served on the advisory board for scientific information for F. Hoffmann-La Roche Ltd. He has also been a consultant for clinical trial design and received grant/research support from F. Hoffmann-La Roche Ltd. Dr Kavanaugh has received grant/research support from Abbott Laboratories, Amgen Inc., Bristol-Myers Squibb Company, Centocor, Inc., F. Hoffmann-La Roche Ltd., Genentech, Inc., and UCB S.A. Dr Smolen has served on the advisory board for scientific information for Abbott Laboratories, Amgen Inc., Bristol-Myers Squibb Company, Centocor, Inc., F. Hoffmann-La Roche Ltd., Schering-Plough Corporation, UCB S.A., and Wyeth. He has been a consultant for clinical trial design for Abbott Laboratories, Centocor, Inc., F. Hoffmann-La Roche Ltd., UCB S.A., and Wyeth. He has also received grant/research support from Abbott Laboratories, Bristol-Myers Squibb Company, F. Hoffmann-La Roche Ltd., Schering- Plough Corporation, and UCB S.A. INDEPENDENT CLINICAL PEER REVIEWER Rodolfo V. Curiel, MD: No relevant relationships with any commercial interests. MEDICAL WRITERS Bret Fulton, RPh, and Mindy Tanzola, PhD: No relevant financial relationships with any commercial interests. PLANNING COMMITTEE John J. D. Juchniewicz, MCIS, American Academy of CME, and Debbie Dean and Michelle Yechout, Alliance Medical Communications: No relevant relationships with any commercial interests. OFF-LABEL INVESTIGATIONAL USE The following identifies the off-label or investigational (not yet approved for any purpose) use of pharmaceuticals or medical devices or products mentioned within this CME activity: use in rheumatoid arthritis. METHOD OF PARTICIPATION There are no fees to participate in this CME supplement. To receive credit, participants must read the CME information to include the learning objectives, disclosure statements, and content of the supplement, and then complete the self-assessment, evaluation form, and activity certificate information. FOR CME CERTIFICATE Option 1: Log on to RAOUT09 to complete the self-assessment and evaluation and receive your certificate immediately. Option 2: Complete the hard copy of the selfassessment, evaluation, and activity certificate information and fax to (609) or mail to: American Academy of CME, 1330 Route 206, Suite , Skillman, NJ A certificate will be mailed to you in 4 to 6 weeks. For any questions, please contact: American Academy of CME, Inc Route 206, Suite Skillman, NJ Phone: (609) jjuchniewicz@academycme.org Biologic Agents: Practice Implications and Improved Patient Outcomes 3

4 Examining the Role of IL-6 in the Pathophysiology of RA R heumatoid arthritis (RA) is characterized by an abundance of cytokines, including the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). 1 Although therapies targeting these cytokines have demonstrated efficacy in the treatment of RA, these inhibitors have limitations. Not all patients respond to the currently available agents; and they are associated with toxicities, including infusion reactions, infections, and an increased risk of malignancy. Moreover, some patients are not eligible for these therapies because of chronic infection or cardiac failure. 2 Thus, other cytokines have been investigated as potential therapeutic targets in RA. One of these is the pleiotropic cytokine IL-6, which plays a central role in the development of RA, both locally and systemically. IL-6 exerts effects on immune cells, osteoclasts, synoviocytes, and the liver. Together, these functions contribute to the development and severity of RA and make IL-6 an attractive biologic target for RA therapy. Pathogenesis of RA RA is a complex inflammatory condition involving multiple immune cell types and mediators. T cells contribute to RA by secreting cytokines and directly activating other immune cells, including macrophages and B cells. 3 B cells contribute to RA by forming autoantibodies and immune complexes and by presenting antigens to T cells. Many of the effects of RA are mediated by small signaling molecules such as cytokines. Cytokines are either pro-inflammatory or anti-inflammatory; in a tissue environment, the balance of these cytokines determines whether a tissue becomes inflamed. 2 Unlike hormones, cytokines are not stored in glands, but rather are synthesized rapidly and secreted after stimulation. 4 Cytokines tend to act on target cells close to the site of secretion through specific surface receptors. In patients with RA, CD4+ T cells infiltrate the synovial fluid and activate monocytes, macrophages, and synovial Ernest H. S. Choy, MD, FRCP Consultant and Clinical Reader in Rheumatology King s College, London, England fibroblasts to overproduce pro-inflammatory cytokines, primarily IL-1, IL-6, and TNF-α. 3 The presence of inflammatory cytokines, chemokines, and angiogenic factors further stimulates the production of other cytokines, chemokines, tissue-degrading enzymes, and cell-surface molecules that mediate the inflammation and joint destruction in RA. This complex cytokine network contributes to the development of RA through effects on T-cell and B-cell development and activation; stimulation of macrophages, fibroblasts, synoviocytes, and chondrocytes; and induction of acute-phase proteins and hepcidin in the liver (Table). 5 Biologic agents have been developed that inhibit different steps of the inflammatory process of RA. The selective T-cell costimulation modulator abatacept inhibits T-cell activation. The anti-cd20 antibody rituximab interferes with various B-cell functions, including antigen presentation, T-cell activation, autoantibody production, and pro-inflammatory cytokine secretion. The TNF inhibitors bind to TNF molecules, preventing TNF-induced joint damage. Given its central role in multiple biologic processes associated with RA, IL-6 is another attractive therapeutic target. Properties of IL-6 IL-6 is a small polypeptide with a fourα-helix bundle structure stabilized by intramolecular disulfide bridges. 4,6 The IL-6 receptor complex has multiple subunits: the cognate membrane-bound IL-6 receptor, which is expressed in a subpopulation of cells in healthy tissue, and the signaltransducing glycoprotein (gp) 130, which is expressed in most cells in the body. 7-8 IL-6 can also transduce signals through soluble IL-6 receptors, which can form through proteolytic cleavage of the extracellular portion of the membrane-bound IL-6 receptor or through alternative mrna splicing. Whereas, most soluble cytokine receptors are antagonists competing against membrane-bound receptors for cytokine binding, the soluble IL-6 receptor can transduce signaling by interacting with membrane-bound gp130. This process, called trans-signaling, enables IL-6 to activate cells not expressing membrane-bound IL-6 receptor. 8 Thus, an IL-6 inhibitor would need to inhibit both membranebound signaling and trans-signaling or could inhibit the IL-6 ligand itself. Table. Cytokines Have a Broad and Distinct Range of Highly Relevant Biological Effects in Rheumatoid Arthritis 5 IL-6 TNF IL-1 Joint Inflammation Bone Destruction Autoimmunity Systemic Effects Levels in blood and synovial fl uid Endothelium activation PMN (neutrophil migration) Proteases, MMP secretion Osteoclast activation Osteoblast inhibition B-cells function and survival ++ (+) T H 17 promotion ++ + Acute phase-proteins production Bone marrow (anemia) CNS CNS=central nervous system; IL=interleukin; MMP=metalloproteinase; PMN=polymorphonuclear leukocyte; TH=T-helper; TNF=tumor necrosis factor. 4 Biologic Agents: Practice Implications and Improved Patient Outcomes

