Clinical Updates in Rheumatoid Arthritis by Integritas Communications

JONATHAN Kay, MD ALAN J. Kivitz, MD, CPI This activity is jointly provided by Global Education Group and Integritas Communications. This activity is supported by an educational grant from Genzyme, a Sanofi Company, and Regeneron Pharmaceuticals.

This activity is jointly provided by Global Education Group and Integritas Communications. This activity is supported by an educational grant from Genzyme, a Sanofi Company, and Regeneron Pharmaceuticals.

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TABLE OF CONTENTS Faculty iv Preamble vi Chapter 1 Rheumatoid Arthritis Pathophysiology and the Roles of IL-6

Chapter 2 Comprehensively Evaluating Patients With Rheumatoid Arthritis

Chapter 3 Biologic Inhibitors of IL-6 Signaling 17 Chapter 4 Individualizing Rheumatoid Arthritis Management and the Role of IL-6 Inhibition

Rheumatoid Arthritis 35 Clinical Resource Centerâ&#x201E;˘ Rheumatoid Arthritis 41 Supplemental Video Library

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

FACULTY Jonathan Kay, MD Timothy S. & Elaine L. Peterson Chair in Rheumatology & Professor of Medicine University of Massachusetts Medical School Director of Clinical Research, Rheumatology UMass Memorial Medical Center Worcester, Massachusetts

Dr. Jonathan Kay is Professor of Medicine at the University of Massachusetts Medical School and a physician at UMass Memorial Medical Center in Worcester, where he directs clinical research in the Division of Rheumatology. He received his medical degree from the University of California School of Medicine in San Francisco, California. He then completed an internship and residency at the Hospital of the University of Pennsylvania in Philadelphia and fellowships in rheumatology and immunology at The Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts. Dr. Kay is an ad hoc reviewer for many journals, a member of the editorial boards of Best Practice and Research Clinical Rheumatology and the Journal of Clinical Rheumatology, and a member of the Advisory Board of Arthritis Research and Therapy. Section Editor of “Systemic Disorders with Rheumatic Manifestations” for Current Opinion in Rheumatology, he has presented his work at international lectures and authored more than 100 journal articles and book chapters. Dr. Kay is a Fellow of the American College of Rheumatology and of the American College of Physicians. His clinical interests span the spectrum of rheumatic diseases, with special interest in rheumatoid arthritis and other forms of inflammatory arthritis. He was a member of the group that developed the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Diagnostic and Classification Criteria for Rheumatoid Arthritis. He chairs the Rheumatology Working Group and is a member of the Internal Medicine and Musculoskeletal Topic Advisory Groups for the World Health Organization in its Revision of the International Classification of Diseases (ICD)-11.

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FACULTY

Alan J. Kivitz, MD, CPI President of Altoona Arthritis and Osteoporosis Center Medical Lab Director for Adult and Pediatric Rheumatology Lab Duncansville, Pennsylvania

Dr. Alan J. Kivitz is the Founder and Medical Director of the Altoona (Pennsylvania) Center for Clinical Research and Altoona Arthritis and Osteoporosis Center in Duncansville, Pennsylvania. As a practicing physician, Dr. Kivitz has more than 34 years of experience treating patients with arthritis and rheumatic disorders. He received his medical degree from Albany Medical College in Albany, New York. He completed training in internal medicine at the North Shore University Hospital in Manhasset, New York, and at Memorial Sloan Kettering Cancer Center in New York, New York. He then completed his fellowship in rheumatology at Albany Medical College. He is board certified in internal medicine as well as the subspecialty of rheumatology. Dr. Kivitz has authored and coauthored more than 200 research articles and abstracts covering osteoarthritis, osteoporosis, rheumatoid arthritis, and pain management. He has also served as a Principal Investigator or Sub Investigator in more than 900 clinical trials. In addition, his studies have been published in several prestigious medical journals including The New England Journal of Medicine, Pain Medicine, Journal of the American Medical Association, Arthritis & Rheumatology, and Journal of Clinical Rheumatology. He has served as a consultant on numerous osteoarthritis and rheumatoid arthritis clinical trials. Dr. Kivitz is an active member of the Pennsylvania Medical Society, the American Medical Association, and the International Society for Clinical Densitometry. He holds certifications in Human Subjects Protection and HIPAA Research Training, and is deemed a Certified Principal Investigator by the Association of Clinical Research Professionals. His research has focused on the development of newer strategies for treating patients with arthritis and rheumatic disorders.

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

PREAMBLE Target Audience The educational design of this activity addresses the needs of rheumatologists and other clinicians involved in the ongoing management of patients with rheumatoid arthritis (RA).

Statement of Need/Program Overview RA is a chronic, progressive inflammatory autoimmune disease producing both articular and extra-articular manifestations.1,2 Of note, studies have shown that mortality risks are 50% higher in people with RA compared with the general population.3 The differential responses seen with current treatment modalities suggest that overlapping signaling pathways driven by proinflammatory cytokines can control the characteristic autoreactivity and other clinical manifestations of RA.4 In particular, elevated levels of interleukin-6 (IL-6) and its receptor are found in affected joints, where they contribute to cartilage damage and bone erosion.5 Additionally, signaling via soluble IL-6 receptor likely contributes to the systemic inflammatory effects of RA.6 Adopting treat-to-target strategies and actively targeting remission in each patient has shown great promise in improving RA outcomes, but up to 40% of patients do not adequately respond to conventional disease-modifying antirheumatic drugs (DMARDs) or inhibitors of tumor necrosis factor.6 These data highlight the need for other options, including 2 biologic DMARDs that are specific for the IL-6 receptor.6,7 This eHealth Sourceâ&#x201E;˘ activity has been developed as a text-based eBook with additional video clips to update clinicians on the latest evidence-based information to guide RA management, with a focus on inhibition of IL-6 signaling.

References

1. Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. 2. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51 (suppl 5):v3-v11. 3. Young A, et al. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford). 2007;46(2):350-357. 4. Goetz I, et al. Review of treatment response in rheumatoid arthritis: assessment of heterogeneity. Curr Med Res Opin. 2011;27(4):697-711. 5. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24. 6. Bykerk VP, et al. Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis. 2012;71(12): 1950-1954. 7. Burmester GR, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847.

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PREAMBLE

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Educational Objectives After completing this activity, the participant should be better able to: • Discuss the proinflammatory cellular and cytokine networks underlying localized and systemic RA pathophysiology • Employ treat-to-target strategies based on objective measures of RA activity and comprehensive evaluations of patient health status • Describe the clinical profiles of current and emerging biologic DMARDs targeting IL-6 signaling for the treatment of RA • Tailor treatment regimens for moderate-to-severe RA based on ongoing monitoring of disease activity, functional status, treatment response, and other patient-specific factors • Educate patients with RA to facilitate shared decision-making and encourage self-management

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Instructions to Receive Credit In order to receive credit, participants must complete the preactivity questionnaire, postactivity questionnaire, and program evaluation at www.ExchangeCME.com/RAeHealth

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

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System Requirements PC

MAC

Microsoft Windows 2000 SE or above. Flash Player Plugin (v7.0.1.9 or greater) Internet Explorer (v5.5 or greater), or Firefox Adobe Acrobat Reader*

MAC OS 10.2.8 Flash Player Plugin (v7.0.1.9 or greater) Safari Adobe Acrobat Reader* Internet Explorer is not supported on the Mac

*Required to view printable (PDF) version of the lesson.

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers, and other individuals and their spouses/life partners who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Jonathan Kay, MD Consultant: AbbVie Inc.; Amgen Inc.; AstraZeneca; Boehringer Ingelheim GmbH; Bristol-Myers Squibb Company; Epirus Biopharmaceuticals, Inc.; Genentech, Inc.; GlaxoSmithKline plc; Hospira Inc.; Janssen Biotech, Inc.; Merck Sharp & Dohme Corp.; Pfizer Inc.; Roche Laboratories, Inc.; Samsung Bioepis Co., Ltd.; Sandoz Inc.; UCB, Inc. Research Support: AbbVie Inc.; Genentech, Inc.; Pfizer Inc.; Roche Laboratories, Inc.; UCB, Inc. Alan J. Kivitz, MD, CPI Consultant/Independent Contractor: Regeneron Pharmaceuticals, Inc., sanofi-aventis U.S. LLC.; Grant/Research Support: Regeneron Pharmaceuticals, Inc., sanofi-aventis U.S. LLC.; Speakers Bureau: Regeneron Pharmaceuticals, Inc., sanofi-aventis U.S. LLC.

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PREAMBLE

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Karen Kaufman

Nothing to disclose

Ashley Marostica, RN, MSN

Nothing to disclose

Andrea Funk

Nothing to disclose

Laura Gilsdorf

Nothing to disclose

Rose Oâ&#x20AC;&#x2122;Connor, PhD

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) and Integritas Communications do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturerâ&#x20AC;&#x2122;s product information, and comparison with recommendations of other authorities.

