Solidifying the Data. In Supportive Care Oncology. Coverage from the ACR 2014 Meeting

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1 C A N A D I A N V I S I O N F O R R H E U M A T O L O G Y In Supportive Care Oncology Number 13 February 215 Solidifying the Data PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO Coverage from the ACR 214 Meeting NEW EVIDENCE 2645 BLOOR ST. WEST, SUITE 51 TORONTO ON M8X 1A3 I N S I D E New Evidence in Rheumatology is an independent medical news reporting service providing educational updates on current medical events. Views expressed are those of the participants and do not necessarily reflect those of the publisher or the sponsor. Support for development and distribution of this report was provided by Hoffmann-La Roche Rheumatology. Any therapies mentioned in this report should be used in accordance with the recognized prescribing information. No claims or endorsements are made for any products, uses, or doses presently under investigation. Information provided herein is not intended to serve as the sole basis for individual care. Our objective is to facilitate understanding of current trends in rheumatology for physicians and allied healthcare providers. T H I S I S S U E TOCILIZUMAB IN RA TREATMENT VASCULITIS Real-world data show efficacy of tocilizumab monotherapy Predicting relapse in patients given rituximab maintenance RITUXIMAB IN RA TREATMENT OTHER BIOLOGICS IN RA Rituximab does not increase infection risk with subsequent biologics in real-world settings Assessing abatacept, adalimumab, and etanercept as first-line treatments Interviews with Dr. Burmester, Dr. Haraoui, Dr. Pagnoux, and Dr. Wade

2 In Supportive Care Oncology Publisher Paul Borlinha Managing Director Anna Christofides, MSc, RD Medical Writers Wissam Assaily, PhD Sarah Di Clemente, MSc Editor Ben Fuerth, MSc Creative Director Jobet Dimaculangan Art Directors Glen Cho Cara O Donnell Website Design Ronaji Naranjo Website Development Xinyu Pu New Evidence in Rheumatology is published by New Evidence 67 Mowat Ave., Suite 21 Toronto, Ontario M6K 3E3 Correspondence should be addressed to: New Evidence 67 Mowat Ave., Suite 21 Toronto, Ontario M6K 3E3 fax: info@newevidence.com website: To join our mailing list or to request back issues, please contact us by mail, fax: , or info@newevidence.com New Evidence in Rheumatology is also available online at Canada Post Canadian Publications Mail Product Sales Agreement Number New Evidence in Rheumatology is a publication for Canadian rheumatology healthcare professionals. Our journal provides rheumatology specialists with scientific data from research presented at international and Canadian rheumatology conferences. A special feature of the journal, the Canadian Perspective, gives key opinion leaders a forum to discuss recent developments in rheumatology and to comment on how these advances may shape Canadian clinical practice. In addition, the Investigator Commentary sections provide information on key clinical studies from interviews with principal investigators. New Evidence also publishes discussion and expert opinion papers on timely topics of interest to rheumatologists in Canada. Our February 215 issue summarizes and discusses the latest research in rheumatoid arthritis (RA). Included in this issue are real-world studies on patterns of use of tocilizumab, and the safety of rituximab in RA. In addition, studies on the use of tocilizumab in early RA, factors predicting relapse with rituximab-maintenance in vasculitis, and the use of other biologics in RA are presented. We would like to thank Dr. John Wade and Dr. Boulos Haraoui for their Canadian Perspectives, as well as Dr. Gerd-Rüdiger Burmester and Dr. Christian Pagnoux for their Investigator Commentaries. We invite you to visit our website at for the online version of New Evidence and more reports on current research. Slide presentations on various topics are available for download. Cert no. SW-COC New Evidence in Rheumatology February 215 1

3 Contents Tocilizumab in Rheumatoid Arthritis Treatment In Supportive Care Oncology Tocilizumab in Rheumatoid Arthritis Treatment 6 Tocilizumab is Safe and Effective in Real-Life Settings Patterns of tocilizumab use and safety in patients with rheumatoid arthritis: interim results from a multinational observational study (ACT-UP). (Haraoui B, et al. ACR 214:519) Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naïve patients with early RA: 2-year clinical and radiographic results from the randomized, placebo-controlled FUNCTION trial. (Burmester GR, et al. ACR 214:1845) Real-world use of tocilizumab in rheumatoid arthritis patients in Canada: interim results from the ACT-UP CARE study. (Haraoui B, et al. ACR 214:517) Tocilizumab use in patients with rheumatoid arthritis who have failed one previous anti-tnf agent: comparison with adalimumab, etanercept, and infliximab from the provincial electronic database and registry RHUMADATA. (Payette MP, et al. ACR 214:52) First confirmation data of long-term safety for tocilizumab in a real-world setting: 3-year follow-up postmarketing surveillance of 5573 patients with RA in Japan. (Yamamoto K, et al. ACR 214:457) Efficacy and safety study of sequential therapy with tocilizumab, and in case of initially inadequate response to tocilizumab, followed by rituximab in patients with RA and inadequate response to traditional DMARDs. (Dörner T, et al. ACR 214:497) Canadian Perspective by Dr. Boulos Haraoui Investigator Commentary 36 An interview with Dr. Gerd Burmester on his study which examined long-term efficacy and safety of tocilizumab in early rheumatoid arthritis Rituximab in Rheumatoid Arthritis Treatment 39 Rituximab is Not Associated with an Increased Rate of Infections Use of rituximab compared to anti-tnf agents as second- and third-line therapy in patients with RA: a report from the RHUMADATA clinical database and registry. (Choquette D, et al. ACR 214:1535) Risk of infection associated with subsequent biologic use following rituximab results from a national RA patient registry. (Harrold RL, et al. ACR 214:518) Frequency of significant infection in patients with RA following initiation of rituximab with up to five years of follow-up in a U.S. observational study (SUNSTONE). (Saag KG, et al. ACR 214:844) Sustained clinical benefit with rituximab in second line for all RA patients irrespective of the previously used tumour necrosis factor inhibitor. (Ancuta I, et al. ACR 214:1538) A structured approach for benefit-risk assessment of rituximab for the treatment of rheumatoid arthritis. (John A, et al. ACR 214:55) Canadian Perspective by Dr. John Wade 2 New Evidence in Rheumatology February 215

4 Tocilizumab in Rheumatoid Arthritis Treatment In Supportive Care Oncology Other Biologics in Rheumatoid Arthritis Treatment 58 Assessing Abatacept, Adalimumab, Etanercept, and Infliximab as First-Line Treatments in Rheumatoid Arthritis Comparing abatacept to adalimumab, etanercept, and infliximab as first-line agents in patients with rheumatoid arthritis. (Choquette D, et al. ACR 214:1536) Bio-naïve patients with RA benefit more from abatacept treatment compared to those who are inadequate responders to other biologics. (Turesson C, et al. ACR 214:51) Comparison of patient characteristics, healthcare costs, and biologic persistence between patients with RA initiating first- or second-line subcutaneous abatacept, adalimumab, or etanercept. (Johnston S, et al. ACR 214:95) Discontinuation of biologics in patients with rheumatoid arthritis after achieving low activity disease status. (Ochiai M, et al. ACR 214:495) Efficacy meta-analysis of randomized controlled trials of biologics in methotrexate-naïve patients with early rheumatoid arthritis. (Yazici Y, et al. ACR 214:2528) Vasculitis 7 Predicting Relapse in Patients with ANCA-Associated Vasculitis Given Rituximab Maintenance Factors predictive of ANCA-associated vasculitis relapse in patients given rituximab-maintenance therapy. (Terrier B, et al. ACR 214:1776) Rituximab versus azathioprine for ANCA-associated vasculitis maintenance therapy: impact on health-related quality of life. (Pugnet G, et al. ACR 214:1778) Analysis of employment, work disability, and quality of life of patients with ANCA-associated vasculitis. (Benarous L, et al. ACR 214:1759) Biomarkers of disease activity in vasculitis. (Rodriguez-Pla A, et al. ACR 214:88) Investigator Commentary 82 An interview with Dr. Christian Pagnoux on the role of rituximab in maintenance therapy of ANCA-associated vasculitis New Evidence in Rheumatology February 215 3

5 Contributors Canadian Perspectives Boulos Haraoui, MD, FRCPC Dr. Boulos Haraoui is an Associate Professor of Medicine at the Université de Montréal and Head of the Clinical Research Unit in Rheumatology at the Centre Hospitalier de l Université de Montréal (CHUM) and the Institut de rhumatologie de Montréal. Dr. Haraoui is a Past-Chairman of the Scientific Committee of the Canadian Rheumatology Association (CRA). He is a founding member and vice-chairman of the Canadian Rheumatology Research Consortium (CRRC). He also chairs the Canadian Initiative in Outcomes in Rheumatology Care (CIORA), the research granting committee of the CRA. Dr. Haraoui serves on several provincial, national, and international educational and advisory committees, especially on issues pertaining to the diagnosis and management of rheumatoid arthritis. John Wade, MD, FRCP Dr. John Wade, a Clinical Assistant Professor at the University of British Columbia, has been in active rheumatology clinical practice since He is affiliated with the Vancouver General Hospital and is a consultant to a number of pharmaceutical companies. Dr. Wade s interests are in a variety of clinical rheumatology areas including gout, osteoarthritis, and psoriatic arthritis. Currently, he works in an academic rheumatology group practice. 4 New Evidence in Rheumatology February 215

6 Investigator Commentaries Gerd R. Burmester, M.D. Dr. Gerd Burmester is Professor of Medicine in the Department of Rheumatology and Clinical Immunology at the Charité University Hospital, Free University and Humboldt University of Berlin, Germany. Dr. Burmester earned his medical degree from Hannover Medical School and completed a residency at the Medical School of the University of Erlangen-Nuremberg. He was awarded a postdoctoral fellowship at Rockefeller University in New York, and was a visiting scholar at the Hospital for Joint Diseases, Mount Sinai School of Medicine, New York. Dr. Burmester is the recipient of numerous awards, including the Jan van Breemen Medal of the Dutch Society of Rheumatology and the Carol-Nachman Prize for Rheumatology. He serves on several editorial boards, including The Journal of Rheumatology and Journal of Clinical Rheumatology, and he is the Associate Editor of Annals of the Rheumatic Diseases. Dr. Burmester served as President of the German Society of Rheumatology from 21 to 22. He was a member of the Executive Committee of the European League Against Rheumatism (EULAR) from 23 to 26, acting as Chairman of the Standing Committee on Investigative Rheumatology and became an honorary member of EULAR in 26. From 211 to 213, he served as Treasurer of EULAR, and he was elected President Elect of EULAR in 213. Christian Pagnoux, MD, MPH Dr. Christian Pagnoux has held a full faculty position in the Division of Rheumatology at Mount Sinai Hospital since September 212. Prior to that, he completed a twoyear clinical fellowship at Mount Sinai Hospital and the University Health Network that was partially funded by the Vasculitis Clinical Research Consortium. He founded CanVasc, the Canadian network for research on vasculitides, whose main objectives are to help conduct studies in the area of vasculitis, provide support and educational materials for physicians and trainees across Canada, and optimize patient care. Trained in France, Dr. Pagnoux graduated from Tours Medicine University in 1995 and completed his post-graduate training in internal medicine and clinical immunology at Paris-Descartes University in 22. He also obtained a master s degree in advanced immunology from the Pasteur Institute and another in methodology of clinical trials from the Diderot University. He has served as vice-president of the French Vasculitis Study Group (FVSG) since 23 and continues to be involved as principal investigator or co-investigator in several therapeutic trials and cohort studies in vasculitis conducted by FVSG in France or by the European Vasculitis Study Group. He has written more than 1 peer-reviewed publications and several textbook chapters on vasculitis. New Evidence in Rheumatology February 215 5

7 Tocilizumab in Rheumatoid Arthritis Treatment Tocilizumab is Safe and Effective in Real-Life Settings Interleukin-6 (IL-6) is a powerful proinflammatory cytokine with many important functions that include promoting the differentiation of pre-b cells to antibody-producing B cells and regulating the balance of regulatory T cells (Treg) to helper T cells (Th17). 1 The dysregulation of IL-6 production leading to an imbalance between Treg and Th17 cells is thought to be the underlying cause responsible for the pathology of rheumatoid arthritis (RA). Several phase III clinical trials have shown tocilizumab to be effective and safe both as monotherapy and in combination with methotrexate. 2 However, the inference that findings from clinical trials can be applied to real-life settings is limited due to the strict inclusion and exclusion criteria of those trials. Confirming clinical trial findings in real-life settings is thus an important objective in the establishment of treatment, and may reveal efficacy and safety issues which could have been missed in controlled settings. Two large studies that recently addressed this question are the ACTemra Umbrella Program (ACT-UP) by Haraoui et al., and the postmarketing surveillance study from Japan by Yamamoto et al. These studies have shed light on patterns of use of tocilizumab and long-term safety and efficacy in real-life settings. At the American College of Rheumatology (ACR) 214 Annual Meeting, investigators presented data on the efficacy and safety of tocilizumab in RA in several real-life setting studies, new data on the efficacy of tocilizumab in early RA, and data on the use of tocilizumab as an alternative to tumour necrosis factor inhibitors (TNF-Is) after a first TNF-I failure. This article reports on six presentations given at ACR 214: Interim results from the ACT-UP study, which examined patterns of use of tocilizumab in realworld practice, showed that 37% of patients were initiated on tocilizumab monotherapy. A phase III clinical trial on the role of tocilizumab in patients with early RA provided evidence of its efficacy and safety in this patient population. The Canadian arm of the ACT-UP study, ACT-UP CARE, confirmed that tocilizumab in Canadian reallife settings is safe and effective, and that patterns of use are consistent with observations in the global arm of the study. A comparison of tocilizumab with adalimumab, etanercept, and infliximab in patients who failed one previous anti-tnf agent showed that tocilizumab may be a better option than an alternative TNF-I. A three-year follow-up postmarketing surveillance study of 5573 patients with RA in Japan confirmed the long-term safety of tocilizumab in a real-world clinical setting. An efficacy and safety study of sequential therapy with tocilizumab in patients who were inadequate responders to disease-modifying antirheumatic drugs showed there were very few non-responders to tocilizumab. References: 1. 1Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 21;4: Ogata A, Hirano T, Hishitani Y, Tanaka T. Safety and efficacy of tocilizumab for the treatment of rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 212;5: New Evidence in Rheumatology February 215