5 Role of Cytokines in Immune Development Cytokines play a central role in the development of the adaptive immune system, exerting effects on both B cells and T cells. During T-cell differentiation, the cytokines present in the microenvironment determine which type of T-helper subset an antigen-naive CD4+ T cell (T H 0 cell) will become. Interferon-γ and IL-12 stimulate the production of inflammatory-type T H 1 cells; IL-4 stimulates the production of T H 2 cells, which promote antibody production; transforming growth factor-β induces T-regulatory cells; and IL-6 stimulates the production of T H 17 cells, a subset of T cells that secretes IL-17 and promotes autoimmune tissue injury In a study illustrating the importance of T H 17 cells in an animal model of RA, Fugimoto and colleagues showed that IL-6 blockade suppresses autoimmune arthritis in mice by inhibiting T H 17 responses. 11 Cytokines also have direct and indirect effects on B-cell activation and differentiation. In an inflammatory environment, antigen-specific T H 1 cells interact with antigen-specific B cells and produce cytokines, including IL This process primes the B cells, activating them to proliferate and differentiate into antibody-secreting plasma cells. IL-6, produced by antigenpresenting dendritic cells, also directly stimulates the differentiation and proliferation of these activated B cells. Clearly, IL-6 works at multiple levels to stimulate the immune system promoting inflammation, autoimmunity, and tissue damage. IL-6 and Joint Destruction More than 10 years ago, Straub and colleagues 13 showed a correlation between serum IL-6 levels and the joint destruction of RA. Among 20 patients with RA undergoing disease-modifying antirheumatic drug therapy, reductions in serum IL-6 levels during the first year of therapy correlated significantly with multiple clinical outcomes after 3 years, including decreases in morning stiffness, the number of inflamed joints, and Lansbury index score (a joint-stiffness measure). In vitro evidence suggests that IL-6 could promote localized inflammation in RA through several mechanisms. First, IL-6 contributes to leukocyte recruitment at inflammatory sites by causing increased expression of adhesion molecules on leukocytes and by activating endothelial cells to produce a subset of chemokines. 14 These interactions are dependent on the presence of soluble IL-6 receptor, as endothelial cells express only gp130 and not the membranebound IL-6 receptor. IL-6 also supports neutrophil recruitment by mediating interactions between synovial fibroblasts and endothelial cells. 15 In addition to promoting neutrophil recruitment, IL-6 also promotes neutrophil survival in inflammatory sites by inhibiting apoptosis. 16 IL-6 contributes to joint destruction through its effects on osteoclasts, which mediate local bone destruction in RA within the synovial tissue. 17 Along with TNF-α and IL-1, IL-6 induces synovial fibroblasts to secrete receptor activator of nuclear factor-κb ligand (RANKL), which promotes the differentiation of macrophages into osteoclasts. IL-6 also appears to directly induce osteoclast formation through a RANKLindependent mechanism (Figure). 18 In vitro, osteoclast-like cells can be induced by the addition of IL-6 and soluble IL-6 receptor or by adding synovial fluid from patients with RA Axmann and colleagues 20 recently showed that IL-6 blockade reduces osteoclast differentiation and bone resorption in RANKL-stimulated monocyte cultures. This occurs independently of inflammation, as IL-6 blockade in TNF-αtransgenic mice reduces osteoclast formation and bone erosion in inflamed joints, but has no effect on joint inflammation. IL-6 also contributes to pannus formation by stimulating the production of vascular endothelial growth factor (VEGF) from synovial fibroblasts. VEGF, a central mediator of angiogenesis, also promotes pannus formation, as invasion of cartilage and bone requires an increased blood supply. In vitro studies have shown that IL-6 and IL-1β each induce slight amounts of VEGF production by synovial cells, and the two cytokines act synergistically to stimulate VEGF production. 21 IL-6 can also synergize with TNF-α to stimulate VEGF production. In the presence of all three cytokines (IL-1, IL-6, and TNF-α), the addition of an anti IL-6 receptor monoclonal antibody inhibits VEGF production, whereas the addition of an IL-1 receptor inhibitor or a TNF-α inhibitor does not. IL-6 as a Hepatocyte Growth Factor IL-6 is a major hepatocyte growth factor, stimulating the production of a range of proteins involved in the acute-phase response, which is an innate body defense. Changes in plasma concentration of these acute-phase reactants reflect the presence and intensity of inflammation and are used as a clinical guide to diagnosis and management. The major proteins involved in the acute-phase response are C-reactive protein (CRP) and serum amyloid A, concentrations of which can increase by 1000-fold or more. Others include haptoglobin, fibrinogen, ceruloplasmin, C3, and C4. Concentrations of the negative acutephase proteins albumin and transferrin are consistently reduced during the acute-phase response CRP is considered a biomarker of IL-6 activity. The association between IL-6 and CRP is particularly notable, given that CRP is an independent prognostic factor for radiographic damage in early RA. In a study of 191 patients with early RA, a high CRP level at baseline was significantly associated with the total Sharp score at 3 years and the risk of radiographic progression. 24 Figure. Interleukin-6 (IL-6) Directly Induces Osteoclast Formation by a Receptor Activator of Nuclear Factor- B Ligand (RANKL)-Independent Mechanism 19 M-CSF IL-6, TNF-, IL-1 RANKL Expression Macrophage M-CSF=macrophage colony-stimulating-factor; TNF=tumor necrosis factor. RANKL RANK Differentiation Bone Synovial Fibroblast Cathepsin K IL-6 Activation Osteoclast Biologic Agents: Practice Implications and Improved Patient Outcomes 5