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

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CHAPTER 1

Rheumatoid Arthritis Pathophysiology and the Roles of IL-6

heumatoid arthritis (RA) is a chronic, progressive inflammatory autoimmune disease.1-3 It is a relatively common form of arthritis among adults, with an estimated prevalence between 0.6% and 2% in the United States.4,5 Importantly, patients can suffer from a number of problematic medical and psychosocial outcomes. For example, studies have shown that mortality risk is 50% higher among patients with RA compared with the general population, a gap that has not closed over the past few decades despite improvements in other treatment goals.2,6-8 Patients with persistently active disease are likely to report poor healthrelated quality of life and develop significant functional disability.9 Indeed, patients with RA are more likely to be limited in performance of their daily activities, as compared with healthy individuals.10 RA also is associated with substantial economic burdens, including direct medical expenses and lost lifetime earnings.11 Studies have documented significant work restrictions, decreased productivity, and increased unemployment rates for affected individuals.12 These and other studies continue to show several important unmet needs in the management of patients with RA (see link to supplementary VIDEO 1).

ARTICULAR AND EXTRA-ARTICULAR DISEASE MANIFESTATIONS Synovial inflammation and hyperplasia in RA result in joint damage, most commonly affecting the small joints of the hands and feet.2,5,13 Extra-articular manifestations may also occur.1,13 Peripheral articular involvement manifests with the hallmark signs and symptoms of RA: joint pain, swelling, stiffness, and, eventually, without proper treatment, permanent joint damage and deformity.13 Interestingly, progression of joint damage may be dissociated from clinical disease activity, which is the primary target for RA treatment.14 Thus, patients who meet some criteria for remission may still exhibit progression of structural damage Download this activity and additional tools at

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

VIDEO 1. Unmet Needs in Patients With Rheumatoid Arthritis Jonathan Kay, MD on radiographs; others may exhibit minimal or no progression of joint damage, even with measurable RA disease activity.15,16 This suggests that, in addition to targeting a state of remission in every patient (see Chapter 2), clinicians should assess for progression of joint damage on a regular basis.14 Extra-articular manifestations can develop throughout the course of RA, including in early-stage disease (Table 1).17 These complications are more likely to appear in patients who smoke and in those with rheumatoid factor or anti-citrullinated protein antibodies (ACPA).18 Rheumatoid nodules are the most common extra-articular manifestation of RA and may be associated with other extra-articular involvement, especially when these nodules develop within 2 years of RA diagnosis.19,20 Cardiovascular disease develops more commonly among RA patients compared with age-matched controls, and is among the leading causes of premature death in these patients.6,21,22 In RA, the development of cardiovascular disease cannot be explained entirely by traditional risk factors, suggesting that chronic inflammation contributes to its pathogenesis.23,24 Patients with RA also may develop

CHAPTER 1 Rheumatoid Arthritis Pathophysiology and the Roles of IL-6

TABLE 1. More Common Extra-Articular Manifestations in RA20 Affected System or Organ

Extra-articular Manifestations

Inflammatory-process associated features

• Normochromic-normocytic anemia • Secondary Sjögren’s syndrome • Sarcopenia • Osteoporosis

Skin

• Rheumatoid nodules • Cutaneous vasculitis

Pulmonary system

• Pulmonary nodules • Pleural effusion • Interstitial lung disease

Cardiovascular system • Ischemic cardiovascular disease • Congestive heart failure • Pericarditis or myocarditis • Coronary vasculitis Kidneys

• Interstitial nephritis

Hematologic system

• Felty’s syndrome

pulmonary manifestations, most notably interstitial lung disease with an associated risk for premature mortality.7,25 Interstitial lung disease in RA resembles idiopathic pulmonary fibrosis.20 RA-associated interstitial lung disease most commonly presents morphologically and pathologically as usual or nonspecific interstitial pneumonia, but is more likely to respond favorably to immunosuppressive drug therapy than idiopathic pulmonary fibrosis.20,26 Besides specific organ involvement, more generalized symptoms of RA—eg, fatigue, weight loss, generalized muscle weakness, and depression—are common, often markedly impinging on patients’ quality of life.20,27

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

FACTORS CONTRIBUTING TO RA DEVELOPMENT: A FOCUS ON IL-6 Although the precise cause of RA is not known, the disease develops as a result of interactions among genetic, environmental, and stochastic events.28 Research has identified genetic and environmental factors that increase the chances of RA onset.28,29 The pathogenesis of RA involves various cells, including T and B lymphocytes, dendritic cells, neutrophils, mast cells, monocyte/macrophages, fibroblast-like synoviocytes, and osteoclasts (Figure 1).2,30,31 Proinflammatory cytokines produced by these cells, such as interleukin (IL)-1, IL-6, and tumor necrosis

Healthy Joint

Capsule Synovium Neutrophil Cartilage

RA Joint

Osteoclast Fibroblast Macrophage Dendritic Cell T Cell Plasma Cell B Cell Extensive Angiogenesis Mast Cell

Synoviocytes

Hyperplastic Synovial Lining

Bone

FIGURE 1. Increased inflammation and cellular activity in the RA joint.2,37

CHAPTER 1 Rheumatoid Arthritis Pathophysiology and the Roles of IL-6

factor (TNF), drive downstream pathologic processes that mediate neoangiogenesis, synovial hyperplasia, and ultimately joint destruction (see link to supplementary VIDEO 2).32 Of note, the functions of these cytokines somewhat overlap and reinforce each other in RA; however, the balance among these signaling cascades may differ from patient to patient, a phenomenon supported by the differential responses observed with currently available targeted agents.33,34

VIDEO 2. Pathophysiologic Underpinnings of Rheumatoid Arthritis Jonathan Kay, MD Since the demonstration that its inhibition ameliorates RA disease activity, TNF has been known to contribute to the inflammatory process in RA. Within the RA joint, TNF activates monocytes; decreases synovial fibroblast proliferation; regulates T cell development; reduces collagen synthesis; and increases the release of proinflammatory cytokines and matrix metalloproteinases.38 Targeting TNF with various biologic medications has significantly reduced clinical signs of inflammation, halted progression of structural damage, and improved other outcomes in patients with RA.39 However, some patients do not respond adequately to anti-TNF agents; in these patients, targeted therapies with alternative modes of action may be beneficial.

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

Another proinflammatory factor that plays a central role is IL-6, a pleiotropic cytokine involved in multiple aspects of RA pathogenesis (Table 2). IL-6 functions by binding to membrane-bound (classic signaling) or soluble (trans signaling) IL-6 receptor (IL-6R).2,38 The ligandreceptor complex recruits 2 gp130 molecules to form the functional receptor complex.2 Patients with RA have elevated serum levels of IL-6 and soluble IL-6R, which correlate positively with disease activity and joint damage.39 In one study, compared with healthy controls, patients with RA had increased serum levels of IL-6 and other proinflammatory cytokines (eg, TNF, IL-1Î˛, IL-17, interferon-Îą), but only the IL-6 level significantly correlated with the disease activity score using 28 joints (DAS28) before treatment.40 Downstream effects of IL-6/IL-6R signaling include neutrophil recruitment through activated fibroblasts, and the activation of T cells, B cells, and endothelial cells.2,38 In RA, increased levels of IL-6 and IL-6R have been detected in affected joints.41 IL-6-mediated inflammatory processes contribute to suppression of osteoblast activity, differentiation of osteoclasts, activation of fibroblastic synovial cells, and synovial pannus formation, all of which result in cartilage destruction and bone erosion.38 Further, signaling via soluble IL-6R likely contributes to the systemic effects of IL-6, allowing induction of responses in tissues that do not express the membrane-bound IL-6R, which may be distance from the cells producing the cytokine.2,38 Potential extraarticular consequences of IL-6 signaling include anemia of chronic disease, osteoporosis, and increased production of acute phase proteins and autoantibodies (ACPA and rheumatoid factor).2,38

TABLE 2. Roles of IL-6 in the Pathogenesis of RA2,38 Articular Effects

Systemic Effects

Osteoclast activation

Acute-phase reactant production

Neutrophil recruitment

Cardiovascular disease

Pannus formation

Osteoporosis

B-cell proliferation

Anemia

T-cell proliferation

Fatigue Depression

CHAPTER 1 Rheumatoid Arthritis Pathophysiology and the Roles of IL-6

KEY CLINICAL HIGHLIGHTS • RA is associated with premature mortality, which is often the result of cardiovascular complications • Differences among patients in their response to available treatments suggest that a variety of immune and inflammatory pathways result in the clinical manifestations of RA • Among the cytokines that can be therapeutically targeted in patients with RA, TNF and IL-6 signaling contribute to synovial inflammation and joint damage, as well as systemic effects of inflammation

REFERENCES 1. Cojocaru M, et al. Extra-articular manifestations in rheumatoid arthritis. Maedica (Buchar). 2010;5(4):286-291. 2. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51 (suppl 5):v3-v11. 3. Singh JA, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. 4. Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. 5. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Handout on Health: Rheumatoid Arthritis. Bethesda, MD: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; 2016. NIH Publication No. 14-4179 6. Skeoch S, Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol. 2015;11(7):390-400. 7. Young A, et al. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford). 2007;46(2):350-357. 8. Widdifield J, et al. Trends in excess mortality among patients with rheumatoid arthritis in Ontario, Canada. Arthritis Care Res (Hoboken). 2015;67(8):1047-1053. 9. Salaffi F, et al. Health-related quality of life in fibromyalgia patients: a comparison with rheumatoid arthritis patients and the general population using the SF-36 health survey. Clin Exp Rheumatol. 2009;27(5 suppl 56):S67-S74. 10. Dominick KL, et al. Health-related quality of life among older adults with arthritis. Arthritis Rheum. 2004;51(3):326-331. 11. Miranda LC, et al. Finding Rheumatoid Arthritis Impact on Life (FRAIL Study): economic burden. Acta Reumatol Port. 2012;37(2):134-142. 12. Filipovic I, et al. Quantifying the economic burden of productivity loss in rheumatoid arthritis. Rheumatology (Oxford). 2011;50(6):1083-1090. 13. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358(9285):903-911. 14. Lafeber FP, Van der Laan WH. Progression of joint damage despite control of inflammation in rheumatoid arthritis: a role for cartilage damage driven synovial fibroblast activity. Ann Rheum Dis. 2012;71(6):793-795. 15. Lillegraven S, et al. Remission and radiographic outcome in rheumatoid arthritis: application of the 2011 ACR/EULAR remission criteria in an observational cohort. Ann Rheum Dis. 2011;71(5):681-686.