8 In Supportive Care Oncology Haraoui B, et al. ACR 214:519 Patterns of tocilizumab use and safety in patients with rheumatoid arthritis: interim results from a multinational observational study (ACT-UP) Background Tocilizumab is a humanized anti-human interleukin-6 receptor (IL-6R) monoclonal antibody indicated for the treatment of patients with rheumatoid arthritis (RA) who have had an inadequate response to 1 diseasemodifying antirheumatic drugs (DMARD). 1 Tocilizumab may be administered either as monotherapy or in combination with DMARDs. Registry reports have shown that 25 33% of patients receive biologics for RA as monotherapy. Patients previously exposed to a biologic are significantly more likely than biologic-naïve patients to initiate a biologic as monotherapy. The objective of this study was to analyse patterns of use, adherence of label recommendations, and safety issues from interim data on six months of intravenous tocilizumab therapy in patients with RA treated in routine clinical practice in the ACT-UP study. Study design ACT-UP is an umbrella project with data pooled from several independent, observational, postmarketing, multicentre studies of similar design to observe routine practice patterns of tocilizumab use in different countries. A dosing regimen was not prespecified in the study. Dose and duration of tocilizumab treatment were determined according to the investigator s judgment and in accordance with the local label and recommendations as part of routine clinical practice. Additional study visits, study-specific medications, or interventional procedures were not performed outside routine clinical practice. The decision to begin tocilizumab therapy in accordance with the local label was made by the treating physician. There were no restrictions on concomitant medications other than that they should be prescribed according to the investigator s judgment and the local label for tocilizumab. Key inclusion criteria: Adult patients who were 18 years of age or older and who had moderate to severe RA based on the revised (1987) American College of Rheumatology criteria were included. 1 Key exclusion criteria were: Treatment with tocilizumab for greater than eight weeks before enrollment, in a clinical trial, or on a compassionate-use basis; Enrollment in an ongoing clinical trial, treatment with any investigational agent within four weeks (or five half-lives of investigational agent, whichever was longer) before starting tocilizumab, or both; History of autoimmune disease or inflammatory joint disease other than RA. ACT-UP assessments: All patients receiving 1 dose of tocilizumab were included in the analysed population. Patients were observed in routine local clinical practice for six months after tocilizumab initiation. For the current analysis, patients were categorized based on whether they were receiving tocilizumab in combination with a DMARD (combination therapy) or as monotherapy (monotherapy) at baseline. The primary endpoint of the study was the proportion of patients continuing tocilizumab at six months after treatment initiation. To be considered in the study at six months, patients had to receive a tocilizumab infusion or have an efficacy measurement during the sixmonth window. The secondary endpoints of the study were treatment patterns over six months from the initiation of tocilizumab and safety, including dosing schedule, combination DMARD therapy, and rates of adverse events (AEs) and serious adverse events (SAEs). New Evidence in Rheumatology February 215 7

9 Key findings Baseline demographics and disease characteristics were similar between subgroups. As of June 3, 213, 961 patients were enrolled in 16 countries and had received 1 dose of tocilizumab: 352 (36.6%) patients had received tocilizumab as monotherapy; and 69 (63.4%) patients had received tocilizumab in combination with a DMARD. Most monotherapy patients (33/352 [93.8%]) and combination therapy patients (58/69 [95.2%]) started tocilizumab at a dose of 8 mg/kg. (Figure 1) During the six-month observational period, 34 (9.7%) monotherapy patients and 66 (1.8%) combination therapy patients changed their tocilizumab dose. Among monotherapy patients, seven (2.%) increased their dose, 11 (3.1%) decreased their dose, and 16 (4.5%) both increased and decreased their dose. Among combination therapy patients, 11 (1.7%) increased their dose, 2 (3.3%) decreased their dose, and 35 (5.7%) both increased and decreased their dose. Of those patients who changed their tocilizumab dose, 38.2% (13/34) of monotherapy and 45.4% (3/66) of combination therapy patients changed because of an AE, whereas 17.6% (6/34) of monotherapy and 4.5% (3/66) of combination therapy patients changed because of lack of efficacy. At six months, 767 (8%) patients overall (255 [72.4%] monotherapy patients and 512 [84.1%] combination therapy patients) continued to receive tocilizumab, primarily at a dose of 8 mg/kg. (Figure 1) The proportions of patients who discontinued tocilizumab monotherapy vs. combination therapy were 27.6% (97/352) vs. 15.9% (97/69), respectively. Discontinuations were equally distributed during the first and last three months of the six-month observational period. Discontinuations were due to (monotherapy vs. combination therapy): AEs: 26.8% (26/97) vs. 28.9% (28/97); Lack of efficacy: 11.3% (11/97) vs. 26.8% (26/97); Unknown: 29.9% (29/97) vs. 32.% (31/97); Other: 32.% (31/97) vs. 12.4% (12/97). Figure 1. Tocilizumab dosing regimen at baseline and six months TCZ <8 mg/kg TCZ 8 mg/kg TCZ >8 mg/kg Patients receiving TCZ dose (%) Baseline (n = 352) 6.3 Month 6 (n = 255) 4.4 Baseline (n = 69) 5.7 Month 6 (n = 512) TCZ Monotherapy TCZ + DMARD Combination therapy DMARD = disease-modifying antirheumatic drug; TCZ = tocilizumab 8 New Evidence in Rheumatology February 215

10 In Supportive Care Oncology Methotrexate was the most common DMARD and was used by 482 (79.1%) patients on combination therapy. (Figure 2) Other common DMARDs used in the combination therapy group included hydroxychloroquine (28.6% [174/69]), leflunomide (21.% [128/69]), sulfasalazine (18.7% [114/69]), gold (2.5% [15/69]), and cyclosporine (2.3% [14/69]) 28 (8.%) patients on monotherapy added a DMARD after they initiated tocilizumab treatment. Figure 2. Concomitant methotrexate use for all patients* Patients (%) n N 51 Received MTX *All patients regardless of treatment subgroup. Percentage of total population. Percentage of patients receiving 1 dose of MTX. MTX = methotrexate; TCZ = tocilizumab All TCZ Increased MTX dose During the study, 64/493 (13%) patients changed their methotrexate dose. Among patients receiving methotrexate, the median methotrexate dose was 15. mg/week. (Table 1) Baseline corticosteroid use (oral or parenteral administration) was lower among monotherapy (45.7% [161/352]) than combination therapy (57.3% [349/69]) patients. (Figure 3, Table 2) 3 11 Decreased MTX dose During the study, 27.9% (56/21) of monotherapy and 21.% (89/424) of combination therapy patients changed their corticosteroid dose. Corticosteroid dose decreases were more common than dose increases in both treatment subgroups. A larger percentage of monotherapy (25.4% [51/21]) than combination therapy (18.6% [79/424]) patients decreased their corticosteroid dose. A similar proportion of patients in both treatment subgroups increased their corticosteroid dose (monotherapy, 9.% [18/21]; combination therapy, 8.5% [36/424]). At 6 months, 44.6% (157/352) of monotherapy and 53.2% (324/69) of combination therapy patients received corticosteroids at a median prednisone-equivalent dose of 5. mg/day for both treatment subgroups. Overall rates of AEs and SAEs were comparable between treatment subgroups. (Table 3) Infections were the most common AEs and SAEs among treatment subgroups, and they occurred more often in combination therapy than in monotherapy patients. In total, 32 (9.1%) monotherapy and 42 (6.9%) combination therapy patients experienced AEs that led to withdrawal. No gastrointestinal perforations were reported in either group. Four patients (two in each treatment subgroup) died during the study. Reasons for death included pneumonia, sepsis, arrhythmia, and cerebrovascular accident. None of the deaths were deemed related to tocilizumab treatment. In total, 41 (11.6%) monotherapy patients and 87 (14.3%) combination therapy patients experienced AEs that required dose modification or abnormal laboratory test results that required follow-up. In these instances, investigators reported following local label or protocol recommendations in 97.6% (4/41) of monotherapy patients and 95.4% (83/87) of combination therapy patients. Table 1. Concomitant methotrexate dose and dose changes for all patients MTX Dose Changes Median MTX dose (range), mg/week Changes, n Increase Median change (range), mg/week Changes, n Decrease Median change (range), mg/week All TCZ N = (2.5 to 25.) (.5 to 15.) ( 15. to 2.5) MTX = methotrexate; TCZ = tocilizumab New Evidence in Rheumatology February 215 9

11 Figure 3. Concomitant corticosteroid use by treatment groups 1 9 TCZ Monotherapy TCZ Combination therapy 8 7 Patients (%) Receiving CS at baseline* Receiving CS at 6 months* 9 9 Increased CS dose Decreased CS dose n N *Percentage of total subgroup population. Percentage of patients receiving 1 dose of CS in respective subgroup CS = corticosteroid; TCZ = tocilizumab Table 2. Concomitant corticosteroid dose and dose changes by treatment subgroup Baseline median CS dose (range),* mg/day Changes, n Increase Median change (range), mg/day CS dose changes Changes, n Decrease Median change (range), mg/day Median CS dose at 6 months (range),* mg/day TCZ mono n = (2. to 3.) (2. to 74.2) ( 95. to 1.) 5. (2. to 87.5) TCZ + DMARD combo n = (. to 4.) (1. to 35.) ( 33. to 1.) 5. (. to 33.3) *Prednisone-equivalent dose. For the subset of patients with corticosteroid dose, unit, and frequency data available. CS = corticosteroid; TCZ = tocilizumab 1 New Evidence in Rheumatology February 215

12 In Supportive Care Oncology Table 3. AEs, SAEs, and AEs that led to withdrawal by treatment subgroup TCZ monotherapy n = 352 TCZ + DMARD combination therapy n = 69 All patients N = 961 AEs, n (%) (Events/1 PY [95% CI]) 185 (52.6) (193 [ ]) 324 (53.2) (25 [19 219]) 59 (53.) (21 [ ]) AEs reported in 1% of patients by SOC, n (%) Infections & infestations Investigations* 56 (15.9) 38 (1.8) 132 (21.7) 71 (11.7) 188 (19.6) 19 (11.3) SAEs, n (%) (Events/1 PY [95% CI]) 34 (9.7) (23 [16 29]) 49 (8.) (19 [15 24]) 83 (8.6) (21 [17 24]) SAEs of interest by SOC Infections & infestations, n (%) (Events/1 PY [95% CI]) Cardiac disorders, n (%) 6 (1.7) (3 [1 6]) 6 (1.7) 15 (2.5) (5 [3 7]) 3 (.5) 21 (2.2) (4 [2 6]) 9 (.9) Total AEs leading to withdrawal, n (%) (Events/1 PY [95% CI]) 32 (9.1) (21 [14 27]) 42 (6.9) (14 [1 17]) 74 (7.7) (16 [13 19]) AEs leading to withdrawal reported in 1% of patients by SOC, n (%) Skin and subcutaneous tissue disorder 6 (1.7) 5 (.8) 11 (1.1) Infections & infestations 5 (1.4) 6 (1.) 11 (1.1) Gastrointestinal disorders 4 (1.1) 1 (.2) 5 (.5) Cardiac disorders 4 (1.1) 4 (.4) Blood and lymphatic system disorders 3 (.9) 7 (1.1) 1 (1.) Neutropenia 1 (.3) 3 (.5) 4 (.4) Pancytopenia 1 (.3) 1 (.2) 2 (.2) Thrombocytopenia 1 (.3) 1 (.2) 2 (.2) * Includes laboratory tests such as liver function tests, complete blood counts, and lipid panels and includes assessments such as weight and blood pressure. Infection and infestation SAEs occurring in >1 patient by preferred term: pneumonia (monotherapy, 2 [.6%]; combination therapy, 2 [.3%]), postprocedural infection (monotherapy, ; combination therapy, 2 [.3%]), upper respiratory infection (monotherapy, ; combination therapy, 2 [.3%]). Cardiac disorder SAEs occurring in >1 patient by preferred term: acute myocardial infarction (monotherapy, 1 [.3%]; combination therapy, 1 [.2%]), myocardial infarction (monotherapy, 1 [.3%]; combination therapy, 1 [.2%]). Blood and lymphatic system disorders leading to withdrawal occurring in >1 patient by preferred term. AEs = adverse events; CI = confidence interval; DMARD = disease-modifying antirheumatic drug; PY = patient-years; SAEs = serious adverse events; SOC = system organ class; TCZ = tocilizumab Key conclusions In this multinational, observational study, 37% of patients started tocilizumab as monotherapy in clinical practice, which is consistent with estimates of biologic monotherapy use reported from registry data. The majority of patients (8%) who initiated tocilizumab continued to receive it after six months regardless of whether they started it as monotherapy or in combination with DMARDs. Tocilizumab was well tolerated both as monotherapy and in combination with DMARDs. Physician adherence to local label recommendations for tocilizumab following an AE was high in clinical practice. Reference: 1. Haraoui, B, Casado G, Theander E, et al. Patterns of tocilizumab use and safety in patients with rheumatoid arthritis: interim results from a multinational observational study (ACT-UP). ACR Annual Meeting Abstracts 214:519. New Evidence in Rheumatology February

13 Burmester RG, et al. ACR 214:1845 Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naïve patients with early RA: 2-year clinical and radiographic results from the randomized, placebo-controlled FUNCTION trial Background Early and efficacious treatment can lead to long-term clinical and radiographic benefits for patients with rheumatoid arthritis (RA). 1 In combination with disease-modifying antirheumatic drugs (DMARDs) or as monotherapy, tocilizumab has demonstrated efficacy and safety in the treatment of patients with RA. In methotrexate-naïve patients with early RA, treatment with tocilizumab in combination with methotrexate or as monotherapy resulted in improved signs and symptoms and inhibition of joint damage at week 52 of the 14-week, doubleblind, placebo-controlled FUNCTION trial. The objective of this study was to assess the efficacy and safety of tocilizumab plus methotrexate and tocilizumab monotherapy versus methotrexate monotherapy in patients with early RA treated for up to 14 weeks in the FUNCTION trial. Study design The FUNCTION trial was a randomized, phase III study which compared four treatment groups: Methotrexate alone (MTX); Tocilizumab 4 mg/kg plus methotrexate (TCZ4 + MTX); Tocilizumab 8 mg/kg plus methotrexate (TCZ8 + MTX); and Tocilizumab monotherapy 8 mg/kg (TCZ8 Mono). Efficacy was assessed in the intent-to-treat population and in a subgroup of patients who received TCZ8 + MTX escape therapy from week 52. End points at weeks 52 and 14 were: Disease Activity Score in 28 joints erythrocyte sedimentation rate (DAS28 ESR), American College of Rheumatology (ACR) 2/5/7 responses; Clinical Disease Activity Index (CDAI), and van der Heijde-modified Total Sharp Score (vdh-mtss). Statistical analysis on week 14 was not performed because it was exploratory. Adverse events (AEs) were evaluated in the safety population under the treatment group in which they occurred. Key inclusion criteria were: Adults with RA 2 years in duration; DAS28 ESR >3.2; Methotrexate naïve; ESR 28 mm/hour or C-reactive protein 1 mg/dl; Rheumatoid factor or anti-cyclic citrullinated peptide positive or 1 joint erosion; Oral glucocorticoids permitted ( 1 mg/day prednisone or equivalent). Study design Screening (3 weeks) Year 1 Blinded treatment Year 2 Blinded treatment Treated (n = 1157) Randomization (1:1:1:1) Placebo + MTX* (MTX) TCZ 4 mg/kg + MTX* (TCZ4 + MTX) TCZ 8 mg/kg + MTX* (TCZ8 + MTX) TCZ 8 mg/kg + placebo (TCZ8 Mono) Baseline Week 24 Week 52 Week 14 Primary end point: DAS28 remission at week 24 Primary analysis Week 14 analysis *The dose of methotrexate was mg/week with a stable dose of 5 mg/week folic acid or equivalent. The dose of methotrexate increased as follows: week 3, 7.5 mg/week; week 4 7, 15 mg/week; week 8 onward, 2 mg/week. Methotrexate dose increased in patients with swollen or tender joints. Escape therapy: at week 52, patients on MTX or TCZ4 + MTX with DAS28 >3.2 were increased to TCZ8 + MTX. DAS28 = Disease Activity Score in 28 joints; MTX = methotrexate; TCZ = tocilizumab 12 New Evidence in Rheumatology February 215