6 IL-6 also stimulates hepatocytes to produce the iron-regulatory hormone hepcidin, which is a central mediator of the low serum iron levels observed in patients with inflammatory disorders. Hepcidin causes iron deficiency by inhibiting the release of iron from macrophages (reticuloendothelial block) and the absorption of dietary iron in the intestines. 25 In vitro studies indicate that IL-6 is necessary and sufficient for inducing the production of hepcidin from hepatocytes during inflammation. 26 Thus, IL-6 may be responsible for all or most of the anemia associated with inflammation. Multiple studies have verified the association between IL-6 and iron levels. In a study of 105 anemic and 127 nonanemic patients with RA, median serum IL-6 levels were significantly higher in the anemic than in the nonanemic patients (6.8 vs 3.9 pg/ml, respectively; P=0.0001). 27 In a rat model, intraperitoneal IL-6 infusions administered daily for 2 weeks resulted in anemia, adding further evidence supporting the role of IL-6 in the development of anemia. 28 Other Systemic Effects of IL-6 Systemic osteoporosis is a common feature of RA. 29 IL-6 promotes the development of osteoporosis through its pro-osteoclastic activity, which causes bone resorption. 19 Poli and colleagues 30 showed that IL-6 deficient mice are protected from bone loss caused by estrogen depletion, providing in vivo evidence for the link between IL-6 and systemic osteoporosis. IL-6 also influences the hypothalamic-pituitary-adrenal (HPA) axis, one of the peripheral limbs of the stress system. Three inflammatory cytokines, IL-6, TNF-α, and IL-1, are responsible for most of the HPA axis stimulating activity in plasma, although other cytokines can also contribute. 31 These cytokines stimulate the secretion of corticotropin-releasing hormone and arginine vasopressin from neurons in the hypothalamus, inducing the production of corticotropin and cortisol. Changes in the HPA axis can affect energy level and mood, which is important in RA, as fatigue is the second most common symptom of the disease. IL-6 and Cardiovascular Risk An increased incidence of cardiovascular events has been noted in individuals with RA compared with that in the general population. An analysis of 236 consecutive patients with RA revealed a nearly fourfold increase in the rate of incident cardiovascular events compared with that in the general population after adjusting for age and sex (odds ratio [OR], 3.96; 95% confidence interval [CI], ). 32 The risk remained more than three times higher after adjusting for cardiovascular risk factors (OR, 3.17; 95% CI, ), indicating that the high rate of cardiovascular events could not be explained by conventional risk factors alone. One possible risk factor is inflammation because elevated CRP concentration is an independent predictor of cardiovascular risk in the normal population. In an analysis of 27,939 apparently healthy women, elevated serum CRP concentrations correlated with future cardiovascular risk across the range of Framingham risk scores. 33 Increased incidence of cardiovascular events has been noted in individuals with RA compared with that in the general population. IL-6 plasma levels also correlate with cardiovascular risk. In a prospective analysis of 14,916 healthy men, median IL-6 concentrations were significantly higher among 202 participants who subsequently developed a myocardial infarction compared with 202 matched participants who did not develop cardiovascular disease within 6 years (1.81 vs 1.46 pg/ml, respectively; P=0.002). 34 For each quartile increase in IL-6 level, the risk of future myocardial infarction increased by 38%. This trend remained significant after adjusting for other cardiovascular risk factors, including CRP. Other evidence has implicated IL-6 in the development of coronary artery disease. IL-6 is the chief inducer of CRP, which stimulates macrophages to produce tissue factor, a procoagulant found in atherosclerotic plaques. 35 IL-6 also induces thrombocytosis. 2 Moreover, IL-6 levels have been shown to predict outcomes following hospitalization for unstable angina. An analysis of 43 patients showed that an increase in IL-6 levels 2 days after admission was associated with a complicated hospital course, whereas a decline in IL-6 levels in the first 2 days was associated with an uneventful course. 36 Multiple factors likely contribute to the link between RA and increased cardiovascular risk. The systemic inflammatory response characteristic of RA includes the presence of inflammatory cytokines that alter the function of various tissues, including adipose, skeletal muscle, liver, and vascular endothelial cells. 37 These alterations lead to multiple proatherogenic changes, including insulin resistance, elevated lipid concentrations, prooxidative stress, and endothelial dysfunction. Together, these conditions likely accelerate the atherogenic process. Conclusion Inflammatory cytokines, including IL-6, have a broad and distinct range of highly relevant biological effects that contribute to the joint inflammation, bone destruction, autoimmunity, and cardiovascular risk characteristic of RA. Therapies that effectively target these cytokines and suppress the inflammatory response could have multiple clinical benefits for patients by reducing joint damage, improving long-term outcomes, and reducing the cardiovascular risk associated with RA. References 1. Nature. 2003;423: Rheum Dis Clin N Am. 2004;30: Nat Rev Drug Disc. 2003;2: Biochem J. 1998;334: Rheumatology. February 2010 e-pub. 6. EMBO J. 1997;16: Biochem J. 2003;374: J Leukoc Biol. 2006;80: Nature. 2006;441: Nature. 2006;441: Arthritis Rheum. 2008;58: Curr Dir Autoimmun. 2005;8: Br J Rheumatol. 1997;36: Immunity. 1997;6: Arthritis Rheum. 2005;52: J Leukoc Biol. 1995;58: Arthritis Res Ther. 2007;9(suppl 1):S Bone. 2003;32: J Bone Miner Res. 1996;11: Arthritis Rheum. 2009;60: Arthritis Rheum. 2003;8: Kidney Int Suppl. 2000;76:S96-S N Engl J Med. 1999;340: Arthritis Rheum. 2001;44: J Clin Invest. 2004;113: J Clin Invest. 2004;113: Clin Immunol. 1999;92: Clin Exp Immunol. 1996;103: Arthritis Res Ther. 2006;8(suppl 2):S EMBO J. 1994;13: N Engl J Med. 1995;332: Arthritis Rheum. 2001;44: Circulation. 2004;109: Circulation. 2000;101: Arthritis Res Ther. 2006;8:R Circulation. 1999;99: Circulation. 2003;108: Biologic Agents: Practice Implications and Improved Patient Outcomes

7 Correlation Between IL-6 Inhibition and Anti IL-6 Observed Efficacy and Safety Outcomes I nterleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis of rheumatoid arthritis (RA). 1 Patients with RA have elevated levels of IL-6 in the serum and synovial fluid that correlate with markers of disease activity and clinical symptoms. 2,3 Tocilizumab is a humanized, anti IL-6 receptor monoclonal antibody that blocks multiple IL-6 mediated proinflammatory responses. 4 This article will review data from clinical trials evaluating the effect of IL-6 inhibition on efficacy, safety, and laboratory outcomes. Efficacy of Tocilizumab In the treatment of RA, tocilizumab has been evaluated in randomized, controlled trials in a wide range of patient populations. Indeed, the phase III program for tocilizumab is perhaps the largest to date of any biologic in the treatment of RA with approximately 4200 patients enrolled (Table). 5-9 The program consisted of four 24-week studies (tocilizumab Pivotal Trial in methotrexate Inadequate responders [OPTION]), (Tocilizumab in combination With traditional dmard therapy [TOWARD]), (Actemra versus Methotrexate double-blind Investigative Trial In monotherapy [AMBITION]), (Research on Actemra Determining efficacy after Anti TNF failures [RADIATE]), and an ongoing 52-week study to evaluate physical function and prevention of joint damage (TociLIzumab Safety and THE Prevention of Structural Joint Damage [LITHE] study). DMARD-Inadequate Responders The OPTION and TOWARD studies evaluated tocilizumab versus placebo in patients who had inadequately responded to methotrexate (MTX) (OPTION) or disease-modifying antirheumatic drugs (DMARDs) (TOWARD). 