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

16. Landewe R, et al. Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results from the trial of etanercept and methotrexate with radiographic and patient outcomes. Arthritis Rheum. 2006;54(10):3119-3125. 17. Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21(5):907-927. 18. Prete M, et al. Extra-articular manifestations of rheumatoid arthritis: An update. Autoimmun Rev. 2011;11(2):123-131. 19. Turesson C, et al. Predictors of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol. 2000;29(6):358-364. 20. Vela P. Extra-articular manifestations of rheumatoid arthritis, now. EMJ Rheumatol. 2014;1:103-112. 21. Shoenfeld Y, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation. 2005;112(21):3337-3347. 22. Nicola PJ, et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 2005;52(2):412-420. 23. Crowson CS, et al. How much of the increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease? Arthritis Rheum. 2005;52(10):3039-3044. 24. del Rincon ID, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44(12):2737-2745. 25. Dawson JK, et al. Predictors of progression of HRCT diagnosed fibrosing alveolitis in patients with rheumatoid arthritis. Ann Rheum Dis. 2002;61(6):517-521. 26. Lee HK, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127(6):2019-2027. 27. Kirwan JR, et al. OMERACT 10 Patient Perspective Virtual Campus: valuing health; measuring outcomes in rheumatoid arthritis fatigue, RA sleep, arthroplasty, and systemic sclerosis; and clinical significance of changes in health. J Rheumatol. 2011;38(8):1728-1734. 28. Klareskog L, et al Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006;2(8):425-433. 29. Silman AJ, et al. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum. 1996;39(5):732-735. 30. Smolen JS, et al. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370(9602):1861-1874. 31. Szekanecz Z, Koch AE. Mechanisms of disease: angiogenesis in inflammatory diseases. Nat Clin Pract Rheumatol. 2007;3(11):635-643. 32. Siebert S, et al. Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol Rev. 2015;67(2):280-309. 33. Malaviya AM. Cytokine network and its manipulation in rheumatoid arthritis. J Assoc Physicians India. 2006;54 (suppl):15-18. 34. Goetz I, et al. Review of treatment response in rheumatoid arthritis: assessment of heterogeneity. Curr Med Res Opin. 2011;27(4):697-711. 35. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2(6):473-488. 36. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-442. 37. Aaltonen KJ, et al. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7(1):e30275. 38. Kim GW, et al. IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch Pharm Res. 2015;38(5):575-584. 39. Kishimoto T. Interleukin-6: from basic science to medicine--40 years in immunology. Annu Rev Immunol. 2005;23:1-21. 40. Shimamoto K, et al. Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis. J Rheumatol. 2013;40(7):1074-1081. 41. Kotake S, et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996;11(1):88-95.

CHAPTER 2

Comprehensively Evaluating Patients With Rheumatoid Arthritis

linical research over the past 2 decades supports early diagnosis and relatively aggressive treatment of rheumatoid arthritis (RA) to optimize patient outcomes.1 In 2010, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) jointly published revised RA classification criteria to improve case identification.2 The previous version of the ACR’s criteria— published in 1987—included radiographic evidence of joint damage as 1 of the 7 possible criteria, and did not include markers of disease pathogenesis, such as anti-citrullinated protein antibodies (ACPA).2 Thus, while the 1987 classification criteria identified patients with established disease, these criteria did not classify patients with early disease, asymmetric involvement of only 1 or 2 joints, and no radiographic evidence of structural damage as having RA.2 One study found that more than a third of patients with a initial diagnosis of undifferentiated arthritis according to the 1987 ACR classification criteria would be classified as having RA using the 2010 ACR/EULAR revised classification criteria.3 Importantly, the newer classification system emphasizes clinical features of early-stage disease, which, when identified quickly and treated appropriately, can often result in clinical remission, thereby preventing joint damage and preserving function.2 In contrast, delaying diagnosis and treatment until irreversible joint damage is visible on radiographs results in loss of function and permanent disability.2,4,5 As discussed briefly in Chapter 1, treatment goals should be multidimensional, including disease remission primarily based on clinical evaluation of synovial inflammation, to prevent joint damage and systemic manifestations and to improve patient-reported outcomes.4-6

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

CORE TENETS OF TREATING TO TARGET IN RA The concept of treating RA early and aggressively has now been structured within a broader management framework, referred to as â&#x20AC;&#x153;treating-to-target.â&#x20AC;?4,5 In its simplest form, the treat-to-target paradigm seeks tight control of RA pathologic processes by adjusting therapeutic regimens based on repeated quantitative assessment of disease activity at regular intervals. The paradigm aims to achieve clinical remission for all cases.4,5 However, in patients who cannot achieve remission because of preexisting structural damage or who are unable to aggressively escalate therapy for medical or other reasons, a state of low disease activity may be acceptable as an alternative to clinical remission, as long as synovial inflammation is minimized to prevent joint damage and improve or at least maintain physical function.4,5 An international task force of expert rheumatologists published 4 overarching principles for treating to target in RA: 1) therapy must be based on shared decision-making between patients and rheumatologists; 2) treatment regimens should aim to maximize long-term health-related quality of life via control of symptoms, prevention of structural damage, and normalization of social and workrelated functioning; 3) the most important factor to achieve these goals is abrogation of inďŹ&#x201A;ammation; and 4) disease activity should be monitored and repeatedly measured, allowing for appropriate adjustments to therapy to optimize RA outcomes (see link to supplementary VIDEO 3).7 The task force also provided 10 specific recommendations to help clinicians treat RA to target (Box 1).7 Critical to this approach are recurrent quantitative evaluations of disease activity (as often as every 1 to 3 months for active RA) and targeting acceptable thresholds for low disease activity or remission.4,5,7 Further, both the patient and provider must be willing to tailor management regimens until the recommended outcome has been achieved. When the patient is not responding adequately to treatment and RA remains active, therapy should be adjusted at least every 3 months, an evidence-based time point at which treatment responses are highly predictive of whether a patient is likely or unlikely to achieve remission at a later date.7-9 Studies have shown that a treat-to-target approach results in better outcomes for patients with RA compared with usual care without quantitative assessment of disease activity and protocol-driven escalation of therapy, including lower disease activity, higher remission rates, fewer comorbidities, lower risk of cardiovascular comorbidities, better work productivity, and more costeffective health care.10-13

CHAPTER 2 Comprehensively Evaluating Patients With RA

VIDEO 3. Treating to Target in Rheumatoid Arthritis Jonathan Kay, MD

VALIDATED MEASURES OF DISEASE ACTIVITY The number of approaches to assess RA disease activity continues to expand, including increased consideration of patient-reported outcomes, better use of existing disease activity measures, and the introduction of additional quantitative biomarkers.14-17 Many published reports characterize and validate RA disease activity measures, providing both opportunities and complexities for practicing clinicians. In 2012, the ACR whittled 63 identified options down to a panel of 6 recommended disease activity measures based, in part, on their psychometric properties and reports from practicing rheumatologists (Table 1).18 Additionally, considering the diversity of health care settings in which patients with RA are managed, the measures selected by the ACR include various approaches to collecting the required information, such as using entirely patient-reported parameters or combining provider-based evaluations with or without analyses of acute-phase reactants.18 Each measure has potential benefits and drawbacks in helping clinicians assess patients with RA over time. For instance, patient-reported instruments can be completed in the waiting room and are easy to incorporate into the work flow of busy practices,

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

BOX 1. Recommendations on treating RA to target based on evidence and expert opiniona,7 1. The primary target for treatment of RA should be a state of clinical remission 2. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity 3. While remission should be a clear target, low-disease activity may be an acceptable alternative therapeutic goal, particularly in long-standing disease 4. The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions 5. The choice of the (composite) measure of disease activity and the target value should be influenced by comorbidities, patient factors, and drug-related risks 6. Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every 6 months) for patients in sustained low-disease activity or remission 7. Structural changes, functional impairment, and comorbidity should be considered when making clinical decisions, in addition to assessing composite measures of disease activity 8. Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months 9. The desired treatment target should be maintained throughout the remaining course of the disease 10. The rheumatologist should involve the patient in setting the treatment target and the strategy to reach this target Recommendations are summaries that should be interpreted in the context of the accompanying text (visit www.ExchangeCME.com/RAResources for access to the full publication). a