14 In Supportive Care Oncology Key findings The study randomized 1162 patients into four treatment groups (1:1:1:1): (Figure 1) MTX, n = 289; TCZ4 + MTX, n = 29; TCZ8 + MTX, n = 291; TCZ8 Mono, n = 292. Baseline characteristics between the treatment groups were similar. Remission according to DAS28 criteria was maintained through week 14 of the study, with similar proportions of patients achieving DAS28 ESR <2.6 at weeks 52 and 14 in the TCZ8 + MTX and TCZ8 Mono groups. (Figure 2) After 52 weeks of escape therapy with TCZ8 + MTX, 51% and 31% of patients originally in the MTX and TCZ4 + MTX groups, respectively, achieved DAS28 remission. (Figure 3) Clinical efficacy was maintained through week 14 in both of the tocilizumab 8 mg/kg groups, both as monotherapy and in combination with methotrexate, with similar proportions of patients achieving ACR2, 5, and 7 responses at weeks 52 and 14. (Figure 4) Figure 1. Patient disposition Screened N = 1846 Randomized N = 1162* MTX n = 289 TCZ4 + MTX n = 29 TCZ8 + MTX n = 291 TCZ8 Mono n = 292 Withdrew 63 (22%) 58 (2%) 65 (22%) 55 (19%) Completed week (78%) 232 (8%) 226 (78%) 237 (81%) Escape Withdrew Escape n = 142 No escape n = 84 Escape n = 95 No escape n = (15%) 4 (5%) 18 (19%) 18 (13%) 21 (9%) 3 (13%) Completed week (7%) 196 (68%) 25 (7%) 27 (71%) *1162 patients randomly assigned of 1846 patients screened. Includes 5 patients who received no treatment (MTX, n = 2; TCZ8 + MTX, n = 1; TCZ4 + MTX, n = 2). Patients in the MTX and TCZ4 + MTX arms switched to TCZ8 + MTX at week 52 if DAS28 >3.2. Includes patient 25688/17396, who was reported as having completed the study; exit data, however, show that the patient withdrew during weeks 64 to 72. The reason for withdrawal is not known. Mono = monotherapy; MTX = methotrexate; TCZ = tocilizumab Figure 2. Proportions of patients with DAS28 ESR <2.6 (ITT population) 6 MTX (n = 287) TCZ4 + MTX (n = 288) TCZ8 + MTX (n = 29) TCZ8 Mono (n = 292) Patients with DAS28 ESR <2.6, % Week 52 Week 14 DAS28 = Disease Activity Score in 28 joints; ESR = erythrocyte sedimentation rate; ITT = intent-to-treat; Mono = monotherapy; MTX = methotrexate; TCZ = tocilizumab New Evidence in Rheumatology February

15 Figure 3. DAS28 ESR <2.6 on escape therapy (ITT population; post-escape baseline) Patients with DAS28 ESR <2.6, % Similar proportions of patients achieved remission at weeks 52 and 14 according to CDAI criteria. (Figure 5) Similar proportions of patients achieved remission at weeks 52 and 14 according to ACR/EULAR Boolean and Index criteria. (Figure 6) 51 Inhibition or slowing of radiographic progression was maintained through week 14 in the TCZ8 + MTX group and the TCZ8 Mono group. (Figure 7) MTX TCZ4 + MTX 31 Escape patients (post-escape, weeks 52 14) n/n 73/142 29/95 DAS28 = Disease Activity Score in 28 joints; ESR = erythrocyte sedimentation rate; ITT = intent-to-treat; MTX = methotrexate; TCZ = tocilizumab The annualized progression rate for mtss was numerically lower in the tocilizumab groups than the methotrexate group. (Figure 8) The annualized progression rate decreased in the second year of treatment (weeks 52 to 14) after the switch to escape therapy with TCZ8 + MTX. (Figure 9) Tocilizumab serum levels were similar between the TCZ8 Mono group and the TCZ8 + MTX group. (Figure 1) The rates of AEs were similar across groups, with serious adverse event (SAE) rates numerically higher in the tocilizumab groups. (Table 1) 14 deaths were reported in the study, with nine reported by the first year, and five occurring during the second year. The underlying cause of death was variable, and included four due to infection (two each in the MTX and TCZ4 + MTX groups), three due to malignancy (one in the TCZ8 + MTX group and two in the TCZ8 Mono group), and two due to cardiovascular disease (one in each of the TCZ4 + MTX and TCZ8 + MTX groups). Rates of serious infections were numerically higher in the tocilizumab groups than the methotrexate group. (Table 2) Rates of other SAEs of interest were similar between groups. The majority of patients who had normal alanine aminotransferase and aspartate aminotransferase levels at baseline either continued to have normal levels or had elevations less than three times the upper limit of normal during the course of the study. (Figure 11) Figure 4. Proportions of patients with ACR2/5/7 responses (ITT population) MTX (n = 287) TCZ4 + MTX (n = 288) TCZ8 + MTX (n = 29) TCZ8 Mono (n = 292) Patients (%) ACR2 ACR5 ACR7 ACR2 ACR5 ACR7 Week 52 Week 14 ACR = American College of Rheumatology; ITT = intent-to-treat; Mono = monotherapy; MTX = methotrexate; TCZ = tocilizumab 14 New Evidence in Rheumatology February 215

16 In Supportive Care Oncology Figure 5. Proportions of patients with CDAI 2.8 (ITT Population) Patients with CDAI remission (CDAI 2.8), % MTX (n = 287) TCZ4 + MTX (n = 288) TCZ8 + MTX (n = 29) TCZ8 Mono (n = 292) 33 Week 52 Week 14 CDAI = Clinical Disease Activity Index; ITT = intent-to-treat; Mono = monotherapy; MTX = methotrexate; TCZ = tocilizumab Figure 6. Proportions of patients with ACR/EULAR Boolean and index remission (ITT population) Patients with ACR/EULAR remission, % MTX (n = 287) TCZ4 + MTX (n = 288) TCZ8 + MTX (n = 29) TCZ8 Mono (n = 292) Week 52 Week 14 Week 52 Week 14 Boolean Index ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; ITT = intent-to-treat; Mono = monotherapy; MTX = methotrexate; TCZ = tocilizumab New Evidence in Rheumatology February

17 Figure 7. Radiographic efficacy: absolute vdh-mtss from baseline to week 14 (ITT population) MTX (n = 287) TCZ4 + MTX (n = 288) TCZ8 + MTX (n = 29) TCZ8 Mono (n = 292) 8. Mean vdh-mtss MTX, n TCZ4 + MTX, n TCZ8 + MTX, n TCZ8 Mono, n Baseline Week Week Week ITT = intent-to-treat; Mono = monotherapy; MTX = methotrexate; TCZ = tocilizumab; vdh-mtss = van der Heijde modified Total Sharp Score Figure 8. Radiographic efficacy: mean annualized progression rate for vdh-mtss (ITT population) MTX (n = 287) TCZ4 + MTX (n = 288) TCZ8 + MTX (n = 29) TCZ8 Mono (n = 292) Mean (SE) annualized progression rate Baseline to week 52 Baseline to week 14 Week 52 to week 14 n = ITT = intent-to-treat; Mono = monotherapy; MTX = methotrexate; SE = standard error; TCZ = tocilizumab; vdh-mtss = van der Heijde modified Total Sharp Score 16 New Evidence in Rheumatology February 215

18 In Supportive Care Oncology Figure 9. Radiographic efficacy on escape therapy: mean annualized progression rate for vdh-mtss (ITT population; original baseline) Mean (SE) annualized progression rate MTX escape (n = 142) TCZ4 + MTX escape (n = 95) Baseline to week 52 Baseline to week 14 Week 52 to week 14 n = 138 n = 9 n = 117 n = 78 n = 117 n = 75 ITT = intent-to-treat; MTX = methotrexate; SE = standard error; TCZ = tocilizumab; vdh-mtss = van der Heijde modified Total Sharp Score Figure 1. Mean C min tocilizumab serum concentration over time (PK-evaluable population) Mean C min TCZ concentration, mg/ml TCZ4 + MTX (n = 288) TCZ8 + MTX (n = 525) TCZ8 Mono (n = 292) Week C min = minimum concentration; Mono = monotherapy; MTX = methotrexate; PK = pharmacokinetics; TCZ = tocilizumab Table 1. Safety: rates of adverse events (safety population)* MTX n = 282 TCZ4 + MTX n = 289 TCZ8 + MTX n = 527 TCZ8 Mono n = 292 Exposure, PY AEs, rate/1 PY [95% CI] (n) Overall AEs Withdrawal due to AE Overall SAEs Deaths [ ] (1249) 6.5 [ ] (22) 9.1 [ ] (31).59 [ ] (2) [ ] (1545) 9.9 [ ] (39) 14.7 [ ] (58) 1.27 [ ] (5) [ ] (2418) 12. [ ] (86) 11.6 [ ] (83).56 [ ] (4) [ ] (171) 1. [ ] (5) 13.3 [ ] (67).6 [ ] (3) * Patients were assigned to treatment groups according to the treatment they actually received. Multiple occurrences of the same AE in a patient were counted. AE = adverse event; CI = confidence interval; MTX = methotrexate; PY = patient-years; SAE = serious adverse event; TCZ = tocilizumab New Evidence in Rheumatology February

19 Figure 11. Shift in liver transaminase levels from normal at baseline to highest post-baseline value over 14 Weeks Normal >ULN to 3 x ULN >3 x ULN to 5 x ULN >5 x ULN MTX (n = 255) TCZ4 + MTX (n = 263) ALT TCZ8 + MTX (n = 456) TCZ8 Mono (n = 274) MTX (n = 27) TCZ4 + MTX (n = 27) AST TCZ8 + MTX (n = 484) TCZ8 Mono (n = 283) % 2% 4% 6% 8% 1% ALT = alanine aminotransferase; AST = aspartate aminotransferase; Mono = monotherapy; MTX = methotrexate; SE = standard error; TCZ = tocilizumab; ULN = upper limit of normal Table 2. Adverse events of special interest Rate/1 PY [95% CI] (n) Infection AEs* Infection SAEs* Malignancy SAEs Stroke SAEs Myocardial infarction SAEs GI perforation SAEs MTX n = [ ] (333) 1.8 [.6 3.8] (6).9 [.2 2.6] (3).6 [.1 2.1] (2). [. 1.1] ().3 [. 1.6] (1) Hepatic SAEs. [. 1.1] () TCZ4 + MTX n = [ ] (447) 4.1 [ ] (16) 1. [.3 2.6] (4).8 [.2 2.2] (3).8 [.2 2.2] (3). [..9] (). [..9] () TCZ8 + MTX n = [ ] (642) 3.5 [ ] (25).4 [.1 1.2] (3).4 [.1 1.2] (3).3 [. 1.] (2). [..5] (). [..5] () TCZ8 Mono n = [ ] (474) 4. [ ] (2) 1. [.3 2.3] (5).2 [. 1.1] (1).2 [. 1.1] (1).2 [. 1.1] (1). [..7] () * Three opportunistic infections occurred during year 2 in 2 patients receiving TCZ8 + MTX and in 1 patient receiving TCZ8 Mono. There were 2 cases of primary pulmonary tuberculosis: 1 SAE in the TCZ8 + MTX group in year 1 (case originated from Europe; patient had exposure to a patient with active tuberculosis) and 1 AE in a patient with an unknown history of tuberculosis in the MTX group who received escape therapy in year 2. As identified by hepatic failure, fibrosis, and cirrhosis and other liver damage-related conditions based on standardized MedDRA queries. AE = adverse event; CI = confidence interval; GI = gastrointestinal; Mono = monotherapy; MTX = methotrexate; PY = patient-years; SAE = serious adverse event; TCZ = tocilizumab 18 New Evidence in Rheumatology February 215

20 In Supportive Care Oncology Key conclusions Patients with early RA who received TCZ8 + MTX or TCZ8 monotherapy for the duration of the study maintained improvement in disease activity and maintained joint damage inhibition over 14 weeks. Efficacy improved further in patients receiving MTX or TCZ4 + MTX who switched to escape with TCZ8 + MTX at week 52. The overall degree of joint damage (though generally minor) was still greater than that in patients who received TCZ8 for the entire study, highlighting the importance of early initiation of optimal therapy. Safety was consistent with the known safety profile of tocilizumab. Reference: 1. Burmester GR, Rigby W, van Vollenhoven RF, et al. Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naïve patients with early rheumatoid arthritis: 2-year clinical and radiographic results from a randomized, placebo-controlled trial. ACR Annual Meeting Abstracts 214:1845. Haraoui B, et al. ACR 214:517 Real-world use of tocilizumab in rheumatoid arthritis patients in Canada: interim results from the ACT-UP CARE study Background Tocilizumab is a humanized monoclonal antibody that inhibits soluble and membrane-bound interleukin-6 (IL-6) receptors. 1 It is approved for the treatment of patients with rheumatoid arthritis (RA) who have had inadequate response to, or have been intolerant of, previous disease-modifying antirheumatic drugs (DMARD) or anti-tumor necrosis factor (TNF-I) therapy. Tocilizumab may be administered as combination therapy with traditional DMARDs or as monotherapy. Tocilizumab monotherapy has been shown to effectively treat the signs and symptoms of RA in patients who were methotrexate-naïve, patients who were intolerant of, or who had inadequate responses to, methotrexate, and patients for whom methotrexate had not failed. Approximately one-third of patients receiving biologic therapy for RA receive it as monotherapy. The objective of this study was to describe the pattern of tocilizumab use at baseline and after six months of treatment in Canadian patients enrolled in ACT-UP (Actemra Umbrella Program). Study design ACT-UP is an ongoing, multi-national, prospective cohort, non-interventional study of RA patients treated with tocilizumab. CARE (Canadian Physician Observance of RA Patients on Tocilizumab) represents the Canadian arm of the ACT-UP study. As of June 214, 1,375 patients were enrolled in 14 countries and had received 1 dose of tocilizumab. In this analysis, data from the 2 Canadian patients participating in ACT-UP were used. At the time of tocilizumab initiation, 67 (33.5%) patients received tocilizumab as monotherapy and 133 (65.5%) patients received tocilizumab in combination with a DMARD. For this analysis, patients were categorized based on whether they were receiving tocilizumab in combination with a DMARD (combination therapy) or as monotherapy (monotherapy) at baseline. Key findings A total of 171 (85.5%) patients remained in the study at six months. Of those, 58 (86.6%) remained in the monotherapy group and 113 (85.%) remained in the combination group. Mean methotrexate dose among patients on combination therapy was 19.9 mg/week (range: mg/week). New Evidence in Rheumatology February