5,10 In the OPTION trial, patients received tocilizumab 4 or 8 mg/kg every 4 weeks; in TOWARD, all patients in the tocilizumab group received an 8-mg/kg dose. A pooled analysis of 1008 patients who received tocilizumab 8 mg/kg found that Mark C. Genovese, MD Professor of Medicine, Co-Chief, Division of Immunology and Rheumatology Stanford University Medical Center, Palo Alto, California tocilizumab was associated with significantly higher American College of Rheumatology (ACR)20, 50, and 70 response rates (60.3%, 38.9%, and 20.8%, respectively) than the rates of 25.1%, 9.6%, and 2.6%, respectively, for the placebo-treated patients (P<.0001 for all comparisons). 11 Individual ACR core parameters (ie, swollen and tender joint counts, patient and physician global assessments, C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], Health Assessment Questionnaire Disability Index [HAQ-DI]) all significantly favored tocilizumab (P< for all). Disease activity, as assessed by the Disease Activity Score using 28 joints (DAS28), was also significantly reduced in the tocilizumab group at week 24 compared with placebo (-3.30 vs -1.35, respectively; P<0.0001). 12 Tocilizumab was associated with an early onset of response, with 7.1% of patients in DAS28 remission (ie, DAS28 <2.6) by week 4 versus only 0.7% of those in the control group. Good or moderate responses were attained by 64.1% of tocilizumab-treated patients as early as week 2, compared with only 17.2% of patients receiving placebo. At week 24, DAS28 remission was achieved in 29.7% and 2.7% of patients, respectively, in the tocilizumab and placebo groups (P<0.0001). 12 Disability was also improved Table. Study Designs of Tocilizumab Phase III Trials 5-9 Study Patient Population No. of Patients AMBITION MTX-naive/free 673 OPTION MTX-IRs 623 TOWARD DMARD-IRs 1220 RADIATE TNF-IRs 499 LITHE MTX-IRs 1190 among those treated with tocilizumab, with a significantly greater percentage of patients achieving an improvement in the HAQ-DI score of 0.25 at week 24 than that of patients receiving placebo (67.9% vs 49.9%, respectively; P<0.0001). 13 Comparison With MTX The AMBITION study was a randomized controlled trial involving 673 patients who were MTX-naive or who had discontinued MTX for reasons other than lack of efficacy or toxicity. 6 Patients were randomized to receive monotherapy with MTX 7.5 to 20 mg/wk or tocilizumab 8 mg/kg every 4 weeks, or placebo. The placebo arm was a substudy in which patients were eligible for rescue therapy with tocilizumab 8 mg/kg if they experienced a 20% worsening from baseline in swollen or tender joint counts before week 8. The primary end point of the trial was the proportion of patients with an ACR20 response at week 24. In the intent-to-treat population, tocilizumab was superior to MTX, with 69.9% of patients achieving an ACR20 response compared with 52.5% of those receiving MTX (P<0.0001). Disease activity was also reduced significantly more in the tocilizumab group; DAS28 remission rates at week 24 were 33.6% and 12.1%, respectively, in the tocilizumab and MTX groups. 6 Treatment Tocilizumab monotherapy vs MTX Tocilizumab + MTX vs MTX Tocilizumab + DMARD vs DMARD Tocilizumab + MTX vs MTX Tocilizumab + MTX vs MTX Clinical End Point Signs and symptoms Signs and symptoms Signs and symptoms Signs and symptoms Prevention of joint damage and disability DMARD=disease-modifying antirheumatic drug; DMARD-IRs=DMARD inadequate responders; LTE=long-term extension; MTX=methotrexate; MTX-IRs=MTX inadequate responders; TNF-IRs=tumor necrosis factor inadequate responders. Please see text for expanded trial names. Study Duration 6-month LTE 6-month LTE 6-month LTE 6-month LTE 5 years (ongoing) Biologic Agents: Practice Implications and Improved Patient Outcomes 7

8 Use in Anti-TNF Failures The efficacy of tocilizumab for the treatment of patients who had an inadequate clinical response or were intolerant to one or more anti-tnf therapies was evaluated in RADIATE. 7 In this study, patients were randomized to receive tocilizumab 4 mg/kg, 8 mg/kg, or placebo every 4 weeks, with all patients receiving stable MTX therapy (10-25 mg/wk). No other DMARDs were allowed. The primary efficacy end point was ACR20 response at week 24. The large majority of patients (95%) had failed prior TNF therapy because of lack of efficacy. ACR responses at week 24 are illustrated in Figure 1. 7 ACR20 responses were significantly higher in the tocilizumab 4-mg/kg (30.4%) and 8-mg/kg (50.0%) groups than in the placebo group (10.1%), with both doses significantly superior to placebo (P< for both doses vs placebo). Function (as assessed by HAQ) was significantly improved in the tocilizumab groups, with values reduced by 0.31 and 0.39, respectively, in the 4-mg/kg and 8-mg/kg groups, compared with a reduction of 0.05 for placebo-treated patients (P=0.003 and P<0.001 vs placebo, respectively). Disease activity was also significantly reduced, particularly in the tocilizumab 8-mg/kg group. DAS28 remission rates at week 24 were 7.6% in the 4-mg/kg group (P= vs placebo) and 30.1% in the 8-mg/kg group (P= vs placebo), compared with 1.6% for the placebo group. Low disease activity DAS28 (<3.2) rates were 15.2%, 51%, and 4.9% for the 4-mg/kg, 8-mg/kg, and placebo groups, respectively. 7 Prevention of Structural Damage The LITHE study is a long-term trial designed to evaluate the efficacy of tocilizumab for preventing structural damage in patients who had an inadequate response to prior MTX therapy. 8 In this study, patients were randomized to receive tocilizumab 4 mg/kg or 8 mg/kg or placebo, with all patients receiving background MTX therapy. Patients who failed to respond to treatment at 16 weeks were offered blind rescue therapy with tocilizumab. Those who failed to respond to the first rescue were offered a second step of tocilizumab rescue therapy at any time between week 28 and week 52. After 24 weeks of therapy, the tocilizumab 4-mg/kg and 8-mg/kg groups had ACR20 response rates that were higher than that of the placebo group (46%, 56%, 27%, respectively; P< for the 8-mg/kg Figure 1. ACR Responses at 24 Weeks in Anti-TNF Inadequate Responders (TNF-IRs) Receiving Tocilizumab (TCZ) or Placebo in the RADIATE Trial (ITT Population) 7 Patients (%) % P< P< % ACR % 3.8% group vs placebo). ACR50 (29%, 36%, and 10%, respectively) and ACR70 (16%, 20%, and 4%, respectively) response rates showed a similar trend (P< for the 8-mg/kg group vs placebo). Mean joint erosion, joint space narrowing, and total Genant-modified Sharp scores indicated that both tocilizumab doses were associated with significant inhibition of radiographic progression from baseline compared with that of placebo (Figure 2). 8 The proportion of patients with no radiographic progression was also lower in the tocilizumab groups. Rates of progression for joint erosion (83%, 87%, and 70%, respectively), joint space narrowing (91%, 91%, and 85%, respectively), and total Genant-modified Sharp score (81%, 85%, and 67%, respectively) were lower in the tocilizumab 4-mg/kg and 8-mg/kg groups than in the placebo group. 8 A followup 2-year analysis reported at ACR 2009 revealed that the responses were durable, with continued inhibition of radiographic progression, improvement in physical function, and improved DAS28 remission. 