CHAPTER 2 Comprehensively Evaluating Patients With RA

Pain

Remission Definitions

Provider Global VAS

Patient Global VAS

Physician Joint Count

TABLE 1. Validated Composite Measures of RA Disease Activity18

PAS

•

0.00-0.25

PAS-II

•

0.00-0.25

RAPID-3

•

0-1.0

Patient-driven composite tools

Patient and provider composite tool CDAI

•

≤2.8

Patient, provider, and laboratory composite tools DAS28 (ESR or CRP)

•

SDAI

•

<2.6 •

≤3.3

CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score with 28 joint count; ESR, erythrocyte sedimentation rate; NA, not applicable; PAS, Patient Activity Scale; RAPID, Routine Assessment of Patient Index Data; SDAI, Simple Disease Activity Index; VAS, visual analog scale.

but these measures do not include formal joint counts, which some experts think are essential for monitoring disease activity.19 No single measure is preferred over any other. Rather than the specific disease activity measure itself, it is most important to pick a measure, use it consistently, and document results over time to guide clinical decisionmaking (see link to supplementary VIDEO 4).18

ADDITIONAL EVALUATION CONSIDERATIONS Individualized management plans are based on comprehensive assessment of RA manifestations—both articular and extra-articular— and associated comorbidities. Rheumatologists must monitor disease activity as but one component of the multidimensional evaluation of each patient.20 Indeed, treat-to-target strategies aim to arrest both

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

VIDEO 4. Disease Activity Measures for Rheumatoid Arthritis Jonathan Kay, MD localized joint disease activity and systemic inflammation, reducing their associated signs, symptoms, health risks, and tissue damage.21 As discussed in Chapter 1, RA may present with a number of extra-articular manifestations. The international COMORA study demonstrated that comorbidities and their risk factors are highly prevalent among patients with RA.22 This and other studies have shown that additional efforts are needed to identify, prevent, and manage these complications. Thus, rheumatologists must be vigilant about the broad range of comorbid conditions that may affect RA patients, during their initial and subsequent evaluations.22,23 Structured approaches to patient evaluation and laboratory testing are imperative. Certain comorbid risks must be interpreted in light of the RA diagnosis. For example, outcomes from cardiovascular disease prediction models, such as the Framingham Risk Score, should be adjusted by multiplying by a factor of 1.5 to account for additional RA-related risks.24 Increased monitoring for serious infections is also needed, especially when immunomodulatory therapies have been initiated.25 It is clear that psychological burdens

CHAPTER 2 Comprehensively Evaluating Patients With RA

can be problematic; and patients commonly describe feelings of depression, which can negatively and reciprocally interact with disease symptoms.25 Thus, patients should be screened for psychological status and appropriately managed based on findings.25 There has also been increased focus on joint imaging in patients with both early and established RA, as well as in individuals at risk for RA.26,27 The need for objective measures of joint inflammation and structural damage combined with technologic advances has led many rheumatologists to image affected joints for disease courses and treatment responses.26 Moreover, imaging can help clinicians educate patients and shape shared decision-making using images of their disease.26 Numerous publications from national and international societies address the roles of various imaging approaches in the diagnosis and evaluation of rheumatic disorders. For example, in 2012, the European Society of Musculoskeletal Radiology (ESSR) produced recommendations on how to best use ultrasonography and magnetic resonance imaging (MRI) to diagnose musculoskeletal diseases, highlighting ultrasonography as the method of choice for imaging peripheral synovitis.28,29 Ultrasonography is also discussed in the 2010 ACR/EULAR RA classification criteria as a tool to detect

KEY CLINICAL HIGHLIGHTS • Comprehensively evaluating patients with RA requires assessment of articular and extra-articular disease and associated comorbidities • The revised ACR classification system emphasizes clinical features of early-stage disease so that treatment can be initiated as early as possible • Treat-to-target approaches for RA entail adjusting therapeutic regimens when ongoing evaluations of disease activity suggest that the disease is not in remission (or low disease activity in certain situations) • The ACR recommends the use of any of 6 validated disease activity measures to monitor patients with RA over time • The use of imaging modalities, especially ultrasound, can provide objective evidence of disease activity and assist in patient education and shared decision-making

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

articular inflammatory changes that may otherwise be ambiguous.2 In the EULAR recommendations about medical imaging of joints in RA, 9 of the 10 recommendations address ultrasonography to detect inflammation, predict progression and treatment responses, monitor disease activity, and identify joints that are in imaging remission.30

REFERENCES 1. Ruderman EM, et al. Incorporating the treat-to-target concept in rheumatoid arthritis. J Manag Care Pharm. 2012;18(9):1-18. 2. Aletaha D, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. 3. de Hair MJ, et al. The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria: is this still the same disease? Arthritis Rheum. 2012;64(2):389-393. 4. Singh JA, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. 5. Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977. 6. Felson DT, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573-586. 7. Smolen JS, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3-15. 8. Soubrier M, et al. Disease activity score-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis: data from the GUEPARD trial and ESPOIR cohort. Ann Rheum Dis. 2011;70(4):611-615. 9. Aletaha D, et al. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum. 2007;56(10):3226-3235. 10. Stoffer MA, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update. Ann Rheum Dis. 2016;75(1):16-22. 11. Vermeer M, et al. Treating to the target of remission in early rheumatoid arthritis is costeffective: results of the DREAM registry. BMC Musculoskelet Disord. 2013;14:350. 12. Grigor C, 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(9430):263-269. 13. Goekoop-Ruiterman YP, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum. 2008;58(suppl 2):S126-S135. 14. Aletaha D. New insights into the measurement of disease activity in rheumatoid arthritis. Curr Opin Rheumatol. 2015;27(3):268-272. 15. Baker JF, et al. Development and validation of modified disease activity scores in rheumatoid arthritis: superior correlation with magnetic resonance imagingâ&#x20AC;&#x201C;detected synovitis and radiographic progression. Arthritis Rheumatol. 2014;66(4):794-802. 16. Rintelen B, et al. Comparison of three rheumatoid arthritis disease activity scores in clinical routine. Scand J Rheumatol. 2009;38(5):336-341. 17. Klarenbeek NB, et al. Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis. Ann Rheum Dis. 2011;70(10):1815-1821. 18. Anderson J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640-647.

CHAPTER 2 Comprehensively Evaluating Patients With RA

19. Pincus T, et al. RAPID3 (Routine Assessment of Patient Index Data 3), a rheumatoid arthritis index without formal joint counts for routine care: proposed severity categories compared to disease activity score and clinical disease activity index categories. J Rheumatol. 2008;35(11):2136-2147. 20. Salomon-Escoto KI, et al. Assessment of control of rheumatoid arthritis disease activity. Best Pract Res Clin Rheumatol. 2011;4(25):497-507. 21. Porter D, et al. DAS28 and rheumatoid arthritis: the need for standardization. Musculoskeletal Care. 2011;9(4):222-227. 22. Dougados M, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62-68. 23. Vela P. Extra-articular manifestations of rheumatoid arthritis, now. EMJ Rheumatol. 2014;1:103-112. 24. Agca R, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017;76(1):17-28. 25. Roubille C, et al. Evidence-based recommendations for the management of comorbidities in rheumatoid arthritis, psoriasis, and psoriatic arthritis: expert opinion of the Canadian Dermatology-Rheumatology Comorbidity Initiative. J Rheumatol. 2015;42(10):1767-1780. 26. Dâ&#x20AC;&#x2122;Agostino MA, et al. Diagnosis and management of rheumatoid arthritis; What is the current role of established and new imaging techniques in clinical practice? Best Pract Res Clin Rheumatol. 2016;30(4):586-607. 27. Dâ&#x20AC;&#x2122;Agostino MA, et al. Is it time to revisit the role of ultrasound in rheumatoid arthritis management? Ann Rheum Dis. 2017;76(1):7-8. 28. Plagou A, et al. Recommendations of the ESSR Arthritis Subcommittee on Ultrasonography in Inflammatory Joint Disease. Semin Musculoskelet Radiol. 2016;20(5):496-506. 29. Sudol-Szopinska I, et al. Recommendations of the ESSR Arthritis Subcommittee for the Use of Magnetic Resonance Imaging in Musculoskeletal Rheumatic Diseases. Semin Musculoskelet Radiol. 2015;19(4):396-411. 30. Colebatch AN, et al. EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis. Ann Rheum Dis. 2013;72(6):804-814.

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

CHAPTER 3 Biologic Inhibitors of IL-6 Signaling

nalyses of large rheumatoid arthritis (RA) patient registries and studies examining managed care networks have shown that the vast majority of Americans with diagnosed RA are being treated with conventional and/or targeted disease-modifying antirheumatic drugs (DMARDs).1,2 Moreover, as the rheumatology community has increasingly adopted treat-to-target recommendations in daily practice, long-term outcomes for patients with RA have generally improved.3,4 Nevertheless, there is room for improvement. For example, even in selected clinical trial populationsâ&#x20AC;&#x201D;in which common comorbidities and complications are often excludedâ&#x20AC;&#x201D;treat-to-target protocols fail to get 20% to 70% of patients to goal.5 Additionally, as many as 1 in 3 patients treated with conventional DMARDs or tumor necrosis factor (TNF) inhibitors do not achieve even a 20% improvement in American College of Rheumatology criteria (ACR20), whereas others with initially positive responses can experience secondary failure or acquire resistance to their therapeutic regimens.6-10 Based on these data, rheumatologists need to be comfortable treating patients with other targeted DMARDs. There are now 2 antibodies specific for interleukin-6 receptor (IL-6R) that are available as RA therapies in the United States.11,12 These approvals together with numerous antiâ&#x20AC;&#x201C;IL-6/IL-6R agents in various stages of clinical development make it clear that rheumatologists and other clinicians who manage patients with RA need to be up-todate on the efficacy data, safety issues, and monitoring requirements associated with this biologic class.