21 Overall, baseline characteristics were similar between treatment groups. However, patients receiving tocilizumab monotherapy reported significantly higher mean (standard deviation [SD]) patient global assessment levels than patients receiving combination therapy (68.1 [19.8] vs. 6.6 [21.], respectively; p =.17). The proportions of patients previously treated with biologics and DMARDs are shown in Figures 1 and 2, respectively. Figure 1. Previous biologic use: (A) Proportion of TCZ monotherapy and TCZ plus DMARD combination therapy patients who received a biologic (taken by >5%) before initiating TCZ therapy; (B) Reasons for discontinuation of previous biologic therapy by treatment group A B Biologic Abatacept Adalimumab Certolizumab Etanercept Golimumab Infliximab Rituximab Patients (%) Combination therapy (n = 133) Monotherapy (n = 67) Treatment discontinuation (%) Monotherapy (n = 115)* Combination therapy (n = 239)* Lack of efficacy Intolerance Patient decision Other Unknown *n = number of discontinued drugs. Drugs were counted each time they were discontinued; therefore, patients might have taken an agent more than once. Figure 2. Previous traditional DMARD use: (A) Proportion of TCZ monotherapy and TCZ plus DMARD combination therapy patients who received prior traditional DMARD therapy (taken by >5%) before initiating TCZ therapy; (B) Reasons for discontinuation of previous traditional DMARDs A B DMARD Sulfasalazine Methotrexate Leflunomide Hydroxychloroquine Gold Patients (%) Combination therapy (n = 133) Monotherapy (n = 67) Treatment discontinuation (%) Monotherapy (n = 273)* Combination therapy (n = 448)* Lack of efficacy Intolerance Patient decision Other Unknown *n = number of discontinued drugs. Drugs were counted each time they were discontinued; therefore, patients might have taken an agent more than once. DMARD = disease-modifying antirheumatic drugs 2 New Evidence in Rheumatology February 215

22 In Supportive Care Oncology At baseline, tocilizumab dose was comparable between the monotherapy and combination therapy groups, with the majority (91% in each) receiving 8 mg/kg. (Figure 3A) Upon six months of treatment, there was no change in 86.6% of patients in the monotherapy group, and 85.% in the combination therapy group were still on tocilizumab. Reasons for changing dose were significantly (p =.15) different between monotherapy and combination therapy groups; the primary reasons being missing a dose (31.8%) for the former group and intolerance (54.5%) for the latter group. (Figure 3C) At Month six, disease parameters significantly (p <.1) improved in both monotherapy and combination therapy groups. (Figure 4) At Month six, a statistically comparable proportion of monotherapy and combination therapy patients were in remission or had low, moderate, and high disease activity according to Disease Activity Score in 28 joints (p =.99), Clinical Disease Activity Index (p =.137), and Simplified Disease Activity Index (p =.662) criteria, although the proportion in remission and low disease activity was numerically higher in the monotherapy group. (Figure 5) Figure 3. TCZ dose at initiation and at Month 6 of treatment: (A) Proportion of TCZ monotherapy and TCZ plus DMARD combination therapy patients receiving 8 mg/kg versus <8 mg/kg at baseline and at six months; (B) Proportion of patients down-titrating, up-titrating, or maintaining stable dose by six months; (C) Breakdown (% of cases) of reasons for dose changes A p >.999 TCZ <8 mg/kg TCZ 8 mg/kg p > Patients receiving TCZ dose (%) Baseline Month 6 Baseline Month 6 Monotherapy Combination therapy B C Down-titrated 1 Lack of efficacy Patients changing TCZ dose (%) p = Stable dose Up-titrated Treatment discontinuation (%) p = Intolerance Patient decision Dose missed Other 18.5 Monotherapy 12.7 Combination therapy Monotherapy (n = 22)* 6.1 Combination therapy (n = 33)* *n = number of discontinued drugs. Drugs were counted each time they were discontinued; therefore, patients might have taken an agent more than once. DMARD = disease-modifying antirheumatic drugs; TCZ = tocilizumab New Evidence in Rheumatology February

23 Figure 4. Improvement in disease parameters after six months of treatment: Mean (SD) changes in disease parameters (DAS28, SDAI, CDAI) among TCZ monotherapy and TCZ plus DMARD combination therapy patients Monotherapy Combination therapy. DAS28. CDAI SDAI Mean (SD) change (1.2) p < (1.5) p < (15.6) p < (16.5) p < (13.1) p < (16.1) p <.1 CDAI = Clinical Disease Activity Index; DAS28 = Disease Activity Score in 28 joints; DMARD = disease-modifying antirheumatic drugs; SD = standard deviation; SDAI = Simplified Disease Activity Index Figure 5. Improvement in disease parameters after six months of treatment: Disease activity state among TCZ monotherapy and TCZ plus DMARD combination therapy patients Remission Low disease activity Moderate disease activity High disease activity Patients (%) Monotherapy p = p =.137 p = Combination therapy Monotherapy Combination therapy Monotherapy DAS28 CDAI SDAI Combination therapy 22 New Evidence in Rheumatology February 215

24 In Supportive Care Oncology Key conclusions In this real-world observational study, 33.5% of patients received tocilizumab as monotherapy, which is consistent with reported estimates of biologic monotherapy use from registry data. Overall, 81.5% and 94.5% of patients had previously received a biologic (monotherapy: 8.6%; combination therapy: 82.%) and a traditional DMARD (monotherapy: 98.5%; combination therapy: 92.5%), respectively. Despite the fact that 81.5% of patients had been previously treated with a biologic, more than 85% of patients remained on tocilizumab treatment after six months of treatment. Reasons for discontinuing prior biologics were comparable between the monotherapy and combination therapy groups; the most common being lack of efficacy (7.4% and 68.2%, respectively) and intolerance (12.2% and 1.9%, respectively). Tocilizumab treatment alone or in combination with DMARD(s) over six months was effective in inducing significant improvements in all disease parameters studied. Reference: 1. Haraoui B, Jamal S, Ahluwalia V, Manchanda T, Khraishi M. Real-world use of tocilizumab in rheumatoid arthritis patients in Canada: interim results from the ACT-UP CARE study. ACR Annual Meeting Abstracts 214:517. Payette MP, et al. ACR 214:52 Tocilizumab use in patients with rheumatoid arthritis who have failed one previous anti-tnf agent: comparison with adalimumab, etanercept, and infliximab from the provincial electronic database and registry RHUMADATA Background The intravenous formulation of tocilizumab was approved for the treatment of rheumatoid arthritis (RA) in Canada on April 3 th, Tocilizumab was the sixth approved agent after adalimumab, etanercept, abatacept, infliximab, and rituximab. It has been demonstrated to be effective in the treatment of RA, either in monotherapy or in combination therapy, after the use of non-biologic or biologic disease-modifying antirheumatic drugs. The objective of the study was to describe the effectiveness of tocilizumab in patients with RA who have failed a first tumour necrosis factor inhibitor (TNF-I), and to compare the retention rate for tocilizumab versus adalimumab, etanercept, and infliximab in the same clinical situation. Study design All patients with RA who have failed a first TNF-I and were subsequently treated with tocilizumab after January 1, 25, were extracted from the RHUMADATA database. Four cohorts were created according to when tocilizumab or the subsequent TNF-Is were introduced. One cohort of patients comprised those who had started tocilizumab and three other cohorts consisted of those who had started adalimumab, etanercept, or infliximab. Demographics and baseline characteristics recorded for each cohort included: Age, gender, disease duration, rheumatoid factor and anti-cyclic citrullinated peptides, antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), previous failed treatment number, Disease Activity Score in 28 joints-esr (DAS28- ESR), Clinical Disease Activity Index (CDAI), and Health Assessment Questionnaire-Disability Index (HAQ-DI). New Evidence in Rheumatology February

25 Key findings The data from 259 patients prescribed tocilizumab (n = 53 [2%]), adalimumab (n = 97 [37%]), etanercept (n = 82 [33%]) or infliximab (n = 27 [1%]) as a second biologic agent were extracted from the RHUMADATA registry and clinical database. Most subjects were female (74.5%) and the average age of cohort subjects was 58.2 years (standard deviation = 14.3). No clinically significant differences at baseline were observed between groups. The 4-year retention rates of tocilizumab, adalimumab, etanercept, and infliximab as second-line biologic agents were 44.3%, 27.2%, 37.1%, and 34.%, respectively. (Figure 1) Kaplan-Meier survival analysis revealed significant differences in the drug retention rates (log rank, p =.249). Figure 1. Drug retention rates 1. Logrank, p = Survival probability Treatment groups 1: Tocilizumab 2: Etanercept 3: Adalimumab 4: Infliximab Drug failure or censoring time (days) Key conclusion In patients with RA who have failed their first TNF-I, tocilizumab could be a more valuable alternative than cycling to a second TNF-I agent. Reference: 1. Payette M-P, Bessette L, Choquette D, et al. Tocilizumab use in patients with rheumatoid arthritis having failed one previous anti-tnf agent: comparison with adalimumab, etanercept, and infliximab from the provincial electronic database and registry Rhumadata. ACR Annual Meeting Abstracts 214: New Evidence in Rheumatology February 215

26 In Supportive Care Oncology Yamamoto K, et al. ACR 214:457 First confirmation data of long-term safety for tocilizumab in a real-world setting: 3-year follow-up postmarketing surveillance of 5573 patients with RA in Japan Background Tocilizumab is a humanized monoclonal antibody which targets the interleukin-6 (IL-6) receptor and is indicated for the treatment of patients with rheumatoid arthritis (RA). 1 The objective of this study was to evaluate the long-term safety of tocilizumab for the treatment of RA in a realworld clinical setting in Japan. Study design This was a multicentre, long-term extension of the observational postmarketing surveillance study of tocilizumab. Patients who received at least one dose of intravenous tocilizumab (8 mg/kg) between April 28 and August 21 were observed in a three-year follow-up. Observational points over the course of three years included the incidences of: Fatal events; Serious infection; Malignancy; Gastrointestinal perforation; and Serious cardiac dysfunction. The analysis included adverse events (AEs) during and after discontinuation of tocilizumab. Data were summarized as the proportion (95%, confidence interval [CI]) of patients experiencing each event, as incidence rates presented, or as the number of patients per 1 patient-years (PY). The standardized mortality rate (SMR) and the standardized incidence rate (SIR) were calculated by indirect methods along with the corresponding 95% CI. Key findings In total, 562 patients were enrolled, 47 of whom were excluded from the safety analysis, for a total observation of 15,16 PY. Excluding patients who died, transferred hospitals, or were lost to follow-up, a total of 5327 patients (95.6%) completed one year, 485 (87.%) completed two years, and 4527 (81.2%) completed three years of observation. Patient characteristics are shown in Table 1. Table 1. Patient characteristics Characteristics Patients receiving TCZ N = 5573 Female, n (%) 4542 (81.5) Age, mean (± SD), years 58.7 (± 12.8) Body weight, mean (± SD), kg 53.3 (± 1.3) Disease duration, mean (± SD), years History of comorbidities before TCZ treatment, n (%) Gastrointestinal tract disturbance 1.5 (± 9.2) 1177 (21.1) Respiratory disease 864 (15.5) Diabetes mellitus 585 (1.5) Hepatic disorder 41 (7.2) Cardiac dysfunction 364 (6.5) Renal dysfunction 313 (5.6) Malignancy 32 (.6) Steinbrocker radiographic stage I + II, n (%) Steinbrocker functional class, 1 + 2, n (%) 192 (34.5) 413 (73.6) Previous use of biologics, n (%) 352 (62.8) Baseline conventional synthetic DMARD use, n (%) 3867 (69.4) Baseline methotrexate use, n (%) 2972 (53.3) Baseline steroid use (oral and intravenous), n (%) SD = standard deviation; TCZ = tocilizumab 4156 (74.6) New Evidence in Rheumatology February

27 The overall rate of mortality, malignancies, cardiac disorders, and gastrointestinal perforations were 2.58%, 2.24%, 2.19%, and.65%. (Table 2) The most common cause of death was infection (28.47%), followed by respiratory disease (15.97%), malignancy (14.58%), cardiac dysfunction (9.3%), and others (31.95%). (Figure 1) There was no increase in the rate of any AEs with prolonged observation, whereas the incidence of serious infection and serious cardiac dysfunction decreased. (Figure 2) The overall SIR of malignancies was.79 (95% CI:.66.95). (Table 3) Only malignant lymphoma had a significantly higher incidence compared to the general Japanese population, with a SIR of 3.13 (95% CI: ) which is comparable to that of all RA patients compared with the general population (SIR = 6.7; 95% CI: ). 3 Table 2. Incidence rate of observed adverse events Total patients, N = 5573 All adverse events Serious adverse events n Incidence rate (%) Patients /1 PY n Incidence rate (%) Patients /1 PY Mortality* Malignancies Cardiac disorders GI perforation Serious infections * The SMR in comparison with the general Japanese population was 1.27 (95% CI, ), which is comparable to the SMR reported in a large observational cohort of Japanese patients with RA (all-patient mortality between 1.46 [95% CI, ] and 1.9 [95% CI, ]). 2 GI = gastrointestinal; PY = patient-years; RA = rheumatoid arthritis; SMR = standardized mortality rate Figure 1. Change in the proportion of fatal events and cause of mortality a) The change in the proportion of fatal events during follow-up b) Cause of death during the study 1.6 Infections Proportion (95% CI), % (.92 to 1.5).85 (.62 to 1.14).47 (.29 to.7) > to 12 > 12 to 24 > 24 to 36 After 1 st TCZ treatment (months) 31.95% 9.3% 14.58% 28.47% 15.97% Respiratory disorders Malignancies Cardiac dysfunctions Others 26 New Evidence in Rheumatology February 215

28 In Supportive Care Oncology Figure 2. Change in the proportion of serious infections, malignancies, GI perforations, and serious cardiac dysfunctions during the follow-up period a) Serious Infections b) Malignancies Proportion (95% CI), % (5.8 to 6.31) 3.25 (2.78 to 3.77) 2.16 (1.77 to 2.62) Proportion (95% CI), % (.48 to.93).81 (.59 to 1.1).66 (.45 to.93). > to 12 > 12 to 24 > 24 to 36. > to 12 > 12 to 24 > 24 to 36 After 1 st TCZ treatment (months) After 1 st TCZ treatment (months) c) GI Perforations d) Serious Cardiac Dysfunctions Proportion (95% CI), % (.22 to.55) > to (.7 to.3) (.6 to.31) > 12 to 24 > 24 to 36 Proportion (95% CI), % (.42 to.85) > to (.25 to.62).11 (.3 to.25) > 12 to 24 > 24 to 36 After 1 st TCZ treatment (months) After 1 st TCZ treatment (months) CI = confidence interval; TCZ = tocilizumab New Evidence in Rheumatology February

29 Table 3. Standardized incidence rate of malignancies Site Total, N = 5573 Male, N = 131 Female, N = 4542 n SIR 95% CI n SIR 95% CI n SIR 95% CI All sites Oral cavity and pharynx Esophagus Stomach Colon/rectum Liver Gallbladder and bile ducts Pancreas Lung, trachea Skin Breast Cervix uteri Corpus uteri Ovary Prostate Bladder Kidney /other urinary organs Brain, nervous system Thyroid Malignant lymphoma Leukemia CI = confidence interval; SIR = standardized incidence rate Key conclusions The safety profile of tocilizumab was consistent over time with respect to mortality, serious infections, malignancy, gastrointestinal perforation, and cardiac dysfunction. These data confirm the long-term safety of tocilizumab treatment in patients with RA in a real-world clinical setting in Japan. References: 1. Yamamoto K, Goto H, Hirao K, et al. First confirmation data of long-term safety for tocilizumab in a real-world setting: 3-year follow-up postmarketing surveillance of 5573 patients with rheumatoid arthritis in Japan. ACR Annual Meeting Abstracts 214: Nakajima A, Inoue E, Tanaka E, et al. Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA. Scand J Rheumatol. 21;39(5): Yamada T, Nakajima A, Inoue E, et al. Incidence of malignancy in Japanese patients with rheumatoid arthritis. Rhematol Int. 211;31(11): New Evidence in Rheumatology February 215