14 Laboratory Considerations Effect on CRP Changes in serum levels of CRP reflect the presence and intensity of inflammation. Treatment with tocilizumab produced significant reductions in CRP levels from baseline in the OPTION, TOWARD, AMBITION, RADIATE, and LITHE studies. 9 Pooled data from these studies P< % ACR % ACR=American College of Rheumatology; ITT=intent-to-treat; MTX=methotrexate. Please see text for expanded trial name. Reproduced with permission from BMJ Publishing Group Ltd. 1.3% P= % ACR70 Placebo + MTX (n=158) TCZ 4 mg/kg + MTX (n=161) TCZ 8 mg/kg + MTX (n=170) Figure 2. Effect of Tocilizumab (TCZ; 4 or 8 mg/kg) Versus Placebo on Radiographic Progression in Patients with Inadequate Response to Prior Methotrexate (MTX) Therapy (LITHE Study; ITT Population) 8 Patients Without Progression (%) Genant Total / Sharp Score Erosion Score ITT=intent-to-treat; JSN=joint space narrowing. Please see text for expanded trial name % Placebo + MTX (n=393) TCZ 4 mg/kg + MTX (n=399) TCZ 8 mg/kg + MTX (n=398) JSN Score revealed that CRP levels were significantly reduced from baseline by week 2, and these reductions were maintained throughout the 24 weeks of therapy (Figure 3). Mean decreases in CRP concentrations ranged from 2.3 to 2.8 mg/dl among patients receiving tocilizumab 4 or 8 mg/kg plus DMARDs or tocilizumab monotherapy. The decreases in the tocilizumab 8-mg/kg plus DMARD group were more consistent than were those in the tocilizumab 4-mg/kg plus DMARD group in which CRP levels tended to fluctuate over time. 9 Effect on Erythrocytes Anemia of chronic inflammation is experienced by more than 30% of patients with RA and is often associated with fatigue. 15 Pooled data from OPTION and TOWARD showed that the mean change from baseline in hemoglobin (Hb) was significantly greater among tocilizumab-treated patients than controls (1.04 vs 0.11 g/dl, respectively; P<0.0001). 16 In addition, a significantly greater percentage of patients achieved an increase in Hb of at least 1 g/dl between baseline and week 24 than that of controls (51.7% vs 17.1%, respectively; P<0.0001). Further, Functional Assessment of Chronic Illness Therapy-Fatigue scores were improved significantly more in the tocilizumab-treated patients with a 1.0 g/dl increase in Hb than in those with a <1.0 g/dl increase in Hb (9.85 vs 6.19, respectively; P<0.0001) Biologic Agents: Practice Implications and Improved Patient Outcomes

9 Effect on Neutrophils Since neutrophils express IL-6 receptors and are involved in the acute-phase response, inhibition of IL-6 receptors is expected to have an effect on neutrophil counts. Preclinical studies in cynomolgus monkeys have demonstrated a dose-dependent decrease in neutrophil counts, although there was no effect on neutrophil function. 17 In healthy volunteers, administration of tocilizumab was associated with a transient reduction in neutrophil counts. 18 In the TOWARD trial, a higher proportion of patients receiving tocilizumab had a decrease in neutrophil counts from normal values to low postbaseline values (29% vs 4%, respectively). 10 The majority of these abnormalities were mild to moderate, with grade 1, 2, and 3 neutropenia reported in 18.8%, 11.6%, and 3.7% of patients, respectively. There were no instances of grade 4 neutropenia, and there was no association between low neutrophil counts and infection-related adverse events. 10 These data suggest that the decreases in neutrophil count are a pharmacodynamic effect of tocilizumab. Given this, caution should be exercised when initiating tocilizumab in patients with a very low neutrophil count at baseline, and all patients should have their absolute neutrophil count (ANC) monitored 4 to 8 weeks after the first infusion. In particular, tocilizumab should not be administered in patients with ANC values <2000 cells/mm 3. If the ANC falls to between 500 and 1000 cells/mm 3, drug therapy should be withheld until the ANC climbs above 1000 cells/mm 2. If the ANC falls to below 500 cells/mm 3, the drug should be discontinued. 19 Effect on Liver Enzymes Treatment with tocilizumab resulted in small mean increases in liver enzymes seen in tests from baseline. In pooled data from the five phase III clinical trials, median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels increased Mean CRP (mg/dl) from baseline in tocilizumab-treated patients but remained within the reference ranges during the study. 20 Increases in ALT levels 3 times the upper limit of normal (ULN) were 6.5% for patients receiving tocilizumab 8 mg/kg plus DMARDs and 4.9% for tocilizumab 4 mg/kg plus DMARDs, compared with 1.5% and 2.1%, respectively, for patients receiving monotherapy with DMARDs or tocilizumab. The values for AST elevations 3 times ULN for these 4 groups were 2.0%, 1.2%, 0.3%, and 1.0%, respectively. The majority of ALT and AST elevations were single occurrences and were manageable by temporary treatment interruption. Shifts in total bilirubin levels from normal were mostly <3 times ULN and were primarily because of increases in indirect bilirubin concentrations. 20 It is recommended that tocilizumab not be initiated in patients with ALT/AST >1.5 times ULN or other evidence of liver disease. For all other patients, transaminases should be monitored every 4 to 8 weeks after the first infusion. When ALT or AST values are between 1 and 3 times ULN, the dose of concomitant DMARDs or tocilizumab should be modified. For persistent increases in this range, the tocilizumab dose should be modified. For ALT/ AST values >3 to 5 times ULN, tocilizumab should be interrupted until the level falls to below 3 times ULN. For ALT/AST values above 5 times ULN, the drug should be discontinued. 19 Effect on Lipids In pooled data from the five phase III clinical trials, tocilizumab was associated with increases in all lipid levels, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. 9 Mean increases from baseline for patients receiving tocilizumab 8 mg/kg plus DMARDs were 30.9 mg/dl (total cholesterol), 21.7 mg/dl (LDL cholesterol), Figure 3. Change From Baseline in Mean C-Reactive Protein (CRP) Levels: Pooled Data From OPTION, TOWARD, AMBITION, RADIATE, and LITHE Studies Placebo + DMARD (n=1,170) 3.0 MTX (n=284) TCZ 8 mg/kg (n=288) 2.5 TCZ 8 mg/kg + DMARD (n=1,582) ULN= Time (Weeks) Infusions DMARD=disease-modifying antirheumatic drug; MTX=methotrexate; TCZ=tocilizumab; ULN=upper limit of normal. Please see text for expanded trial names. 4.3 mg/dl (HDL cholesterol), and 30.1 mg/dl (triglycerides). Similar elevations were seen for patients receiving tocilizumab 4 mg/kg plus DMARDs. The increases were apparent by the first assessment at 6 weeks and remained elevated for the 24-week study. Lipid levels reached a plateau after 6 weeks in the 8-mg/kg plus DMARDs group with no further increase. 9 Patients receiving tocilizumab should have lipid levels monitored with a goal toward maintaining levels within the target ranges of the National Cholesterol Education Program Adult Treatment Panel III or local guidelines. Patients should be managed with lipid-lowering agents if appropriate. An analysis of patients from clinical trials who received statin therapy in combination with tocilizumab found that these patients experienced lower increases in mean LDL cholesterol than did the overall tocilizumab group. 