TOCILIZUMAB As discussed in Chapter 1, research characterizing the pathophysiologic roles of IL-6 in RA development and progression laid a foundation for efforts to therapeutically target this proinflammatory cytokine in patients with RA.13 Tocilizumab was the first biologic inhibitor of IL-6

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

signaling available to treat adult patients with RA.11,14 The humanized monoclonal anti–IL-6R antibody is currently approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to ≥1 DMARD of any type.11 Tocilizumab is approved by the FDA for use with or without methotrexate or other conventional DMARDs.11 The antibody was originally formulated to be administered in a 60-minute single intravenous drip with 2 potential dosage regimens (Table 1).11 Alternatively, it can now be injected subcutaneously with an initial dosing frequency based on patient body weight; proper training by a health care provider allows the drug to be administered by patients themselves or their caregivers.11 Tocilizumab has been evaluated in a number of phase 3 studies, versus a variety of comparators, and in diverse patient populations (see link to supplementary VIDEO 5).14 In the OPTION and TOWARD trials of patients with RA who previously failed to respond adequately to nonbiologic DMARDs, tocilizumab plus methotrexate or conventional DMARDs was superior to methotrexate or conventional DMARDs alone, respectively.15 Similar results were observed in the LITHE study

TABLE 1. Approved Dosage Regimens for Tocilizumab in RA11 Route of Administration Intravenous

Initial Dosage

Additional Dosage

If the clinical response is 4 mg/kg of inadequate, increase to body weight 8 mg/kg of body weight every 4 weeks every 4 weeksa

Subcutaneous in patients weighing <100 kg

162 mg every 2 weeks

If the clinical response is inadequate, increase to 162 mg each week

Subcutaneous in patients weighing ≥100 kg

162 mg each week

Doses exceeding 800 mg per infusion are not recommended in patients with RA. NA, not applicable. a

CHAPTER 3 Biologic Inhibitors of IL-6 Signaling

VIDEO 5. Tocilizumab for Patients With Rheumatoid Arthritis Alan J. Kivitz, MD, CPI of tocilizumab plus methotrexate versus methotrexate in patients with previously inadequate responses to methotrexate.16 This 2-year trial included additional focus on the prevention of joint damage and improvements in physical functioning, both of which were significantly better in the tocilizumab plus methotrexate arm of the study.16 Tocilizumab plus methotrexate was also shown to be more effective than methotrexate alone in a group of patients who had not sufficiently benefited from TNF inhibitors (RADIATE).17 Importantly, unlike agents in any other biologic DMARD class, tocilizumab monotherapy was superior to methotrexate monotherapy in the AMBITION trial, which included patients with active RA who had not previously failed either methotrexate or an anti-TNF agent.18 In the head-to-head ADACTA study, patients who were intolerant of or inadequately responsive to methotrexate were randomized to receive monotherapy with either tocilizumab or the TNF inhibitor adalimumab.19 At the end of the 24-week study, tocilizumab produced significantly greater responses than adalimumab on various clinical measures, including mean changes in the disease activity score using 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI).19 Extension studies and postmarketing

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

surveillance efforts have shown the potential for long-term efficacy with tocilizumab as well.20-22 Other notable clinical benefits of tocilizumab include reversal of elevated serum amyloid A levels, which can ameliorate secondary amyloidosis associated with RA.13 As with any immunomodulatory agent, tocilizumab is associated with a number of risks when it is used to treat RA. The most common adverse events from clinical trials (occurring in >5% of patients in at least one tocilizumab treatment arm and more frequently than with placebo) included upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased alanine aminotransferase levels, and injectionsite reactions.11 Rare and potentially fatal hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with either intravenous or subcutaneous tocilizumab; known hypersensitivity to the anti–IL-6R antibody or components of the formulations is the only absolute contraindication to its use.11 Other warnings in tocilizumab’s prescribing information include an increased risk for serious infections.11,23 Prior to initiating therapy, patients should be tested for latent tuberculosis.11 Tocilizumab should not be administered to patients with active infections, and treatment should be paused until any newly developing serious infections are controlled.11 Furthermore, certain cohorts at risk for infections require a particularly careful review of potential risks and benefits (Box 1). Additional safety signals include

BOX 1. Patients with RA and increased infection risks from immunosuppressive DMARDs11,12 A careful review of potential treatment-related beneﬁts and risks is required prior to initiating anti–IL-6R agents in patients with RA and • A history of chronic or recurrent infection • A history of serious or opportunistic infections • Comorbid conditions that increase the risks of infections • Prior exposure to tuberculosis • A history of living in or traveling to areas known for endemic tuberculosis or mycoses

CHAPTER 3 Biologic Inhibitors of IL-6 Signaling

an increased incidence of gastrointestinal perforations, especially in patients with a history of diverticulitis, and problems detectable with laboratory testing (eg, low neutrophil counts, low platelet counts, elevated liver enzyme levels, and lipid abnormalities).11,24 Thus, clinicians should monitor patients closely for new onset abdominal symptoms and changes in laboratory values throughout the course of tocilizumab treatment.14 Moreover, the FDA recommends adjusting tocilizumab dosing to help manage such treatment-emergent adverse events as elevated liver enzymes, neutropenia, or thrombocytopenia (Table 2).11 And although clinical trials have consistently linked tocilizumab therapy to increased lipid levels, including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides, the cardiovascular risks introduced by these changes may be offset by other effects of inhibiting IL-6 signaling, such as reduced systemic inflammation suggested by lower circulating levels of atherogenic and atherothrombotic markers.25 This is supported by results from the recent ENTRACTE trial, which found that, compared with the anti-TNF agent etanercept, tocilizumab and its associated rise in LDL-C levels did not increase the risk of major adverse cardiovascular events in patients ≥50 years of age with RA and ≥1 cardiovascular disease risk factor, extraarticular RA manifestations, or history of a major cardiovascular event.26

SARILUMAB In May 2017, sarilumab—a fully human recombinant monoclonal antibody specific for IL-6R—was approved by the FDA for the treatment of adult patients with moderately to severely active RA who have responded inadequately or are intolerant to ≥1 DMARD.12 Like tocilizumab, sarilumab binds to membrane-bound and soluble IL-6R, thereby inhibiting both local and systemic effects of IL-6 signaling, and the prescribing information states that sarilumab can be used as monotherapy or in combination with methotrexate or other conventional DMARDs.12 The approved dosage of sarilumab is 200 mg once every 2 weeks administered subcutaneously, which is delivered using preﬁlled syringes that on inspection should contain a clear or pale yellow solution.12 A 150-mg dose may be required for patients who develop certain laboratory abnormalities (Table 2). Appropriate training can allow patients or their caregivers to administer subcutaneous sarilumab injections.12

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

TABLE 2. Dosage Modifications of Anti–IL-6R Agents due to Laboratory Abnormalities11,12 Lab Value (cells/µL)

Recommendation

Low Absolute Neutrophil Count >1000

Maintain dose

500–1000

Pause treatment with tocilizumab or sarilumab when the absolute neutrophil count reaches 1000 cells/µL: • Resume tocilizumab 4 mg/kg of body weight IV and increase to 8 mg/kg IV as clinically appropriate • Resume tocilizumab 162 mg SQ injected every other week and increase to injections every week as clinically appropriate • Resume sarilumab 150 mg SQ injected every other week and increase to 200 mg SQ every other week as clinically appropriate

<500

Discontinue tocilizumab or sarilumab

Low Platelet Count 50,000– 100,000

Pause treatment with tocilizumab or sarilumab when the platelet count reaches 100,000 cells/µL: • Resume tocilizumab 4 mg/kg of body weight IV and increase to 8 mg/kg IV as clinically appropriate • Resume tocilizumab 162 mg SQ injected every other week and increase to injections every week as clinically appropriate • Resume sarilumab 150 mg SQ injected every other week and increase to 200 mg SQ every other week as clinically appropriate

<50,000

If confirmed by repeated testing, discontinue tocilizumab or sarilumab Cont’d

CHAPTER 3 Biologic Inhibitors of IL-6 Signaling

Lab Value (cells/µL)

Recommendation

Liver Enzyme Abnormalities ALT levels >ULN to ≤3 times ULN

Consider modifying dosage of concomitant DMARDs as clinically appropriate

ALT levels >3 times ULN to ≤5 times ULN

Pause treatment with tocilizumab or sarilumab when ALT levels fall to <3 times ULN: • Resume tocilizumab 4 mg/kg of body weight IV and increase to 8 mg/kg IV as clinically appropriate • Resume tocilizumab 162 mg SQ injected every other week and increase to injections every week as clinically appropriate • Resume sarilumab 150 mg SQ injected every other week and increase to 200 mg SQ every other week as clinically appropriate

ALT levels >5 times ULN

Discontinue tocilizumab or sarilumab

ALT, alanine aminotransferase; DMARD, disease-modifying antirheumatic drug; IV, intravenous; SQ, subcutaneous; ULN, upper limit of normal.