30 In Supportive Care Oncology Dörner T, et al. ACR 214:497 Efficacy and safety study of sequential therapy with tocilizumab, and in case of initially inadequate response to tocilizumab, followed by rituximab in patients with RA and inadequate response to traditional DMARDs Background The pathogenesis of rheumatoid arthritis (RA) includes activation of cellular and humoral components of innate and adaptive immunity, which has been translated into effective therapies targeting cytokines, such as tumour necrosis factor alpha (TNFα) and interleukin-6 (IL-6), as well as targeting lymphocytes by blocking co-stimulation and anti-b cell therapy. 1 To exploit the biology of RA, this study combined targeting of innate and adaptive immunity with tocilizumab (anti-il-6 therapy) followed by rituximab (B-cell depleting anti- CD2 antibody). The objective of the MIRAI trial was to investigate the efficacy and safety of sequential therapy with tocilizumab, and in case of initially inadequate response (IR) to tocilizumab, followed by rituximab in RA patients who have had an IR to diseasemodifying antirheumatic drugs (DMARDs). Study design MIRAI was a German, multicentre, open-label, non-controlled, two-arm, phase III trial. The trial involved 77 active sites across Germany. The study period was from March 23rd, 211 to February 19th, 214. The key inclusion criteria were: Adult patients with moderate to severe RA (Disease Activity Score in 28 joints [DAS-28] >3.2; disease duration 6 months) and DMARD-IR; Erythrocyte sedimentation rate (ESR) 28 mm/h or C-reactive protein.7 mg/dl; The key exclusion criteria were: Previous treatment with tocilizumab, rituximab, or other biologics (e.g., TNF inhibitors) or preexisting combined methotrexate and leflunomide combination therapy within the last eight weeks before enrollment. The primary endpoint of the study was the proportion of patients achieving early DAS28 remission (DAS28 <2.6) under treatment with tocilizumab at week 16. The secondary endpoints were: Late clinical remission (DAS28 <2.6) and further pre-defined parameters (e.g., European League Against Rheumatism [EULAR] and American College of Rheumatology [ACR] responses) under continued tocilizumab treatment or under sequential rituximab therapy after a treatment period of 32 weeks; Patient-reported outcomes (PRO). For the analyses of all response parameters, patients who prematurely discontinued the study were classified as not having achieved the respective response parameter at the subsequent visits. The following groups were analysed: Intention to treat (ITT)-Main: All patients who received at least one dose of tocilizumab with at least one measurement for DAS28 in the first treatment period (including Week 16); Per protocol (PP): All patients of the ITT-Main population without any major protocol violation; ITT-TCZ2: All patients who received at least one dose of tocilizumab in the first and in the second treatment period with at least one efficacy measurement under tocilizumab; ITT-RTX (TCZ-inadequate responders [IR]): All patients who received at least one dose of tocilizumab in the first treatment period and at least one dose of rituximab in the second treatment period with at least one efficacy measurement under rituximab; Safety population: All patients who received at least one dose of tocilizumab. New Evidence in Rheumatology February

31 Study design Inclusion (DAS >3.2) 4 x TCZ V1 V2 V3 V4 V5 V6 BL w week DAS <2.6 RTX-treament: Patients who failed to respond to TCZ (DAS and DAS28 >3.2; TCZ-IR) 2 x RTX V6 V7 V8 V9 V V6 16 V7 2 4 x TCZ V8 24 V9 28 V In RTX-treated patients: Safety follow-up phase (observational, 34 weeks) V1 V11 V12 V End of study: week 32 Secondary endpoints Early responders complete study (DAS28 < 2.6, DAS-REM) Primary endpoint Patients who have not reached DAS-REM, but have partially responded (DAS28 > 1.2 or DAS ) BL = baseline; DAS = Disease Activity Score; DAS28 = Disease Activity Score in 28 joints; REM = remission; RTX = rituximab; TCZ = tocilizumab; TCZ-IR = tocilizumab-inadequate response; w = week; V = visit Key findings Patient disposition The ITT Main and safety sets were identical in number, including N = 519 patients. A total of 223 patients completed the study at week 16. The number of withdrawals between baseline and week 66 was 71 patients. The most frequent primary reasons for premature withdrawal were adverse events (AEs, n = 34) and withdrawal of consent (n = 15). Patient characteristics The mean baseline DAS28 was similar among analysis arms. The median duration of RA was longest in the ITT-RTX set and shortest in the ITT-TCZ2 set (6.8 years vs. 3.6 years). Almost all patients of the ITT-Main set had previously received conventional DMARDs (mostly MTX [479 patients] or leflunomide [227 patients]), but were not pre-treated with biologics. The number of previous conventional DMARDs ranged between one and seven DMARDs. Most patients had previously received one (27 patients) or two (117 patients) conventional DMARDs. Efficacy At week 16, the proportion of patients achieving DAS28 remission (42.8% or 222/519 patients; 95% CI: 38.5% 47.2%) was very close to the proportion expected ( 45%); however, the primary endpoint was not met. (Figure 1a) DAS28 remission rate at week 16 in the PP set was 43.5% (211/485 patients; 95% CI: 39.% 48.%) As soon as week 24, more than half of the partial tocilizumab responders (51.2%) achieved DAS28 remission under continued tocilizumab treatment (ITT-TCZ2). (Figure 1b) At the end of the observational rituximab safety follow-up (SFU) period in week 66: Six (22.2%) of the 27 patients of the ITT-RTX set were in DAS28 remission; the maximum number of patients achieving DAS28 remission at week 4 was eight (29.6%); (Figure 1) Eight (29.6%) of the 27 patients of the ITT-RTX set achieved low disease activity score (LDAS); the maximum number of patients who achieved LDAS at week 4 was nine (33.3%); Eight (29.6%) patients showed good EULAR response and three (11.1%) patients had moderate EULAR response compared to week 16 (ITT-RTX set); (Figure 2) ACR2/5/7 responses were achieved by 12 (44.4%)/ 7 (25.9%)/4 (14.8%) of the 27 patients of the ITT-RTX set compared to week 16, respectively. (Figure 3) CDAI/SDAI/211 ACR/EULAR remission were achieved by 5 (18.5%)/5 (18.5%)/3 (11.1%) patients, respectively (ITT-RTX). (Figure 4) The percentage of patients achieving a health assessment questionnaire-disease index (HAQ-DI) >.22 at week 16 for the ITT-Main population was 61.1%. The percentage of patients achieving a HAQ-DI >.22 at week 32 for the ITT-TCZ2 and ITT-RTX populations were 57.3% and 33.3%, respectively. 3 New Evidence in Rheumatology February 215

32 In Supportive Care Oncology Figure 1. DAS28 remission (<2.6) a) From baseline to week 16 b) From week 16 to week Primary endpoint: Early DAS28 remission 8 7 Secondary endpoint: Late DAS28 remission 6 6 Patients (%) Patients (%) Week 4 Week 16 ITT-Main (N = 519) ITT-TCZ2 (N = 213) ITT-RTX (N = 27) Week 16 Week 24 ITT-RTX: TCZ-IR received RTX at weeks Week 32 CI = confidence interval; DAS28 = Disease Activity Score in 28 joints; ITT = intent-to-treat; RTX = rituximab; TCZ = tocilizumab; TCZ-IR = tocilizumab-inadequate response Figure 2. EULAR response a) From baseline to week 16 b) From week 16 to week ITT-RTX: TCZ-IR received RTX at weeks Patients (%) Patients (%) Week 4 ITT-Main (N = 519) Week 16 Good EULAR response Moderate EULAR response Week 16 ITT-TCZ2 (N = 213) ITT-TCZ2 (N = 213) Week 32 ITT-RTX (N = 27) ITT-TCZ2: compared to baseline ITT-RTX: compared to week 16 CI = confidence interval; DAS28 = Disease Activity Score in 28 joints; EULAR = European League Against Rheumatism; ITT = intent-to-treat; RTX = rituximab; TCZ = tocilizumab; TCZ-IR = tocilizumab-inadequate response New Evidence in Rheumatology February

33 Figure 3. ACR responses* a) From baseline to week 16 b) From week 16 to week ITT-RTX: TCZ-IR received RTX at weeks Patients (%) Patients (%) Week Week 16 ACR2 ACR5 ACR Week 16 ITT-TCZ2 (N = 213) 34.3 ITT-TCZ2 (N = 213) Week ITT-RTX (N = 27) 22.2 ITT-Main (N = 519) ITT-TCZ2: compared to baseline ITT-RTX: week 32 compared to week 16 *Error bars represent 95% CI ACR = American College of Rheumatology; CI = confidence interval; DAS28 = Disease Activity Score in 28 joints; ITT = intent-to-treat; RTX = rituximab; TCZ = tocilizumab; TCZ-IR = tocilizumab-inadequate response Figure 4. CDAI ( 2.8), SDAI ( 3.3), 211 ACR/EULAR (Boolean) remission a) From baseline to week 16 b) From week 16 to week ITT-RTX: TCZ-IR received RTX at weeks Patients (%) Patients (%) CDAI remission 4.2 SDAI remission ACR/EULAR remission Week 4 Week 16 Week CDAI remission 22.1 SDAI remission ACR/EULAR remission 14.8 CDAI remission 18.5 SDAI remission ACR/EULAR remission ITT-Main (N = 519) ITT-TCZ2 (N = 213) ITT-RTX (N = 27) *Error bars represent 95% CI ACR = American College of Rheumatology; CDAI = Clinical Disease Activity Index; CI = confidence interval; DAS28 = Disease Activity Score in 28 joints; EULAR = European League Against Rheumatism; ITT = intent-to-treat; RTX = rituximab; SDAI = Simplified Disease Activity Index; TCZ = tocilizumab; TCZ-IR = tocilizumab-inadequate response; 32 New Evidence in Rheumatology February 215

34 In Supportive Care Oncology Table 1. Treatment-emergent adverse events Patients (N = 512) n % Adverse event AE related to TCZ AE related to RTX 4.8 AE which led to permanent discontinuation of study drug AEs of special interest * AE of special interest related to TCZ AE of special interest related to RTX. Serious AE SAE related to TCZ SAE related to RTX. SAE which led to permanent discontinuation of study drug Serious infections Serious infections related to TCZ Serious infections related to RTX. Death 1.2 *Definition: Infections including all opportunistic infections and non-serious infections as defined by those treated with intravenous anti-infectives, myocardial infarction/acute coronary syndrome, gastrointestinal perforations and related events, malignancies, anaphylaxis/hypersensitivity reactions, demyelinating disorders, stroke, bleeding events, hepatic events. AE = adverse event; RTX = rituximab; SAE = serious adverse event; TCZ = tocilizumab Safety The overall incidence of treatment-emergent AEs was 65.3%. (Table 1) In most of the patients concerned, the maximum AE intensity was either mild (37.8%) or moderate (52.5%). The highest incidence of treatment-emergent AEs/ tocilizumab-related AEs was seen in infections and infestations (34.1% /16%; mostly nasopharyngitis) and investigations (16.% /11.%; mostly hepatic enzyme increased). Only four of the 27 (14.8%) patients who were treated with subsequent rituximab experienced rituximab-related AEs. Tocilizumab-related serious AEs (SAEs) occurred in 4.4% of patients, most of which categorized to the system and organ class infections and infestations (2.1%); no rituximabrelated SAEs were reported. None of the SAEs in the ITT-RTX set were considered by the investigator as drug-related, neither to tocilizumab nor to rituximab. Treatment-emergent SAEs of special interest occurred in 2 patients (3.9%). One death was reported during the study: fatal craniocerebral injury after fall occurring within 24 hours after infusion of tocilizumab and was assessed by the investigator as possibly related to tocilizumab. Key conclusions Early response to tocilizumab was demonstrated by rapid improvement of RA symptoms until week 16. Initially, partial responders to tocilizumab benefited from continued tocilizumab therapy. The proportion of tocilizumab non-responders was low (27 of 519 patients). One-third of tocilizumab non-responders clearly benefited from subsequent rituximab therapy with lasting effects until week 66. Reference: 1. Dörner T, Tony H-P, Burmester GR, et al. Efficacy and safety study of a sequential therapy of tocilizumab and, if initially inadequately responded to tocilizumab, followed by rituximab in patients with rheumatoid arthritis and inadequate response to traditional disease modifying anti-rheumatic drugs (MIRAI) final analysis. ACR Annual Meeting Abstracts 214:497. New Evidence in Rheumatology February

35 Canadian Perspective by Dr. Boulos Haraoui The use of biologics in rheumatoid arthritis (RA) has significantly improved treatment outcomes. 1 Tumour necrosis factor inhibitors (TNF-Is) were the first biologics to be developed and used in the treatment of RA. Since the discovery of the role of TNF in RA, many other components of the immune system, including B cells, T cells, interleukin-1 (IL-1), and IL-6, have also been shown to play critical roles in the pathogenesis of the disease. This knowledge has been used to develop biologics that inhibit the respective signalling pathways of these molecules, which in turn inhibits disease progression. The advent of new biologics with different mechanisms of action is a significant step forward in the treatment of RA, especially for those who are non-responders to TNF-Is. One of the biologics with a different mechanism of action from TNF-Is is tocilizumab, a monoclonal antibody designed to target the IL-6 receptor. Tocilizumab in combination with methotrexate has been shown to be effective and safe in a number of phase III clinical trials in patients with active RA, 2 and data on its role in the real-world setting continues to grow. At the 214 American College of Rheumatology (ACR) Annual Meeting in Boston, interim results from the Actemra Umbrella Program (ACT-UP) observational study 3 and its Canadian arm (ACT-UP Canadian Physician Observance or RA Patients on Tocilizumab [CARE]) provided important findings regarding efficacy and safety of tocilizumab in a real-world setting. 4 Although tocilizumab has been extensively studied in RA, its role in early RA has yet to be established. In a recent study by Burmester et al. which was also presented at ACR 214, tocilizumab as monotherapy or in combination with methotrexate was investigated in early RA for the first time. 5 In addition to addressing the role of tocilizumab in early RA, the study also addressed the efficacy and safety of tocilizumab monotherapy. This is important for patients who cannot tolerate or are not responders to methotrexate. The ACT-UP study by Haraoui et al. is an umbrella project which examined routine practice patterns of tocilizumab use in different countries in a real-life setting. 3 As of June 214, 1,375 patients were enrolled in 14 countries and had received 1 dose of tocilizumab. The Canadian arm of the study, ACT- UP CARE, analysed 2 Canadian patients participating in ACT-UP. 4 The rationale of ACT-UP was to study the use of tocilizumab in a real-world setting without the limitations of inclusion and exclusion criteria of phase III clinical trials. Dose and duration of tocilizumab treatment were not specified by the study, but were left instead to the investigator s judgment and in accordance with the local label as part of routine clinical practice. The study revealed several important findings about the dose of tocilizumab used, patterns of use of tocilizumab monotherapy versus combination with methotrexate, as well as retention rates. The lack of restriction by the study to specify dose for tocilizumab revealed that of the two doses typically prescribed by physicians (4 or 8 mg/kg), the 8 mg/kg was more common (93.8% as monotherapy, 95.2% as combination therapy), which is expected given the concept of optimizing treatment from the outset and obtaining disease control as early as possible. This pattern was observed in both the global and Canadian populations. Another similarity between the two populations was the finding that % of patients were initiated on tocilizumab monotherapy, and of those, about 8% remained on monotherapy after six months of treatment. The observation that about two-thirds of patients on combination therapy received methotrexate with tocilizumab in ACT-UP indicated that methotrexate remains the preferred disease-modifying antirheumatic drug (DMARD) with tocilizumab. As monotherapy or in combination with methotrexate, tocilizumab was associated with high retention rates in both arms at six months of use (8 85.5%). This finding indicates high tolerability and efficacy with this agent in a real-world setting. No new safety signals were seen, and furthermore, patients in the ACT-UP study were able to significantly reduce corticosteroid use to a median five milligrams per day at six months, which is likely to reduce toxicity associated with steroid use. Although analysis at the six-month mark has provided important and reassuring data on retention rates, the Canadian arm of the study will be examining this question at the oneyear mark as well, and should give us more data on long-term safety and efficacy. Furthermore, data collected regarding comorbidities such as cardiovascular risk in this patient population will also allow us to ask several important questions, including: 1) What is the impact of specific comorbidities on retention rate? and 2) How safe is tocilizumab in patients with these specific comorbidities? 34 New Evidence in Rheumatology February 215