21 Conclusion Results from five large, randomized phase III trials have demonstrated that IL-6 receptor inhibition with tocilizumab resulted in significant clinical improvements in a variety of patient groups with RA, including treatment-naive patients, those with inadequate response to prior DMARD therapy, and patients who are refractory or intolerant to anti-tnf therapy. Further, treatment with tocilizumab has been demonstrated to slow radiographic progression. Despite these beneficial effects, IL-6 inhibition also has potential safety considerations. Effects on neutrophils, liver function, and lipid profiles necessitate appropriate monitoring. References 1. Curr Opin Rheumatol. 2006;18: Arthritis Rheum. 1988;31: Ann Rheum Dis. 1993;32: Handb Exp Pharmacol. 2008;181: Lancet. 2008;371: Ann Rheum Dis Mar 17(epub ahead of print). 7. Ann Rheum Dis. 2008;67: Kremer JM et al. ACR Abstract L Genovese MC et al. ACR Abstract Arthritis Rheum. 2008;58: Genovese MC et al. EULAR Abstract THU Smolen J et al. EULAR Abstract FRI Smolen J et al. EULAR Abstract AB Fleischmann R et al. ACR Abstract Am J Med. 2004;116(suppl 7A):50S-57S. 16. Smolen JS et al. EULAR Abstract THU Clin Immunol. 2001;98: J Rheumatol. 2003;30: Food and Drug Administration Arthritis Advisory Committee. Briefing document for tocilizumab biologic license application Addendum July 29, Available at: gov/ohrms/dockets/ac/acmenu.htm. Accessed October 8, Kremer JM et al. ACR Abstract Genovese MC et al. ACR Abstract Biologic Agents: Practice Implications and Improved Patient Outcomes 9

10 Disease Remission in RA: What Does It Mean? What Is Its Relevance? R heumatoid arthritis (RA) is a chronic debilitating disease associated with enormous clinical and economic consequences for individuals and health care systems. 1 The pain and disability associated with RA has a negative impact on functionality as well as health-related quality of life. Objectives of treatment are focused toward the relief of symptoms (ie, pain, stiffness, swelling, inflammation), prevention of newly evolving joint erosions and joint space narrowing, and the restoration of functional abilities (ie, daily living, work ability, recreational activities). 2 The introduction of new treatment modalities has come a long way toward realizing these goals. However, effective and easy-to-use assessment tools are required to optimize clinical outcomes. Relationship Between Disease Activity, Joint Damage, and Disability Monitoring disease activity is crucial for optimizing outcomes because there is a close relationship between disease activity, joint damage, and disability. 3 There are several indices for measuring disease activity in patients with RA including the American College of Rheumatology (ACR) criteria, the Disease Activity Score (DAS or DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). The DAS, SDAI, and CDAI are particularly useful because they are continuous instruments that allow evaluation and comparison of the actual disease activity and absolute improvement and because they allow for the definition of particular disease activity states (ie, high, moderate, low, remission). 4,5 The SDAI and CDAI are simplified assessment scales that can be easily employed in clinical practice and perform at least as well as more complex indices or response measurements such as the DAS/DAS28 or ACR improvement criteria. 4 There is a strong correlation between the disease activity state and the degree of structural joint damage. Structural damage occurs early in the course of the disease Josef S. Smolen, MD Professor of Medicine. Chairman, Department of Internal Medicine, Division of Rheumatology Medical University of Vienna, Austria and can occur even in the presence of a clinical response, including states of low disease activity. 6 For example, in an analysis of data from the Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial, the level of disease activity during treatment with methotrexate (MTX) was highly associated with joint damage. 6 At week 14, patients who were in remission in terms of disease activity demonstrated virtually no progression of joint damage, whereas higher levels of disease activity and/or a delay in achieving remission were associated with more joint damage. Thus, achieving remission rapidly with traditional disease-modifying antirheumatic drugs (DMARDs) may completely protect patients from the progression of joint damage. 6 Structural damage occurs early in the course of disease and can occur even in the presence of a clinical response. Another study in patients receiving MTX plus tumor necrosis factor (TNF) inhibitors underscored the importance of determining disease activity. 7 In this study, functional outcomes were dependent on the disease activity category attained (Figure 1). 7 Even among patients who achieved profound clinical responses (ie, ACR50 or ACR70), there were statistically significant differences in functional outcomes according to the disease activity state achieved. ACR50 and ACR70 responders with low disease activity or disease in remission had significantly lower (P=0.0001) Health Assessment Questionnaire (HAQ) Disability Index scores than did those with the same level of response but with moderate and/or high disease activity. This suggests that any degree of residual disease activity is associated with physical disability, regardless of treatment. 7 Further, disability in RA has both a reversible and an irreversible component. Inflammation-induced joint tenderness, pain, and stiffness lead to immediate disability (ie, activity-related disability), whereas joint damage leads to laxity and instability in the long term (ie, irreversible disability). 8 These components of disability have been termed ACT-HAQ and DAM-HAQ, respectively. ACT-HAQ reflects functional limitations due to current RA activity, whereas the DAM-HAQ reflects limitations that are not responsive to treatment with antirheumatic drugs. 9 The importance of preventing structural joint damage is evidenced by the strong correlation between joint damage and functional disability even among patients who achieve disease remission. In an analysis of data from 6 clinical trials that included the 295 patients who had achieved disease remission, there was a linear relationship between the degree of joint damage and disability. Higher damage was associated with more disability even during remission. 8 Further, greater structural damage was associated with a decreased reversibility of HAQ scores. These results demonstrate that structural damage is associated with irreversible disability. 8 An examination of data from clinical trials evaluating patients Figure 1. Disability in ACR50 and ACR70 Responders According to Disease Activity in Patients Receiving Methotrexate Plus TNF Inhibitor 7 P< Biologic Agents: Practice Implications and Improved Patient Outcomes Mean HAQ Methotrexate + TNF-Inhibitor Remission Low Disease Activity Moderate Disease Activity P< % 50% 12% 38% 38% 38% ACR50 ACR70 ACR=American College of Rheumatology; HAQ=Health Assessment Questionnaire; TNF=tumor necrosis factor. Reprinted with permission of John Wiley & Sons, Inc.