The efficacy of sarilumab has been established in a number of phase 3 studies, further clarifying which patients are likely to benefit from non-TNF targeted DMARDs (see link to supplementary VIDEO 6). In the 2-part MOBILITY trial examining sarilumab 150 mg or 200 mg every 2 weeks plus methotrexate vs methotrexate alone in patients with RA and a previously inadequate response to methotrexate, the anti–IL-6R antibody produced significant improvements in coprimary symptomatic (ACR20), functional (Health Assessment Questionnaire Disability Index [HAQ-DI]), and radiographic (Sharp/van der Heijde score) endpoints.27 Both sarilumab dosages plus methotrexate also significantly improved a number of patient-reported outcomes.28 Additionally, analyses of serially collected serum samples showed that sarilumab plus methotrexate suppressed circulating levels of biomarkers of bone resorption and joint damage compared with samples obtained

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

VIDEO 6. Sarilumab for Patients With Rheumatoid Arthritis Alan J. Kivitz, MD, CPI from the placebo arm.29 The EXTEND trialâ&#x20AC;&#x201D;an open-label extension of MOBILITYâ&#x20AC;&#x201D;showed that clinical (DAS28-CRP [C-reactive protein] and CDAI) and radiographic (modified total Sharp scores) responses were maintained for 3 years.30 The TARGET trial examined patients who had previously failed to respond or were intolerant to TNF inhibitors. Sarilumab plus conventional DMARDs significantly improved the signs and symptoms of RA and physical functioning compared with conventional DMARDs alone.31 Finally, in the MONARCH trial, patients with RA who stopped taking methotrexate due to a lack of efficacy or intolerable side effects were treated with sarilumab monotherapy or adalimumab monotherapy.32 Sarilumab was significantly more effective at 24 weeks based on the primary endpoint (change from baseline in DAS28-erythrocyte sedimentation rate; Figure 1) and various secondary endpoints (eg, achieving ACR20, ACR50, and ACR70, and better scores on the HAQ-DI).32 To date, studies have shown that the safety profile of sarilumab is very similar to that of tocilizumab. The most common adverse events from clinical trials (same criteria described above for tocilizumab) included neutropenia, increased alanine aminotransferase levels,

CHAPTER 3 Biologic Inhibitors of IL-6 Signaling

LS Mean Change From Baseline (SE)

and injection-site erythema.12 The only absolute contraindication to treatment is known hypersensitivity to sarilumab or the inactive components of the medication.12 Warnings regarding serious infections, liver enzyme elevations, neutropenia, and thrombocytopenia are

0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0

24 Adalimumab 40 mg Q2W Sarilumab 200 mg Q2W

a a

Week

FIGURE 1. Change from baseline in DAS28-ESR with adalimumab vs sarilumab monotherapy.32 a

P<0.001 vs adalimumab.

DAS28-ESR, disease activity score using 28 joints–erythrocyte sedimentation rate; LS, least squares; Q2W, every other week; SE, standard error. N=369 adult patients with active RA who did not tolerate or respond adequately to methotrexate.

KEY CLINICAL HIGHLIGHTS • Despite increased use of treat-to-target strategies, many patients with RA fail to achieve remission with conventional or anti-TNF DMARDs • Two antibodies targeting IL-6R have been approved by the US FDA for adult patients with moderately to severely active RA and an inadequate response to ≥1 DMARD • Based on similar safety signals with tocilizumab and sarilumab, patients treated with these biologic DMARDs should be monitored for infections and laboratory changes in neutrophil counts, platelet numbers, liver enzyme levels, and lipid abnormalities

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

similar to those provided for tocilizumab.11,12 And as with tocilizumab, the sarilumab dosage should be adjusted if problems with liver enzymes, neutropenia, or thrombocytopenia arise during ongoing patient monitoring (Table 2).11,12

REFERENCES 1. Pappas DA, et al. Delays in initiation of disease-modifying therapy in rheumatoid arthritis patients: data from a US-based registry. Rheumatol Ther. 2015;2(2):153-164. 2. Curtis JR, et al. Physiciansâ&#x20AC;&#x2122; explanations for apparent gaps in the quality of rheumatology care: results from the US Medicare Physician Quality Reporting System. Arthritis Care Res (Hoboken). 2013;65(2):235-243. 3. Smolen JS, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3-15. 4. Stoffer MA, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update. Ann Rheum Dis. 2016;75(1):16-22. 5. Solomon DH, et al. Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis? Arthritis Rheumatol. 2014;66(4):775-782. 6. Bykerk VP, et al. Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis. 2012;71(12):1950-1954. 7. Finckh A, et al. Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis. Ann Rheum Dis. 2006;65(6):746-752. 8. Weinblatt ME, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48(1):35-45. 9. Lipsky PE, et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343(22):1594-1602. 10. Weinblatt ME, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340(4):253-259. 11. Tocilizumab [prescribing information]. Initial US approval 2010. South San Francisco, CA: Genentech Inc.; May 2017. 12. Sarilumab [prescribing information]. Initial US approval 2017. Philadelphia PA: sanofi-aventis U.S. LLC. and Tarrytown NY: Regeneron Pharmaceuticals Inc.; May 2017. 13. Kim GW, et al. IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch Pharm Res. 2015;38(5):575-584. 14. Smolen JS, et al. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis. 2013;72(4):482-492. 15. Smolen JS, 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(9617):987-997. 16. Fleischmann RM, et al. Tocilizumab inhibits structural joint damage and improves physical function in patients with rheumatoid arthritis and inadequate responses to methotrexate: LITHE study 2-year results. J Rheumatol. 2013;40(2):113-126. 17. Emery P, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo controlled trial. Ann Rheum Dis. 2008;67(11):1516-1523. 18. Jones G, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88-96.

CHAPTER 3 Biologic Inhibitors of IL-6 Signaling

19. Gabay C, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541-1550. 20. Nishimoto N, et al. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis. 2009;68(10):1580-1584. 21. Yamamoto K, et al. Longterm Safety of Tocilizumab: Results from 3 Years of Followup Postmarketing Surveillance of 5573 Patients with Rheumatoid Arthritis in Japan. J Rheumatol. 2015;42(8):1368-1375. 22. Kivitz A, et al. Long-term safety and efficacy of subcutaneously administered tocilizumab for adult rheumatoid arthritis: a multicenter phase 3b long-term extension study. Rheumatol Ther. 2016;3(2):291-304. 23. Campbell L, et al. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford). 2011;50(3):552-562. 24. Strangfeld A, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis. 2017;76(3):504-510. 25. Strang AC, et al. Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis. Atherosclerosis. 2013;229(1):174-181. 26. Giles JT, et al. Comparative cardiovascular safety of tocilizumab vs etanercept in rheumatoid arthritis: results of a randomized, parallel-group, multicenter, noninferiority, phase 4 clinical trial. Paper presented at: 2016 ACR/ARHP Annual Meeting; November 11-16, 2016; Washington, DC. Abstract 3L. 27. Genovese MC, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III Study. Arthritis Rheumatol. 2015;67(6):1424-1437. 28. Strand V, et al. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18:198. 29. Boyapati A, et al. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther. 2016;18(1):225. 30. van der Heijde D, et al. Clinical and radiographic outcomes after 3 years of sarilumab in patients with rheumatoid arthritis. Pesented at the 2016 ACR/ARHP Annual Meeting: November 11-16, 2016; Washington, DC; Abstract 1633. 31. Fleischmann R, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2017;69(2):277-290. 32. Burmester GR, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847.

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

CHAPTER 4

Individualizing Rheumatoid Arthritis Management and the Role of IL-6 Inhibition

lthough numerous disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis (RA) have produced evidence of efficacy in clinical trials, their effects are highly variable and no single medication has been found to be sufficiently effective and tolerable for the majority of patients with either early (duration <6 months) or established (duration ≥6 months) disease.1 In fact, as discussed in Chapter 1, it appears that RA develops as a consequence of numerous dysregulated inflammatory and immune-related processes.2,3 Thus, interactions among genetic, epigenetic, and environmental factors may create somewhat patient-specific pathophysiologic environments in which certain cell types and/or overlapping signaling cascades play differential roles in the development of RA’s characteristic autoreactivity and other clinical manifestations. This suggests that therapeutic response rates may improve if patients are treated with DMARDs matched to the predominant dysregulated pathways. Unfortunately, there is a paucity of available techniques to help determine which medication class or individual drug is most likely to benefit a given patient with RA.1 Research into genotyping, epigenetic analyses, and biochemical and cellular assays may eventually allow rheumatologists to phenotype RA cases based on underlying pathophysiologic mechanisms, thereby allowing the selection of appropriately targeted DMARDs. In the meantime, the choice of the best DMARDs for an individual patient primarily remains based on any discernable differences from clinical trial results, prior treatment responses, managed care considerations, and patient-specific preferences or safety concerns (see link to supplementary VIDEO 7).