36 In Supportive Care Oncology Although our understanding of the role of tocilizumab in active RA has grown considerably over the past several years, its role in early RA was less clear, until now. In the recently presented phase III trial by Burmester et al., the efficacy and safety of tocilizumab was investigated in early RA. Methotrexate-naïve patients were given tocilizumab as monotherapy (8 mg/kg) or in combination with methotrexate at two different doses of 4 and 8 mg/kg and assessed for efficacy, safety, and radiological endpoints after two years of treatment. 5 There are two significant results in this study by Burmester et al. Firstly, the study showed that tocilizumab was effective in early RA. A significant number of patients who received tocilizumab (8 mg/kg) plus methotrexate or tocilizumab (8 mg/kg) monotherapy achieved remission according to the Disease Activity Score in 28 joints (DAS28) and maintained improvement in disease activity and joint damage inhibition over 14 weeks. Furthermore, patients who received methotrexate alone or tocilizumab (4 mg/kg) plus methotrexate and who switched to escape therapy with tocilizumab (8 mg/kg) plus methotrexate at week 52 showed further improvement. This finding is significant for patients with early RA who fail treatment with DMARDs, and suggests that tocilizumab may be an option in patients who show aggressive signs of early RA activity through biomarkers. Secondly, the study showed that tocilizumab monotherapy was more effective than methotrexate alone, a finding shown in an earlier phase III clinical trial. Biologics that are effective without methotrexate are an important option in cases where patients are intolerant or are non-responders to methotrexate. These findings suggest that tocilizumab could be used as a first-line biologic in early RA instead of TNF-Is. The addition of a new option in the treatment of early RA should be reassuring to physicians. References: 1. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev 29:CD Al-Shakarchi I, Gullick NJ, Scott DL. Current perspectives on tocilizumab for the treatment of rheumatoid arthritis: a review. Patient Prefer Adherence 213;7: Haraoui, B, Casado G, Theander E, et al. Patterns of tocilizumab use and safety in patients with rheumatoid arthritis: interim results from a multinational observational study (ACT-UP). ACR Annual Meeting Abstracts 214: Haraoui B, Jamal S, Ahluwalia Vet al. Real-world use of tocilizumab in RA patients in Canada: interim results from the ACT-UP CARE study. ACR Annual Meeting Abstracts 214: Burmester GR, Rigby W, van Vollenhoven RF, et al. Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early RA: 2-year clinical and radiographic results from a randomized, placebo-controlled trial. ACR Annual Meeting Abstracts 214:1845. New Evidence in Rheumatology February

37 Investigator Commentary An interview with Dr. Gerd Burmester on his study which examined long-term efficacy and safety of tocilizumab in early rheumatoid arthritis At the ACR/ARHP 214 Annual Meeting, New Evidence spoke with Dr. Burmester about the results of the FUNCTION trial. 1 Dr. Gerd R. Burmester is a Professor of Medicine in the Department of Rheumatology and Clinical Immunology at the Charité University Hospital, Free University and Humboldt University of Berlin, Germany. New Evidence: What is your treatment approach when a patient is diagnosed with early rheumatoid arthritis (RA)? Dr. Burmester: Our treatment approach is based on the European League Against Rheumatism (EULAR) recommendations. Patients with newly diagnosed RA receive methotrexate (15 mg orally) plus prednisone (initially 3 mg), which is then tapered down quickly while maintaining methotrexate. Patients are also given folic acid (5 mg/week), which helps to increase the patient s tolerability to methotrexate. New Evidence: Under what circumstances do you treat early RA patients with biologics? Dr. Burmester: We follow the German recommendations which state that biologics should be initiated only after a failure of disease-modifying antirheumatic drugs (DMARDs). Patients with RA first receive methotrexate (15 mg orally) which is then increased to 25 mg (subcutaneous). Patients who do not respond well are then given combination therapy (methotrexate plus leflunomide, for example), or triple combination therapy (methotrexate, hydroxychloroquine, sulfasalazine) for at least three months. Biologics are introduced if these approaches fail. It may take 9 to 12 months in a typical RA patient to receive a biologic. This may seem like a long time, but in the past, patients had to wait 11 years to be eligible for a biologic. New Evidence: What percentage of your RA patients is treated with biologics? Dr. Burmester: It is difficult to estimate how many patients are treated with biologics because we are a university hospital, but the number is about 2 3%. We generally try to place patients with active RA, who consent and are eligible, into clinical trials as soon as possible. New Evidence: What are some of the challenges to beginning RA treatment early? Dr. Burmester: A significant challenge with early RA treatment is that patients may not visit their physicians about their symptoms until a while after symptoms first appear. Patients may attribute joint pain to strenuous sport activities instead of RA, for example. Furthermore, waiting lists at RA clinics in Germany can be as long as 3 6 months. We do have an early arthritis clinic that accepts patients within two weeks of RA diagnosis, but this fast-track system is not available at most other centres. 36 New Evidence in Rheumatology February 215

38 New Evidence: What is the rationale of the FUNCTION study? Dr. Burmester: In RA we want to treat patients as early as possible and as intensively as possible to prevent irreversible damage to joints. Interleukin-6 (IL-6) is a pivotal cytokine that is secreted by a number of cells, including fibroblasts and macrophages, and is responsible for the acute phase of RA. The main rationale of the study was to determine if inhibiting IL-6 is effective in patients with early RA. IL-6 has already been shown to be effective in mature stages of RA but not in very early stages. Tackling the disease early on by targeting a molecule involved in the acute phase of RA should help stop irreversible joint damage, which is of great benefit to the patient. New Evidence: Please describe the study design and the patient population of the study. Dr. Burmester: Patients included in the study were those who had highly active RA, were autoantibody positive and/or had at least one erosion of a joint, as demonstrated by x-ray. These patients had significant disease activity as measured by elevated high acute phase reactants and the presence of swollen and tender joints. From an investigational standpoint, this was the relevant population to examine in an early intervention with a biologic such as tocilizumab. Patients were then randomized into four arms: methotrexate alone, tocilizumab monotherapy (8 mg/kg), methotrexate plus tocilizumab (4 mg/kg), or methotrexate plus tocilizumab (8 mg/kg). We used two different doses of tocilizumab to reflect North American versus European approaches which use 4 and 8 mg/kg respectively. We wanted to know which dose was more effective. New Evidence: What were the clinically relevant findings from this study? Dr. Burmester: The study showed two significant findings: 1) methotrexate plus tocilizumab was more effective than methotrexate alone, and 2) tocilizumab monotherapy was good but not as good as when it is used in combination with methotrexate. With respect to the second finding, the difference between the two treatment arms (methotrexate plus tocilizumab versus tocilizumab monotherapy) was minimal at the end of two years. During the first year, tocilizumab plus methotrexate was numerically better than tocilizumab alone according to the Clinical Disease Activity Index, but this difference shrunk in the second year to 3%. This raises the question of whether the difference is clinically meaningful. One side of the argument is that one should give tocilizumab with methotrexate to produce the best possible response, and the other side is that patients may be happier with taking one drug alone with the option of receiving methotrexate later if they happen to be among the 3% of patients who do not achieve remission. New Evidence: What is the significance of the finding that efficacy further improved in patients who received escape therapy? Dr. Burmester: The data showed that some patients on methotrexate alone needed more therapy, and that some patients on methotrexate plus tocilizumab (4 mg/kg) needed more tocilizumab. The finding that efficacy was further improved provides evidence for the success of a treat-to-target therapy approach where a patient may be initiated on methotrexate alone, or a lower dose of tocilizumab, and if they do not respond well, they can be shifted over to a more effective treatment that can still lead to improvement. However, the issue with this approach is that any joint damage that is incurred in patients who do not respond well to methotrexate alone would be irreversible. This raises an important question that will need to be addressed by physicians and their patients: whether the cost of more expensive treatment is worth avoiding a small but significant amount of joint damage. New Evidence: What did the radiographic data show in this study? Dr. Burmester: The study showed that tocilizumab, either with or without methotrexate, was more effective than methotrexate alone in reducing joint damage. Methotrexate alone reduces radiographic progression but does not stop it, while tocilizumab basically does. New Evidence in Rheumatology February

39 New Evidence: How do the results compare to previous studies on tocilizumab and other biologics in early RA? Dr. Burmester: The findings of this study are supported by other studies which have shown that tocilizumab is highly effective in inducing rapid remission in many patients with very severe RA. In general, all biologics are very effective, but comparing biologics with each other is difficult without a head-to-head comparison. New Evidence: Please describe the safety results of the study. Were there any new safety signals? Dr. Burmester: The study found no new safety signals with tocilizumab; tocilizumab was well tolerated, which is consistent with previous studies. Compared to DMARDs such as methotrexate, tocilizumab resulted in a higher rate of infections, which is what is expected from the use of biologics in general. In the study, serious adverse events in patients treated with methotrexate plus tocilizumab occurred at a rate of per 1 patient-years, which was well below the safety threshold. New Evidence: What impact will these findings have on the use of tocilizumab in early RA? Dr. Burmester: The study will have a strong impact because it showed that tocilizumab is very effective in early, aggressive RA, and that tocilizumab is also effective as monotherapy, which is relevant for patients who cannot tolerate methotrexate. One argument for using methotrexate in conjunction with biologics is that methotrexate increases serum levels of biologics and inhibits development of anti-drug antibodies. Neither of these appears to be relevant in the use tocilizumab. We have found that tocilizumab serum concentrations are not affected by using methotrexate, and furthermore, antibodies to tocilizumab have not been observed to date, which is a very puzzling but advantageous aspect of tocilizumab. New Evidence: Would these data support your use of tocilizumab earlier in the RA treatment algorithm? Dr. Burmester: The study showed that tocilizumab was very effective in very active, early RA. Yes, I support the use of tocilizumab in early RA; however, the guidelines or recommendations for the management of RA need to be observed first using conventional DMARDs such as methotrexate. Reference: 1. Burmester GR, Rigby W, van Vollenhoven RF. Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from a randomized, placebo-controlled trial. ACR Annual Meeting Abstracts 214: New Evidence in Rheumatology February 215

40 In Supportive Care Oncology Rituximab in Rheumatoid Arthritis Treatment Rituximab is Not Associated with an Increased Rate of Infections Rituximab is a chimeric monoclonal antibody against CD2 which has proven very effective in reducing the signs and symptoms of rheumatoid arthritis (RA). 1,2 Based on randomized clinical trials that have demonstrated safety and efficacy in RA, rituximab was approved in Canada, the U.S., and Europe for treating RA patients with an inadequate response (IR) to one or more tumour necrosis factor inhibitors (TNF-Is). Treatment with rituximab results in a transient but almost complete depletion of pre-b cells to memory B cells, without affecting stem cells, pro-b cells, and terminally differentiated plasma cells which do not express CD2. 3 Repopulation of B cells occurs within 6 9 months. This relatively long-term depletion of B cells by rituximab has raised questions about the risk of infections associated with the duration and frequency of rituximab treatment, as well as the risk of infections associated with subsequent use of biologics after rituximab use. Two real-world studies by Saag et al. and Harrold et al. presented at the 214 American College of Rheumatology (ACR) Annual Meeting provide important data regarding these questions. In addition to these issues, a study by Choquette et al. based on the RHUMADATA registry addresses the question whether rituximab is a better treatment option than alternative TNF-Is after an inadequate response to a first TNF-I. Other studies presented at ACR 214 assessed the clinical impact of rituximab in second- and thirdline treatment after failure to TNF-Is, and a novel approach to benefit-risk assessment of biologics. The following is a report on five presentations given at the Annual Meeting: A report from the RHUMADATA clinical database and registry showed that, as a second-line agent, rituximab demonstrated a better five-year retention rate than alternative TNF-Is in patients who were non-responders to TNF-Is. A study from a national RA patient registry demonstrated that subsequent biologic use following rituximab is not associated with an increase in infection rate. A U.S. observational study, which examined the frequency of significant infection in patients with RA following initiation of rituximab up to five years, demonstrated that infection risk did not increase over time or with multiple courses of rituximab. A study which investigated the clinical impact of switching to rituximab after varying lengths of previous anti-tnf treatment showed a sustained clinical response to rituximab. A study demonstrated a positive benefit-risk profile for rituximab in patients who were TNF-IR using a structured approach for benefit-risk assessment. References: 1.Edwards JC, Szczepański L, Szechiński J, et al. Efficacy of B-cell targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 24;35: Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 211;7: Mok CC, et al. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther 214;8:87 1. doi:1.2147/dddt.s New Evidence in Rheumatology February

41 Choquette D, et al. ACR 214:1535 Use of rituximab compared to anti-tnf agents as second- and third-line therapy in patients with RA: a report from the RHUMADATA clinical database and registry Background The order of use of biologic agents after failing a tumour necrosis factor inhibitor (TNF-I) is still a question for debate. 1 Phase III trial data in patients with rheumatoid arthritis (RA) who had an inadequate response to TNF inhibitors (TNF-IR) show comparable efficacy results across biologic agents. However, limited head-to-head studies have been published. Prospective registry studies offer a unique opportunity to observe the effectiveness (combined evaluation of efficacy and safety profile over time) of these agents in a clinical setting. The objectives of this study were to: 1) evaluate if patients with RA treated with rituximab after failing a first or a second anti-tnf agent have a different drug retention rate than patients similarly prescribed other anti-tnf agents (pooled adalimumab, etanercept, or infliximab), and 2) to compare the treatment strategies of using rituximab as a second or third biologic treatment. Study design RHUMADATA is a clinical database and registry used in daily clinical practice at the Institut de rhumatologie de Montréal (IRM) and Centre d ostéoporose et de rhumatologie de Québec (CORQ). Data was extracted from records of patients with RA who were TNF-IR and who were prescribed adalimumab, etanercept, infliximab, or rituximab as second or third biologic agents on or after January 1 st, 27. Subjects taking adalimumab, etanercept, or infliximab were pooled to form the TNF-I cohort. Five-year drug retention rates were estimated and compared using Kaplan-Meier survival estimates. Key findings The data from 224 patients with RA were extracted, with 149 and 75 patients having respectively failed a first and a second TNF-I. No clinically significant differences in baseline variables were observed between treatment groups in second and third intention. The five-year retention rates of second-line rituximab and TNF-I use were 7% and 24% respectively (Log-rank, p <.1). (Figure 1) Figure 1. Five-year retention rates of second-line rituximab and TNF-Is 1. Logrank, p <.1.8 Survival probability Rituximab 2. TNFi TNF-i = tumour necrosis factor inhibitor Survival time 4 New Evidence in Rheumatology February 215