11 with early RA (PREMIER trial; mean disease duration, <1 year) 10 and those with established RA (DE019 Trial; mean disease duration 11 years) 11 shows that structural damage leads to a compression of reversible disability and irreversible loss of function. 12 Despite differences in disease duration, mean HAQ scores were similar between groups at baseline (ie, 1.5) in these two studies. After 1 year of treatment with adalimumab/mtx, the HAQ score decreased more in patients with early disease (HAQ 0.4) than in those with a longer disease duration (HAQ 0.9). This suggests that the DAM-HAQ becomes an increasingly greater component of the overall HAQ score as the disease duration increases. For patients with new-onset disease, the DAM-HAQ accounts for virtually none of the total HAQ score, whereas the DAM-HAQ accounts for nearly half of the total HAQ score for those with a disease duration of 18 years. 9 Thus, the structural damage associated with continued disease activity raises the baseline disability and results in an inability to normalize functionality. Such observations have allowed the development of a numerical formulation to quantify the relationship between joint damage and the DAM-HAQ. In an analysis using data from the Best Life in RA (BELIRA) clinical trial and several others, 9 a strong correlation between the DAM-HAQ and actual joint damage was observed. This analysis found that an increase of 10 points in Total Sharp Score, a possible annual change with inadequate therapy, would irreversibly increase the DAM-HAQ scores by 0.1 points (Figure 2). 9 This relationship allows the correlation of Figure 2. Correlation Between Damage- Related Health-Assessment Questionnaire (DAM-HAQ) With Total Sharp Score (TSS) 9 DAM-HAQ Correlation of DAM-HAQ with Joint Damage r= unit TSS=0.1 units HAQ TSS r=correlation coefficient. Table. Validated Composite Disease Activity Indices 4,14-16 Index Formula Cutpoints Ease DAS DAS x (Ritchie) x SJC x lognat(esr) x GH* 0.56 X (TJC28) x (SJC28) x lognat(esr) x GH* radiographic score findings with functional changes. Prevention of joint damage is, therefore, important because it often occurs early in the disease process of RA and can continue even in the presence of low disease activity if remission is not achieved. 6 Importance of Appropriate Disease Activity Reporting Disease remission in RA is broadly defined as a state of no (or minimal) inflammatory disease activity, which includes no significant joint involvement, no progression of damage, and the best possible functional capacity. Several remission criteria have been proposed, including those of the ACR, as well as those according to composite disease activity measures, such as the DAS/DAS28, the SDAI, and the CDAI. The ACR remission criteria require 5 of 6 variables to be present: no fatigue, morning stiffness <15 minutes, no joint pain, no joint tenderness, no soft tissue swelling, and an erythrocyte sedimentation rate (ESR) of <30 mm/h (female) or <20 mm/h (male). 13 However, these criteria are not very sensitive because they also classify patients as in remission who have considerable residual activity (eg, those with swollen joints in the absence of other abnormalities). Composite indices such as the DAS, SDAI, and CDAI have the advantage of accounting for several aspects of the disease and combining them into a single numeric value. The SDAI and CDAI are particularly useful for clinical practice because they are easy to score and they perform at least as well as other currently used but more complicated 4, indices (Table). A limitation of the DAS28 is that remission criteria are insufficiently stringent. Several studies involving biologic therapies and MTX have reported DAS28 remission rates that exceed the rates of ACR70 response Patients with only a 70% (or less) improvement in signs and 1.6/2.4/3.7 No 2.6/3/2/5.1 No SDAI SJC28 + TJC28 + PGA + EGA + CRP 3.3/11/26 Yes CDAI SJC28 + TJC28 + PGA + EGA 2.8/10/22 Yes *DAS, DAS28: GH expressed in mm (visual analog scale [VAS]). SDAI, CDAI: PGA, EGA expressed in cm (VAS); SDAI: CRP expressed in mg/dl. CDAI=Clinical Disease Activity Index; CRP=C-reactive protein; DAS=Disease Activity Score; EGA=evaluator global assessment; GH=general health; PGA=patient global assessment; SDAI=Simplified Disease Activity Index; SJC=swollen joint count; TJC=tender joint count. symptoms are considered to be in remission according to DAS28. For example, in the Rheumatoid Arthritis Study in Anti- TNF Failures (RADIATE) trial, DAS28 remission was reported in 30% of patients, whereas ACR70 and ACR50 response rates were 12% and 29%, respectively. 17 In a comparable subset of the Golimumab in Patients With Active Rheumatoid Arthritis After Treatment With Tumour Necrosis Factor Alpha Inhibitors (GO-AFTER) trial, DAS28 remission was reported in 16% of patients, but the ACR70 response rate was only 10%. 19 Similarly, in the Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis (COMET) trial evaluating anti-tnf refractory patients with early disease, DAS28 remission was achieved in 50% of patients, whereas the ACR70 response rate was 48%. 18 Data published at the annual ACR scientific meeting in 2009 confirmed that many patients classified as in remission by the DAS after treatment with tocilizumab are not in remission by other indices. 20 Of 269 patients classified as in DAS28 remission, only 25.6% were in remission according to SDAI criteria and 20.7% according to CDAI criteria. The majority of these patients were in a low disease activity state (59.6% and 62.2%, respectively, for SDAI and CDAI), whereas 14.8% and 17.0%, respectively, were in a moderate disease activity state. 20 The key problem with the DAS28 is that tender joint counts and the ESR are overrepresented in the DAS28 formula. 20,21 Tender joints are weighted twice as highly as those of swollen joints, which is a much more specific feature of RA. ESR values contribute even more to the DAS28 score. Twenty millimeters/hour of the ESR contributes two points to the DAS28, and the relative contribution of ESR is even greater at the normal to near-normal range. 12,21 Biologic Agents: Practice Implications and Improved Patient Outcomes 11