SHARED CLINICAL DECISION-MAKING IN RHEUMATOID ARTHRITIS MANAGEMENT Because RA a chronic autoimmune disorder without a universal “cure,” relationships between patients and rheumatologists are often extended,

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VIDEO 7. Educating Patients With Rheumatoid Arthritis About Targeted Therapies Alan J. Kivitz, MD, CPI and management decisions are continually refined to address changing disease manifestations and aspects of patientsâ&#x20AC;&#x2122; lives. Studies have shown that RA outcomes are usually better when treatment goals are clearly defined and open dialogue allows patients to feel comfortable raising any concerns or fears.4 International RA consensus guidelines on treating RA to target clearly highlight the essential role of shared clinical decision-making between patients and rheumatologists.5,6 Indeed, the importance of this construct is indicated by its inclusion as the first of the 4 major overarching treat-to-target principles, together with maximizing long-term health-related quality of life, abrogating inflammation, and repeatedly measuring disease activity to allow therapeutic adjustments.5 To facilitate shared clinical decision-making, rheumatologists must proactively educate patients and at times their caregivers. Guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) recommend wideranging conversations that cover RA pathology and its associated risks, strategies to assess disease activity, desired outcomes,

CHAPTER 4 Individualizing Rheumatoid Arthritis Management and the Role of IL-6 Inhibition

and the potential beneﬁts and risks of treatment options that may help patients reach those goals.5-7 By providing information about the progressive course of RA, clinicians will prepare patients to understand subsequent treatment recommendations. Furthermore, identifying agreed-upon management goals (eg, complete remission or very low disease activity with minimized potential side effects) can increase the likelihood that patients will accept additional tailoring of their treatment regimens, even when they already feel far better than before they started DMARD therapy. The time-limited realities of most rheumatology practices, however, challenge physicians to develop these important relationships and solicit patient perspectives.8 Online patient education and decision aids can assist in this process (Table 1; visit ExchangeCME.com/RAresources).9,10 Bidirectional patient-clinician dialogue also necessitates rheumatologists to consider issues related to culture, social support networks, language, religion, and other beliefs about health care, which left unaddressed can negatively affect acceptance of an RA diagnosis and the patient’s motivation to follow treatment-related instructions.10,11 Treatment adherence and persistence with DMARD regimens are often suboptimal, complicating evaluations of treatment responses and hurting long-term outcomes.12,13 Most rheumatologists are aware of the general lack of adherence among patients with RA, but many underestimate the degree of this behavior in their own practices. In fact, physicians appear to be most likely to overestimate adherence in patients with whom they have the strongest relationships.14,15 Simple and memorable educational messages from rheumatologists or other health care team members supplemented by imaging results that provide visual representations of active disease can improve adherence rates in RA.11 Moreover, empowering patients to take active roles in long-term management plans and medication choices has been shown to promote feelings of self-control over health outcomes and improve treatment adherence and persistence.11,16,17

POSITIONING INHIBITORS OF IL-6 SIGNALING IN RA TREATMENT ALGORITHMS Absent contraindications, methotrexate remains the anchor and preferred initial DMARD for most patients with early or established RA owing to well-documented efﬁcacy, safety (especially with folic acid), dosing flexibility, low cost, and evidence that the drug can reduce risks of

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

TABLE 1. Organizations With Online Materials Designed to Educate Patients About RA Organization

Description

American College of Rheumatology

The American College of Rheumatology provides information for patients and caregivers about the effects of RA, importance of early treatment, access to biologic medications, patient advocacy, and more. The ACR also publishes a rheumatologist directory to help patients find specialists in their region.

Arthritis Foundation

The Arthritis Foundation provides self-care tools and resources covering treatment options, pain management, diet and exercise, and common comorbidities associated with RA.

National Institute of Arthritis and Musculoskeletal Diseases

The National Institute of Arthritis and Musculoskeletal and Skin Diseases publication is a resource for patients and their families that describes how RA develops, how it is diagnosed, and how it is treated. It also highlights current research efforts and addresses what patients can do to help selfmanage their disease.

Rheumatoid Arthritis Support Network

The Rheumatoid Arthritis Support Network provides up-to-date information for patients with RA, including links to patient support groups, blogs written by patients with RA, resources to help pay for medications, and smart device apps to help track RA symptoms over time.

Visit ExchangeCME.com/RAresources for a list of RA-focused organizations, patient education materials, and links to other clinically helpful resources.

CHAPTER 4 Individualizing Rheumatoid Arthritis Management and the Role of IL-6 Inhibition

RA-related mortality and comorbidities.6,7,18,19 Treat-to-target guidelines then recommend treatment regimens that are adjusted at least every 3 months until the desired outcomes are achieved.5 The choice of DMARD therapy when methotrexate fails—ie, suboptimal efﬁcacy following proper dose titration or the presence of intolerable side effects—is less clear.6 Head-to-head comparisons of post-methotrexate DMARDs would allow providers and patients with RA to make informed choices about sequencing targeted therapies. Yet despite increasing regulatory demand for clinical trials that provide direct comparisons of RA therapies in single randomized populations, few head-to-head trials have been completed.20-22 Examples include the 2 trials of the approved anti–IL-6 receptor (IL-6R) DMARDs vs adalimumab (see Chapter 3), and the recently published study of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate.23-25 Historically, when rheumatologists and their patients were ready to move beyond methotrexate monotherapy or combinations with other conventional synthetic DMARDs, the first prescribed biologic agent was almost always an inhibitor of tumor necrosis factor (TNF). However, this paradigm has changed as evidence for efficacy and safety with alternatively targeted biologic and synthetic DMARDs has grown.6,7 For example, the regulatory approvals and guideline recommendations covering biologic inhibitors of interleukin-6 (IL-6) signaling have evolved over the last few years.6,7,26 The anti–IL-6R antibody tocilizumab was originally approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with moderately to severely active RA who had an inadequate response to ≥1 anti-TNF agent.27 Since then, the indication has expanded to include patients who do not respond to ≥1 DMARD of any type.27 This change was mirrored in the FDA’s recent approval of the anti-IL-6R antibody sarilumab for moderately to severely active RA after treatment with ≥1 DMARD.28 The expanded indications are supported by updated national and international RA clinical practice guidelines.6,7,26 For instance, in the 2015 ACR guidelines for RA management, the treatment algorithm for patients with early RA strongly recommends turning to a combination of traditional DMARDs, an anti-TNF agent, or a non-TNF biologic (including anti–IL-6R therapy) as equally reasonable options with or without methotrexate if disease activity remains moderate or high despite monotherapy with a conventional synthetic DMARD.6 Similarly, for established RA, the ACR has placed a strong recommendation on

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

the use of a combination of conventional synthetic DMARDs, a TNF inhibitor, a non-TNF biologic, or a targeted synthetic DMARD (all with or without methotrexate) when the disease is moderately or highly active despite conventional synthetic DMARD monotherapy.6 Recently published EULAR recommendations state that an inadequate response to an initial conventional synthetic DMARD should prompt the addition of a biologic or a targeted synthetic DMARD—without any preference for TNF inhibition—in patients with poor prognostic factors (Box 1).7 Of note, the 2016 EULAR update includes the anti–IL-6R antibodies sarilumab and sirukumab, which target IL-6 directly—even though these medications were not approved at the time of guideline publication—because available clinical trial data suggest efficacy and safety profiles similar to that of tocilizumab.7 Other items from the latest RA algorithms relevant to positioning IL-6 signaling inhibitors include a statement in the EULAR guidelines that monotherapy with IL-6 pathway inhibitors (or a targeted synthetic DMARD) may have advantages over other biologic DMARD classes used alone when patients are unable to tolerate conventional DMARDs in combination regimens.7 Additionally, the ACR advises rheumatologists to avoid cycling through anti-TNF DMARDs if patients with established RA do not achieve treatment goals with an initial agent from this biologic class.6 This recommendation is supported by studies showing clinical

BOX 1. EULAR definitions of poor prognostic factors in patients with RA7 • Moderate-to-high disease activity according to composite measures after treatment with a conventional DMARD • High acute phase reactant levels • High swollen joint counts • Presence of rheumatoid factor and/or ACPA, especially at high levels • Presence of early erosions • Failure to reach goal after treatment with ≥2 conventional DMARDs ACPA, anti-citrullinated peptide antibody; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism.

CHAPTER 4 Individualizing Rheumatoid Arthritis Management and the Role of IL-6 Inhibition

and pharmacoeconomic advantages of switching to targeted DMARDs with different mechanisms of action when patients do not respond to a TNF inhibitor.29,30 The ACR guidelines also call out certain high-risk comorbid conditions in which inhibitors of IL-6 signaling may be a better choice than anti-TNF DMARDs, such as congestive heart failure.6

KEY CLINICAL HIGHLIGHTS • Shared decision-making is a core principle of international treat-to-target guidelines for RA management • Recent practice guidelines on RA management include targeted non-TNF DMARDs, including inhibitors of IL-6 signaling, as first-line biologic options along with TNF inhibitors • If patients cannot use conventional synthetic DMARDs in combination treatment regimens for RA, anti–IL-6R agents and targeted synthetic DMARDs may have some benefit as monotherapy over anti-TNF agents

REFERENCES 1. Goetz I, et al. Review of treatment response in rheumatoid arthritis: assessment of heterogeneity. Curr Med Res Opin. 2011;27(4):697-711. 2. Pitzalis C, et al. New learnings on the pathophysiology of RA from synovial biopsies. Curr Opin Rheumatol. 2013;25(3):334-344. 3. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-442. 4. Dikranian A, et al. Understanding the importance of a patient’s role in the management of RA: results from a patient-based survey. Presented at: ACR/ARHP Annual Meeting; November 6-11, 2015; San Francisco, CA. Abstract 2324. 5. Smolen JS, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3-15. 6. Singh JA, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. 7. Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977. 8. Gvozdenovic E, et al. When rheumatologists report that they agree with a guideline, does this mean that they practise the guideline in clinical practice? Results of the International Recommendation Implementation Study (IRIS). RMD Open. 2016;2(1):e000221. 9. Fraenkel L, et al. Use of decision support for improved knowledge, values clarification, and informed choice in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2015;67(11):1496-1502. 10. Barton JL, et al. The design of a low literacy decision aid about rheumatoid arthritis medications developed in three languages for use during the clinical encounter. BMC Med Inform Decis Mak. 2014;14:104.