42 In Supportive Care Oncology In patients having failed two TNF-Is, subsequent use of rituximab and TNF-Is respectively demonstrated five-year retention rates of 52% and 31% (Log-rank p =.473). (Figure 2) Although numerically superior (7% vs. 52%), second-line use of rituximab did not reach statistically significant difference when compared to third-line usage (Log-rank, p =.536). Figure 2. Subsequent use of rituximab and TNF-Is in patients who failed two TNF-Is 1. Logrank, p = Survival probability Rituximab 2. TNFi TNF-i = tumour necrosis factor inhibitor Survival time Key conclusions As a second-line agent, in patients who were TNF-IR, rituximab demonstrated a better five-year retention rate than TNF-Is. As third-line therapy, rituximab is also statistically superior to TNF-Is. Although no statistically significant difference was demonstrated between second- and third-line use of rituximab, it is evident that positioning rituximab as a second-line treatment offers a better long-term outcome. Reference: 1. Choquette D, Bessette L, Fortin I, et al. Use of rituximab compared to anti-tnf agents as second and third line therapy in patients with rheumatoid arthritis: a report from the RHUMADATA clinical database and registry. ACR Annual Meeting Abstracts 214:1535. New Evidence in Rheumatology February

43 Harrold RL, et al. ACR 214:518 Risk of infection associated with subsequent biologic use following rituximab results from a national RA patient registry Background Tumour necrosis factor inhibitors (TNF-Is) are typically the first choice of biologic therapy for patients with rheumatoid arthritis (RA). 1 However, approximately 4% of patients do not achieve a clinical response with TNF-Is in clinical trials and real-world practice settings. Rituximab, an alternative biologic agent to TNF-Is, is a chimeric monoclonal antibody that targets and depletes CD2-positive B cells. Rituximab is approved for the treatment of RA in combination with methotrexate for patients who have failed TNF-Is. Prolonged B-cell depletion from repeated doses of rituximab treatment may be associated with an increased risk of infection during subsequent biologic use. Limited data exist on rates of infection when switching between biologic classes, particularly in patients who switch to a subsequent biologic following rituximab. The objective of this study was to assess whether time between the last rituximab infusion and the switch to a biologic with a different mechanism of action, and the intensity of rituximab use, influenced the risk of infection in a large, national RA patient registry (Corrona). Study design The Corrona registry is an independent, prospective observational cohort of patients with RA recruited from more than 16 private and academic practice sites across 4 states in the U.S., with more than 6 participating rheumatologists. As of March 31, 214, data on approximately 39,95 patients with RA have been collected. The database includes information about 285,726 patient visits and approximately 119,298 patientyears (PYs) of follow-up observation time, with a mean time of patient follow-up of 3.6 years (median, 2.8 years). Inclusion criteria were: Diagnosis of RA and no psoriatic arthritis at any time during the study period (March 1, 26 through March 3, 214); First-time initiation of rituximab within the Corrona registry; Subsequent initiation of the first non-rituximab biologic following rituximab use; At least one follow-up appointment within 12 months after subsequent biologic initiation; and Available data on rituximab infusion dates to calculate the duration of time between the switch from rituximab to a subsequent biologic. Data were collected from first-time initiators of rituximab in Corrona who initiated a subsequent (non-rituximab) biologic following the end of rituximab use. Patients were categorized by the duration of time between their last rituximab infusion and the switch to a subsequent biologic ( 5 months, 6 11 months, and 12 months). The primary outcomes of the study were time to infection and infection rates by patient category. Patients were followed from the time they initiated the subsequent biologic to the time of the first infectious event. Patient follow-up ended with the infectious event or with the earliest of the following: 12 months elapsed; Discontinuation or switch of the subsequent biologic; infectious events occurring within 9 days of the discontinuation or switch were counted as an event; Retreatment with rituximab; Exiting Corrona. Patient demographic and clinical characteristics at baseline (i.e., the time of the switch to a subsequent biologic) were compared across patient groups. Kaplan-Meier analyses estimated the time to infection and cumulative infection rates for each patient group. A Cox regression model estimated the association between the time to the switch to a subsequent biologic and infection, adjusted for potential confounders. Characteristics that differed by time to initiation and were associated with infection were included in the model, and the adjusted hazard ratio for time to initiation was estimated. The number and rate of rituximab retreatments per year were added to the model regardless of the unadjusted association with infections. 42 New Evidence in Rheumatology February 215

44 In Supportive Care Oncology Study design Number and rate of RTX treatments RTX RTX RTX RTX Initiation of subsequent biologic Discontinuation or switch of biologic Primary exposure* Time to infection 9-day follow-up *The primary exposure of interest was the time (in months) from the last RTX infusion to the start of a subsequent (non-rtx) biologic (categorized by duration between the two: 5 months, 6 11 months, or 12 months). For patients who discontinued or switched their subsequent biologic before infection, infectious events occurring within 9 days of the discontinuation or switch were counted as an event. RTX = rituximab Key findings A total of 215 patients who switched to a subsequent biologic following rituximab use were included in this analysis ( 5 months: n = 14; 6 11 months: n = 67; and 12 months: n = 44). Of the 215 patients included in this analysis, 13 patients switched to a TNF-I and 112 patients switched to a non- TNF-I biologic. Baseline characteristics were similar between the groups, except for a higher tender joint count and a higher rate of rituximab retreatment in patients who switched to a subsequent biologic earliest ( 5 months). A summary of patient selection based on inclusion criteria is shown in Figure 1. The baseline medication history by time to the switch is shown in Table 1. Figure 1. Summary of patient selection based on inclusion criteria N = 1212 Rituximab new initiators n = 184 With infusion dates available n = 128 No infusion dates available n = 32 Switched to another biologic n = 764 No switch to another biologic n = 14 No baseline visit* n = 216 With baseline visit* n = 1 No follow-up visit within 12 months n = 215 With follow-up visit within 12 months *Baseline visit was at the time of subsequent (non-rituximab) biologic initiation. If this initiation occurred between visits, then baseline information was obtained at the visit within 4 months prior to initiation. New Evidence in Rheumatology February

45 Table 1. Baseline medication history by time to the switch Time to switch to a subsequent biologic Medication history 5 months (n = 14) 6 11 months (n = 67) 12 months (n = 44) p-value Currently receiving prednisone, % (n) 45.2 (47) 5.7 (34) 47.7 (21).79 Number of prior DMARDs (including current), median (IQR) 2 (1 3) 2 (1 3) 2 (2 3.5).73 Number of prior biologics (excluding RTX), % Number of RTX retreatments, mean (SD) 1.5 (2.2) 1.5 (1.9) 1.1 (1.7).54 Number of RTX retreatments, % Rate of RTX treatment per year, mean (SD).95 (1.2).72 (.7).37 (.4) <.1 DMARDs = disease-modifying antirheumatic drugs; IQR = interquartile range; RTX = rituximab; SD = standard deviation Time to the first infectious event and the probability of infection over time were similar regardless of time from the switch from rituximab to a subsequent biologic. (Table 2) Less than 5% of patients experienced an infection. (Figure 2A) Of those who had an infection during the 12-month follow-up, the median (interquartile range) time to infection was 4 (2 5) months. (Figure 2B) Kaplan-Meier estimates of time to infection and probability of infection were similar when analyzing TNF-I initiators and non-tnf-i initiators separately. The most common types of nonserious infections observed across all patient groups were upper respiratory infection (n = 15), urinary tract infection (n = 7), and systemic infection (n = 3). (Table 3) The unadjusted hazard ratios (95% confidence interval) for infection were.92 (.46, 1.84) and 1.2 (.57, 2.55) in the 6 11 months and 12 months groups, respectively, relative to the 5 months group. After adjusting for potential confounders, time to the switch to a subsequent biologic was not associated with infection, which remained unchanged when including the number and rate of rituximab retreatments in the models. (Figure 3) Table 2. Infection rates by time to the switch to a subsequent biologic Time to switch to a subsequent biologic 5 months (n = 14) 6 11 months (n = 67) 12 months (n = 44) Total Total duration of follow-up, PY Number of infections Infection rate per PY (95% CI).34 (.22,.52).3 (.17,.52).41 (.22,.77).34 (.25,.46) CI = confidence interval; PY = patient-years 44 New Evidence in Rheumatology February 215

46 In Supportive Care Oncology Table 3. Infection types by time to the switch to a subsequent biologic Figure 2A. Kaplan-Meier estimates of time to infection Time to switch to a subsequent biologic Infection type, n 5 months (n = 14) 6 11 months (n = 67) 12 months (n = 44) Total 1 Serious infections* Non-serious infections (total) Upper respiratory Urinary tract Multiorgan system Skin (cellulitis) Musculoskeletal (joint bursa) 1 1 Other *Serious infections were defined as infections requiring intravenous antibiotics or hospitalization. Includes bronchitis, bronchitis/other, pneumonia, sinusitis, sinusitis/bronchitis, sinusitis/upper respiratory infection and upper respiratory infection. Includes sinusitis/urinary tract infection and urinary tract infection/upper respiratory tract infection. Probability of no infection, % months 6 11 months 12 months Months Figure 2B. Kaplan-Meier estimates of probability of infection by time to the switch months 6 11 months 12 months Probability of infection, % Months 6 Months 9 Months 12 Months New Evidence in Rheumatology February

47 Figure 3. Unadjusted and adjusted* models for infection rate by time to the switch Adjusted HR (with no. and rate of RTX retreatments) Adjusted HR (with rate of RTX retreatments) Adjusted HR (with no. of RTX retreatments) Adjusted HR Unadjusted HR Hazard Ratio (95% CI) 5 months (reference) 6 11 months 12 months *Cox regression models were adjusted for age, sex, duration of RA, smoking status, patient pain, mhaq, CDAI, presence of subcutaneous nodules, history of cardiovascular disease, history of liver disease, history of serious infection, number of prior DMARDs, and number of prior biologics (excluding rituximab). CDAI = Clinical Disease Activity Index; CI = confidence interval; DMARDs = disease-modifying antirheumatic drugs; HR = hazard ratio; mhaq = modified Health Assessment Questionnaire; RA = rheumatoid arthritis; RTX = rituximab Key conclusions In this group of older patients with established RA and moderate to severe disease activity, the overall rate of infection after switching from rituximab to a subsequent biologic was low. There was no significant difference in the rate of infections by time from the last rituximab infusion to initiation of a subsequent (non-rituximab) biologic. Duration of time between the last rituximab infusion and the switch to a biologic with a different mechanism of action was not associated with an increased rate of infection in patients with RA. The number and rate of rituximab retreatments was not correlated with the risk of infection associated with the subsequent biologic. Reference: 1. Harrold RL, Reed GW, Karki C, et al. Risk of infection associated with subsequent biologic use following rituximab results from a national RA patient registry. ACR Annual Abstracts 214: New Evidence in Rheumatology February 215

48 In Supportive Care Oncology Saag KG, et al. ACR 214:844 Frequency of significant infection in patients with RA following initiation of rituximab with up to five years of follow-up in a U.S. observational study (SUNSTONE) Background Rituximab is approved for treatment of rheumatoid arthritis (RA) in patients with an inadequate response (IR) to tumor necrosis factor inhibitor (TNF-I) therapy. 1 Although several phase III clinical trials have demonstrated the efficacy and safety of rituximab in RA, long-term infection risk data of rituximab use in real-world settings remain limited. The objective of this study was to describe the frequency and types of significant infections in patients with RA initiating rituximab in the U.S. in a realworld setting. Study design This was a prospective observational cohort study in patients with RA who were TNF-IR. Patients were followed for five years until death, withdrawal of consent, or loss to follow-up. Patients were treated according to standard of care after rituximab initiation. The study investigated adverse events (AEs) that included significant infections. Significant infections were defined as: Hospitalization; Prolonged hospitalization; Resulted in significant disability; Life-threatening or fatal; Medically significant; Treated with intravenous antibiotics. Follow-up time was censored at time of: First significant infection; Switch to another biologic disease-modifying antirheumatic agent (DMARD); Death, withdrawal of consent, or loss to follow-up. A rituximab course was defined as two infusions (1 mg each) separated by 21 days. Patients not treated according to this regimen were excluded from the course analysis. Among patients who switched to another biologic DMARD during follow-up, the incidence rates of significant infection before and after switch were also calculated. Incidence rates calculated after switch were censored at the time of first event, death, withdrawal of consent or loss to follow-up. Incidence rates were reported per 1 patientyears (PY). Key findings 934 TNF-IR RA patients were treated with rituximab. The mean duration of follow-up was four years (standard deviation [SD] = 1.5), and the total followup was 3778 PY. Patients received an average/mean of four (SD = 3.1) rituximab courses. Not all patients were treated according to the labeled dosing regimen. Study design 1 st RTX Capture only the first event of interest 2 nd RTX 3 rd RTX Time of first significant infection OR start of another biologic Time RTX = rituximab Person-time at risk Date of last observation New Evidence in Rheumatology February

49 Baseline characteristics were significantly different (p <.5) between patients with and without significant infection. (Table 1) Baseline characteristics without a significant difference at baseline included percent of women, race/ethnicity, body mass index, duration of RA, RF positivity, swollen joint count, subcutaneous nodules, and rheumatoid lung. Significant infections occurred in 16 patients (17%). (Figure 1) The incidence rate of significant infections was 6.4 infections/1 PY (95% CI: ) Infections were attributed to the following organisms: bacterial (56%), viral (5%), fungal (4%), and unknown (35%). Multiple infections occurred in 65 patients (7%). Fatal infections occurred in 19 patients (2%). The incidence rate of fatal infections was.5/1 PY (95% CI:.3.8). Sepsis and pneumonia were the most common fatal infections. Significant infection rates over time that occurred from first dose of rituximab are shown in Figure 2. The incidence rate of significant infections per 1 PY by rituximab course number were: Course 1 = 7.4 (95% CI: ); Course 2 = 6.1 (95% CI: ); Course 3 = 7.1 (95% CI: ); Course 4 = 4.8 (95% CI: ); Course 5 = 7.7 (95% CI: ); Course 6 = 6. (95% CI: ); Course 7 = 1.4 (95% CI:.2 9.7); Course 8 = 2.2 (95% CI: ); Course 9 = 7.2 (95% CI: ). The rate of serious infectious events before other biologic DMARDs was 4.6/1 PY (95% CI: ), and after other biologic DMARDs was 4.5/1 PY (95% CI: ). (Table 2) Factors associated with significant infections were: Age: multivariable-adjusted odds ratio [aor] = 1.3 (95% CI: ); Diabetes: aor = 1.73 (95% CI: ); Prior infections: aor = 1.77 (95% CI: ); Joint deformity: aor = 1.78 (95% CI: ); Respiratory events: aor = 1.94 (95% CI: ). Table 1. Baseline characteristics % or mean (SD) No significant infection (n = 774) Significant infection (n = 16) Women Age* 56.1 (12.8) 62.4 (11.8) White Body mass index 29.6 (7.4) 3.6 (8.1) Disease activity/severity Health Assessment Score (HAQ)* 1.4 (.7) 1.6 (.7) Duration of RA (years) 12.1 (1.) 12.9 (1.1) RF positive Swollen joint count 11. (7.9) 1.6 (7.6) Subcutaneous nodules Clinical joint deformity* Rheumatoid lung Medical history 1 comorbid condition* Diabetes* Malignancy* Myocardial infarction* Infection history* Chronic recurrent infections* Respiratory events* *p <.5 Includes chronic recurrent infection (three or more in one year) or an infection that required iv antibiotics or hospitalization. iv = intravenous; RA = rheumatoid arthritis; RF = rheumatoid factor; SD = standard deviation 48 New Evidence in Rheumatology February 215