12 What Should Be Our Treatment Goal? It is becoming increasingly clear that a state of low disease activity may be insufficient to prevent poor outcomes, such as the progression of radiographic joint damage and long-term disability. Instead, a state of remission (ie, no evidence of significant active disease ) is needed to interfere with disease progression. 2 The ACR and European League Against Rheumatism (EULAR) recently convened a joint task force to provide guidance on the disease remission in RA. 22 Key recommendations from the task force include the following: (1) a strict definition of remission with stringent criteria is required; (2) the definition of remission should be independent of long-term outcomes; and (3) a definition of remission for clinical practice that correlates to the clinical trial definition is needed. The task force also identified tender/swollen joints and acute-phase reactants as the most important variables for assessing remission. 22 Criteria from the task force are expected to be completed in the near future. In the meantime, current EULAR guidelines reflect an understanding of the importance of remission for patients with early RA and the need for routine monitoring of disease activity. 23 In particular, the guidelines state that the main goal of DMARD treatment is to achieve remission in order to prevent structural damage and long-term disability. They also state that maintaining remission is as important as is achieving remission and that arthritis activity should be assessed at 1- to 3-month intervals, until remission is achieved. 23 These concepts have been incorporated in a treatment algorithm that we employ in our clinical practice (Figure 3). 24 The approach is intensive therapy designed to achieve a CDAI score of 10 (ie, low Figure 3. Treatment Algorithm for the Treatment of Rheumatoid Arthritis 24 NO (Early) DMARD therapy MTX dose mg/week (within 1 2 months) + glucocorticoids CDAI <10 within 3 6 months Switch to another DMARD + glucocorticoids OR Add a biologic agent (eg,tnf inhibitor or tocilizumab) YES NO CDAI <2.8 within 3 6 months There is residual joint swelling and/or CRP increased OR CDAI governed by pain or tenderness, not swelling; CRP normal disease activity) within 3 to 6 months. If this goal is not achieved, therapy should be amended. If this is achieved, treatment should be continued toward a CDAI remission (CDAI 2.8); if this is not attained, the patient should be examined for residual joint swelling and/or an increase in C-reactive protein (CRP) levels. If these are found, pharmacologic therapy should be intensified (ie, switching to or adding another DMARD [± corticosteroids] or adding a biologic agent) to achieve remission. If pain and/or tenderness are the predominant joint findings, there are no swollen joints, and the CRP value is normal, the current intensive regimen should be continued. 12,24 The use of this algorithm has allowed us to achieve high rates of clinical success. An analysis of 621 outpatients who were treated with DMARDs with or without biologic agents at our clinic revealed remission rates of 33.5% (CDAI and SDAI criteria) and sustained remission rates of 16.7% to 18%. 25 These results indicate that sustained remission is an achievable goal in clinical practice. Clinical Practice Guidance The strong relationship between disease activity and structural and functional outcomes emphasizes the importance of assessing disease activity routinely. However, given the constraints on time, rheumatologists must have assessment tools that are simple and easy to perform and allow for rapid decision making (ie, without waiting for laboratory results). The protocol in our clinic is to determine the CDAI at every visit with a goal toward achieving low disease activity as quickly as possible. 26 Because consistency in the assessment of disease activity is important for improving outcomes, patients are seen often (approximately every 6 weeks) in the early stages of DMARD therapy. Once disease activity Switch to (or add) another DMARD +/- corticosteroids OR Add a biologic agent (eg,tnf inhibitor, abatacept, rituximab or tocilizumab) YES Continue intensive DMARD/biologic therapy (stop biologic?) CDAI=Clinical Disease Activity Index; CRP=C-reactive protein; DMARD=disease-modifying antirheumatic drug; MTX=methotrexate; TNF=tumor necrosis factor. comes into control, subsequent visits can be less frequent (eg, every 3-6 months). The CDAI criteria are stringent and allow for the use of aggressive therapeutic approaches. When patients are in a moderate to high state of disease activity (ie, CDAI >10), the CDAI is generally sufficient to monitor disease activity. However, in the low disease activity range (CDAI 10), it is important to judge the composition of the index. If the CDAI score is primarily driven by swollen joint counts, a change in the therapeutic regimen may be warranted, whereas if the score is driven by the patient global assessment, therapy changes are not warranted. Finally, inclusion of patients in the process is important to maximize outcomes. We provide CDAI diaries to patients so they can enter their CDAI score at each visit, allowing them to monitor their disease activity over time. Well-informed patients who are vested in their disease management are more compliant with therapy, increasing the treating physician s ability to achieve clinical goals. Conclusion Recent evidence underscores the importance of attaining disease remission in patients with RA. Remission, preferably early in the disease, is critical for preventing progression of joint damage and improving physical function. Improvements in treatment modalities and disease assessment have made remission an attainable goal and easy to monitor. Rheumatologists and patients must work together in the routine monitoring of disease activity so that the achievement of optimal clinical outcomes is ensured. References 1. Lancet. 2007;370: Clin Exp Rheumatol. 2006;24(suppl 43):S7-S Arthritis Res Ther. 2009;11: Curr Opin Rheumatol. 2008;20: Best Pract Res Clin Rheumatol. 2007;21: Ann Rheum Dis. 2009;68; Arthritis Rheum. 2008;58: Arthritis Rheum. 2006;54: Ann Rheum Dis. (epub ahead of print), Aug 27, 2009 doi: /ard Arthritis Rheum. 2006;54: Arthritis Rheum. 2004;50: Clin Exp Rheumatol. In press. 13. Arthritis Rheum. 1981;24: Ann Rheum Dis. 1990;49: Arthritis Rheum. 1995;38: Rheumatology. 2003;42: Ann Rheum Dis. 2008;67: Lancet. 2008;372: Lancet. 2009;374: Smolen J et al. ACR Abstract Ann Rheum Dis. 2007;66:iii56-iii Arthritis Rheum. 2009;61: Ann Rheum Dis. 2007;66: Clin Exp Rheumatol. 2003;21(suppl 31):S209-S Rheumatology. 2007;46: Rheum Dis Clin North Am. 2006;32: Biologic Agents: Practice Implications and Improved Patient Outcomes