CLINICAL UPDATES in RHEUMATOID ARTHRITIS

11. Marengo MF, Suarez-Almazor ME. Improving treatment adherence in patients with rheumatoid arthritis: what are the options? Int J Clin Rheumatol. 2015;10(5):345-356. 12. Arshad N, et al. Adherence to methotrexate therapy in rheumatoid arthritis. Pak J Med Sci. 2016;32(2):413-417. 13. Chu LH, et al. Medication adherence and attrition to biologic treatment in rheumatoid arthritis patients. Clin Ther. 2015;37(3):660-666. e5-666.e8. 14. Miller LG, et al. How well do clinicians estimate patientsâ&#x20AC;&#x2122; adherence to combination antiretroviral therapy? J Gen Intern Med. 2002;17(1):1-11. 15. Velligan DI, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(suppl 4):1-46; quiz 47-48. 16. Ha JF, Longnecker N. Doctor-patient communication: a review. Ochsner J. 2010;10(1):38-43. 17. Bonafede M, et al. Etanercept-methotrexate combination therapy initiators have greater adherence and persistence than triple therapy initiators with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2015;67(12):1656-1663. 18. Wasko MC, et al. Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum. 2013;65(2):334-342. 19. Choi HK, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359(9313):1173-1177. 20. Fleischmann R, et al. Review of head-to-head study designs in rheumatoid arthritis. Semin Arthritis Rheum. 2016;46(3):279-285. 21. Sox HC, Greenfield S. Comparative effectiveness research: a report from the Institute of Medicine. Ann Intern Med. 2009;151(3):203-205. 22. Estellat C, Ravaud P. Lack of head-to-head trials and fair control arms: randomized controlled trials of biologic treatment for rheumatoid arthritis. Arch Intern Med. 2012;172(3):237-244. 23. Burmester GR, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847. 24. Gabay C, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541-1550. 25. Fleischmann, R, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet. 2017 [E-pub ahead of print]. 26. Smolen JS, et al. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis. 2013;72(4):482-492. 27. Tocilizumab [prescribing information]. Initial US approval 2010. South San Francisco, CA: Genentech Inc.; May 2017. 28. Sarilumab [prescribing information]. Initial US approval 2017. Philadelphia PA: sanofi-aventis U.S. LLC. and Tarrytown NY: Regeneron Pharmaceuticals Inc.; May 2017. 29. Bonafede MM, et al. Treatment effectiveness and treatment patterns among rheumatoid arthritis patients after switching from a tumor necrosis factor inhibitor to another medication. Clinicoecon Outcomes Res. 2016;8:707-715. 30. Chastek B, et al. Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease-modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis. J Med Econ. 2017;20(5):464-473.

RHEUMATOID ARTHRITIS

CLINICAL RESOURCE CENTER™ GUIDELINES

2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1-26. »» http://onlinelibrary.wiley.com/doi/10.1002/art.39480/epdf

Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Smolen JS, et al. Ann Rheum Dis. 2013;72(4):482-492. »» http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3595138/pdf/annrheumdis-2012-202469.pdf

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Smolen JS, et al. Ann Rheum Dis. 2017;76(6):960-977. »» http://ard.bmj.com/content/annrheumdis/ early/2017/03/06/annrheumdis-2016-210715.full.pdf

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Smolen JS, et al. Ann Rheum Dis. 2016;75(1):3-15. »» http://ard.bmj.com/content/annrheumdis/ early/2015/05/12/annrheumdis-2015-207524.full.pdf Download this activity and additional tools at

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PATIENT RESOURCES American College of Rheumatology Disease Overview The American College of Rheumatology has published a concise overview to help patients and caregivers learn more about rheumatoid arthritis and to provide tips for living well with this rheumatic disease. »» http://www.rheumatology.org/I-Am-A/ Patient-Caregiver/Diseases-Conditions/ Rheumatoid-Arthritis

American College of Rheumatology Patient Education Videos The American College of Rheumatology has produced a library of videos about the impact of rheumatic disease, what to do when diagnosed with rheumatic disease, when to see a rheumatologist, and what patients have to say about their experiences of living with rheumatic disease. »» http://www.rheumatology.org/I-Am-A/ Patient-Caregiver/Patient-Education-Videos

Arthritis Foundation The Arthritis Foundation provides self-care tools and resources covering treatment options, pain management, diet and exercise, and common comorbidities associated with many different arthritic conditions. »» http://www.arthritis.org

Handout on Health: Rheumatoid Arthritis A publication from the National Institute of Arthritis and Musculoskeletal and Skin Diseases for people who have rheumatoid arthritis, as well as for their family members, friends, and others who want to find out more about this disease. »» https://www.niams.nih.gov/Health – Info/Arthritis/ arthritis– rheumatic.asp Download this activity and additional tools at

Rheumatoid Arthritis CLINICAL RESOURCE CENTER™

Rheumatoid Arthritis Support Network The Rheumatoid Arthritis Support Network provides up-to-date information for patients with rheumatoid arthritis, including links to patient support groups, blogs written by patients with rheumatoid arthritis, resources to help pay for medications, and smart device apps to help track symptoms over time. »» https://www.rheumatoidarthritis.org/

SUGGESTED READING Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. McInnes IB, et al. Ann Rheum Dis. 2015;74(4):694-702. »» http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392313/pdf/ annrheumdis-2013-204345.pdf

Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Burmester GR, et al. Ann Rheum Dis. 2017;76(5):840-847. »» http://ard.bmj.com/content/annrheumdis/76/5/840.full.pdf

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Kim GW, et al. Arch Pharm Res. 2015;38(5):575-584. »» http://link.springer.com/article/10.1007%2Fs12272-015-0569-8

Measures of rheumatoid arthritis disease activity. Anderson JK, et al. Arthritis Care Res (Hoboken). 2011;63(suppl 11):S14-S36. »» http://onlinelibrary.wiley.com/doi/10.1002/acr.20621/epdf

The pathogenesis of rheumatoid arthritis. McInnes IB, Schett G. N Engl J Med. 2011;365(23):2205-2219. »» http://dbbs.wustl.edu/curstudents/Documents/Markey/RA-pathogenesis.pdf

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Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Anderson J et al. Arthritis Care Res (Hoboken). 2012;64(5):640-647. »» http://onlinelibrary.wiley.com/doi/10.1002/acr.21649/pdf

Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors. Strand V, et al. RMD Open. 2017;3(1):e000416. »» http://rmdopen.bmj.com/content/rmdopen/3/1/e000416.full.pdf

Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Genovese MC, et al. Arthritis Rheumatol. 2015;67(6):1424-1437. »» http://onlinelibrary.wiley.com/doi/10.1002/art.39093/epdf

Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Fleischmann R, et al. Arthritis Rheumatol. 2017;69(2):277-290. »» http://onlinelibrary.wiley.com/doi/10.1002/art.39944/pdf

Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Dennis G Jr, et al. Arthritis Res Ther. 2014;16(2):R90. »» http://www.ncbi.nlm.nih.gov/pmc/artivstrunck@aol.com, cles/ PMC4060385/pdf/ar4555.pdf

Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Burmester GR, et al. Ann Rheum Dis. 2016;75(6):1081-1091.. »» http://ard.bmj.com/content/early/2015/10/28/annrheumdis-2015-207628. full.pdf+html

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Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Kremer JM, et al. Arthritis Rheum. 2011;63(3):609-621. »» http://onlinelibrary.wiley.com/doi/10.1002/art.30158/epdf

Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Gabay C, et al. Lancet. 2013;381(9877):1541-1550. »» http://www.thelancet.com/journals/lancet/article/ PIIS0140-6736(13)60250-0/abstract

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RHEUMATOID ARTHRITIS

SUPPLEMENTAL VIDEO LIBRARY VIDEO 1. Unmet Needs in Patients With Rheumatoid Arthritis »» www.exchangecme.com/project/ravideos

VIDEO 2. Pathophysiologic Underpinnings of Rheumatoid Arthritis »» www.exchangecme.com/project/ravideos

VIDEO 3. Treating to Target in Rheumatoid Arthritis »» www.exchangecme.com/project/ravideos

VIDEO 4. Disease Activity Measures for Rheumatoid Arthritis »» www.exchangecme.com/project/ravideos

VIDEO 5. Tocilizumab for Patients With Rheumatoid Arthritis »» www.exchangecme.com/project/ravideos

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

VIDEO 6. Sarilumab for Patients With Rheumatoid Arthritis » www.exchangecme.com/project/ravideos

VIDEO 7. Educating Patients With Rheumatoid Arthritis About Targeted Therapies » www.exchangecme.com/project/ravideos

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CLINICAL UPDATES in RHEUMATOID ARTHRITIS

Please visit the CLINICAL RESOURCE CENTER™ for additional information and resources.

www.ExchangeCME.com/RAResources

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