50 In Supportive Care Oncology Figure 1. Proportions of significant infections by type Respiratory 15% Skin/soft tissue Gastrointestinal 1% 14% 37% Genitourinary Musculoskeletal including joints Others 1% 14% Figure 2. Significant infection rates that occurred from first dose of rituximab Significant infection rates over time in 1-year increments 14. Incidence rate (per 1 PY) year >1 2 years >2 3 years >3 4 years >4 5 years Number of patients Total exposure, PY Number of events IR (per 1 PY) 95% CI ( ) ( ) ( ) ( ) ( ) *Patients that switch to another biologic DMARD are censored at time of switch and excluded from IR calculations for subsequent years. CI = confidence interval; IR = incidence rate; PY = patient-years New Evidence in Rheumatology February

51 Table 2. Serious infectious rates Before other biologic DMARD After other biologic DMARD Total exposure, PY SIE, number SIEs/1 PY % CI CI = confidence interval; DMARD = disease-modifying antirheumatic drug; PY = patient-years; SIE = serious infectious event Key conclusions This study presented long-term data from 938 patients treated with rituximab and followed up to five years. Overall, the rate significant infections was 6.4/1 PY. Infection risk did not increase over time or with multiple courses. The use of subsequent biologics was not associated with an increased rate of significant infections. Patients with RA who had significant infections had more baseline comorbid conditions. The strengths of the study were: The design was a large, prospective study with minimal eligibility criteria; Follow-up was five years in a real-world setting; The study targeted significant infections. The limitations of the study were: There was no internal control, unequal surveillance, and potential misclassification; Some infection risk factors were not consistently captured (e.g., disease activity measures, glucocorticoid dose); Not all patients were followed for the full five years. Reference: 1. Saag KG, Winthrop KL, Furst DE, et al. Frequency of significant infection in patients with RA following initiation of rituximab with up to 5 years of follow-up in a US observational study. ACR Annual Meeting Abstracts 214:844. Ancuta I, et al. ACR 214:1538 Sustained clinical benefit with rituximab in second line for all RA patients irrespective of the previously used tumour necrosis factor inhibitor Background In the last decade, biologic therapy has dramatically changed the treatment options for rheumatoid arthritis (RA). However, a significant number of patients fail to maintain the initial response to tumour necrosis factor inhibitors (TNF-Is). More information is needed regarding efficacy and safety of multiple courses of biologics administered over extended periods of time. The objective of the study was to assess the clinical benefit of subsequent courses with rituximab in patients with moderate to severely active RA after failure of various TNF-Is used in routine clinical practice in Romania. 5 New Evidence in Rheumatology February 215

52 In Supportive Care Oncology Study design REPEAT is an open-label, multicentre, prospective observational study that began in 21. Patients were treated with rituximab every six months. Clinical efficacy was assessed at baseline and after each retreatment course at 6, 12, 18, 24, 3, and 36 months. Clinical assessments included Disease Activity Score in 28 joints (DAS28), visual analogue scale (VAS) scores, ΔDAS28, and ΔVAS. The previous TNF-I treatments were: adalimumab, etanercept, and infliximab. For comparison between all treatments, statistical analyses (ANOVA, Kruskal-Wallis, and Nptrend for trend across evaluations) were performed with STATA SE 11. software. Key findings A total of 187 adult patients with active RA and inadequate response to at least one TNF-I received initial rituximab treatment. (Figure 1) There were 929 (85.5%) patients who had received only one previous TNF-I (no switch). (Figure 1) Among patients who had received only one previous TNF- I, 21 (19.3%) patients received adalimumab, 318 (29.3%) received etanercept, and 41 (36.9%) received infliximab. There were 158 (14.5%) patients who had received a second previous TNF-I. (Figure 1) Among patients who had received a second TNF-I, 59 (5.42%) patients received adalimumab, 63 (5.79%) received etanercept, and 36 (3.31%) received infliximab. The median DAS28 values for all patients who had received only one previous TNF-I decreased across evaluations. (Figure 2) The median DAS28 values for the group who had received a second previous TNF-I (n = 158) followed the same linear decrease across evaluations. DAS28 scores were improved for all groups of patients, independent of the TNF-I used as previous treatment. (Figure 3) The VAS scores were also improved, independent of previous treatment. (Figure 4) Figure 1. Patients by previous anti-tnf treatments Figure 2. Median DAS28 by evaluation and previous treatment in patients with only one previous TNF-I 6.5 ADA ETA INF Only one anti-tnf n = 929 (85.5%) INF 36.9% ADA 19.3% ETA 29.3% DAS INF 3.3% ETA 5.8% ADA 5.4% Second anti-tnf n = 158 (14.5%) 2. ADA ETA INF Months *ANOVA test between evaluations: p <.1; Nptrend for trend across evaluations: p <.1. ADA = adalimumab; ETA = etanercept; INF = infliximab; TNF = tumour necrosis factor ADA = adalimumab; DAS28 = Disease Activity Score in 28 joints; ETA = etanercept; INF = infliximab New Evidence in Rheumatology February

53 Figure 3. Median DAS28 and ΔDAS28 by evaluation in all patients DAS28 DAS28 Median score Months 2.65 *ANOVA test between evaluations: p <.1; Nptrend for trend across evaluations: p <.1. DAS28 = Disease Activity Score in 28 joints Figure 4. Median VAS scores by evaluation and previous treatment in all patients 6 ADA ETA INF 5 4 Key conclusion VAS 3 2 Rituximab has been shown to be a reliable therapeutic option for all patients regardless of the TNF-I used in first-line treatment (adalimumab, etanercept, or infliximab) Months Reference: 1. Ancuta I, Ionescu R, Codreanu C, et al. Sustained clinical benefit with multiple courses of rituximab in second line for all rheumatoid arthritis patients irrespective to the inhibitor of tumour necrosis factor previously used: 3-year data from the REPEAT study. ACR Annual Meeting Abstracts 214:1538. *ANOVA test between evaluations: p <.1; Nptrend for trend across evaluations: p <.1. ADA = adalimumab; ETA = etanercept; INF = infliximab; VAS = visual analog scale 52 New Evidence in Rheumatology February 215

54 In Supportive Care Oncology John A, et al. ACR 214:55 A structured approach for benefit-risk assessment of rituximab for the treatment of rheumatoid arthritis Background Assessing the benefit risk-balance of approved drugs and biological products is a challenge for the healthcare system. 1 A structured systematic assessment of a drug s benefit-risk profile is useful to inform decisions at each developmental milestone, and could meaningfully inform multiple stakeholders, physicians, patients, payers, and researchers on the trade-offs between benefits and risks during the lifecycle of a drug product. The anti-cd2 monoclonal antibody rituximab, in combination with methotrexate, is indicated for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA) who have an inadequate response (IR) to anti-tumour necrosis factor therapies (TNF-IR). The objective of this study was to apply a structured descriptive approach to presenting the benefit-risk profile of rituximab using 24-week data from the REFLEX placebo-controlled trial, and to produce a descriptive graphical representation of this benefitrisk profile in patients with RA who were TNF-IR. Study design This was a post-hoc analysis of six-month (24-week) placebo-controlled data from a randomized clinical trial in TNF-IR patients (REFLEX). Current processes in assessing a benefit-risk profile rely primarily on expert judgment; however, recent efforts have focused on new tools that incorporate both qualitative and quantitative analyses of benefit and risk outcomes. The Benefit Risk Action Team (BRAT) Framework has been developed as a toolkit to provide a framework and specific methods that constitute a consistent approach to the benefit-risk assessment of a drug product. The steps in the benefit-risk assessment were: Step 1. Define the decision context; Step 2. Identify outcomes; Step 3. Identify and extract source data; Step 4. Customize framework; Step 5. Assess outcome importance; Step 6. Summarize and interpret key benefit-risk metrics. Study design Screening and atnf/dmard withdrawal period Randomization Treatment period MTX 3 months Rituximab + MTX N = 38 Placebo + MTX N = 29 Screen Rituximab: 1 mg or placebo iv infusion; Methylprednisolone: 1 mg iv before rituximab infusion; Prednisone: 6 mg day 2 7, 3 mg day Day 1 Day 15 Wk 4 Wk 8 Wk 12 Wk 16 Wk 2 Rescue Wk 24 Clinic visit Primary efficacy endpoint Standard of care Rituximab + MTX atnf = anti-tumor necrosis factor agent; DMARD = disease-modifying antirheumatic drug; iv = intravenous; MTX = methotrexate; wk = week New Evidence in Rheumatology February

55 Key findings Benefit-risk assessment of rituximab in patients with RA who were TNF-IR Step 1. Define the decision context Regulatory agencies, including the Food and Drug Administration and the European Medicines Agency, have employed methodologies to develop structured qualitative frameworks for assessing a drug product s benefits and risks in order to improve consistency, transparency, and communication of an approved drug s benefit-risk profile to multiple stakeholders. International task forces recommend conventional synthetic disease-modifying antirheumatic drugs (DMARDs) as first-line therapy in patients with RA, followed by the addition of a biologic or another conventional synthetic DMARD if the treatment target is not reached. In spite of these advances in RA management, approximately 2% to 4% of patients fail to achieve a clinical response ( 2% improvement in American College of Rheumatology [ACR] criteria) with anti-tnf therapies. Data from the 24-week REFLEX study were identified to evaluate the benefit-risk profile of rituximab using a retrospective application of the BRAT Framework. The benefits and risks of rituximab treatment were compared with placebo over 24 weeks. Step 2. Identify outcomes Based on literature review, an initial value tree with potential outcomes (little or no evidence supporting relevance to rituximab in RA) and identified outcomes (with supporting evidence) was constructed. Potential outcomes for each benefit and risk category evaluated include: Disease activity measures; Laboratory assessments; Patient-reported outcomes (PRO); Adverse events (AEs); Serious adverse events (SAEs). Step 3. Identify and extract source data All benefit and risk outcomes data were collected, including REFLEX study patient characteristics and relevant data for each outcome (e.g., overall sample size, important safety and efficacy outcomes identified in Step 2, and the number of patients in each arm achieving each outcome). A significantly higher proportion of rituximab-treated patients achieved ACR2/5/7 response rates, moderate or good European League Against Rheumatism (EULAR) responses, and improvements in Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28- ESR) at 24 weeks compared with placebo-treated patients. Rituximab-treated patients also demonstrated a clinically meaningful improvement in Health Activity Questionnaire- Disability Index (HAQ-DI). Rituximab-treated patients reported similar rates of overall AEs compared with placebo-treated patients (77.39 vs per 1 patient-years [PY]) and SAEs (21.55 vs. 28. per 1 PY) at 24 weeks. Similar proportions of rituximab- and placebo-treated patients reported infections and serious infections. Step 4. Customize framework The value tree was trimmed based on the efficacy, PRO, and safety data available from the REFLEX study. Only AEs that were observed in the context of the 24-week placebo-controlled REFLEX study were included in the final value tree. (Figure 1) Figure 1. Final value tree for the use of rituximab in rheumatoid arthritis ACR response Clinical response EULAR response Benefits DAS28-ESR Patient-reported outcome HAQ-DI Benefit-risk balance Risks Adverse events and serious adverse events Infections Serious infections ACR = American College of Rheumatology; DAS28-ESR = Disease Activity Score in 28 joints erythrocyte sedimentation rate; EULAR = European League Against Rheumatism; HAQ-DI = Health Assessment Questionnaire Disability Index 54 New Evidence in Rheumatology February 215

56 In Supportive Care Oncology Step 5. Assess outcome importance Equal importance weights were assigned for all outcomes in this analysis. Step 6. Summarize and interpret benefit-risk metrics The key benefit-risk summary for the REFLEX study indicates the differences in response and event rates between rituximab and placebo. (Table 1) Point estimates indicate that efficacy, PRO, and safety outcomes favour rituximab over placebo. (Figure 2) Patients who received rituximab demonstrated clinically meaningful and statistically significant improvements in ACR2/5/7 response rates, EULAR response rates, DAS28-ESR, and HAQ-DI compared with patients who received placebo. AEs occurring at a higher incidence in the rituximab group were generally associated with acute infusion-related reactions (IRRs; 23% of rituximab-treated patients experienced IRRs, compared with 18% of patients who received placebo; data not shown). With the exception of IRRs, there were no obvious increases in specific types of AEs associated with rituximab therapy. Overall, compared with placebo, there were no meaningful differences in the rituximab arm in the rates of safety events per 1 PY including in the rates of AEs, SAEs, and infections although a marginal increase in serious infections was observed. Table 1. Key risk-benefit summary Category Outcome Rituximab Placebo Absolute difference (95% CI) ACR2 response, % (26, 41) ACR5 response, % (15, 27) Benefits Clinical response ACR7 response, % (7, 15) Patient-reported outcome EULAR good/moderate response, % DAS28-ESR, mean change from baseline HAQ-DI, mean change from baseline (35, 51) ( 1.76, 1.29) (.45,.21) Category Outcome Rituximab Placebo Absolute difference (95% CI) All adverse events, rate per 1 PY ( 13.2, 18.13) Risks Adverse events and serious adverse events Infections, rate per 1 PY ( 49.39, 16.57) All serious adverse events, rate per 1 PY ( 19.9, 6.99) Serious infections, rate per 1 PY ( 4.35, 7.44) ACR = American College of Rheumatology; CI = confidence interval; DAS28-ESR = Disease Activity Score in 28 joints erythrocyte sedimentation rate; EULAR = European League Against Rheumatism; HAQ-DI = Health Assessment Questionnaire Disability Index; PY = patient-years New Evidence in Rheumatology February

57 Figure 2. Descriptive benefit-risk Forest plot: efficacy and AE rate differences (95% CI) between rituximab and placebo in the 24-week placebo-controlled period of the REFLEX trial* ACR2 33 ACR5 22 ACR7 EULAR good/moderate response 11 Favours rituximab 43 DAS28-ESR HAQ All AEs All SAEs Infections Absolute difference (%) Favours rituximab Difference in mean change from baseline Efficacy Safety Serious infections Favours rituximab Difference (rate/1 patient-years) *Placebo-controlled period includes data up to the Week 24 data cut-off point or date of withdrawal, whichever is earliest. Diamonds represent differences (rituximab vs. placebo) and horizontal bars represent 95% confidence intervals. ACR = American College of Rheumatology; AEs = adverse events; CI = confidence interval; DAS28-ESR = Disease Activity Score in 28 joints erythrocyte sedimentation rate; EULAR = European League Against Rheumatism; HAQ-DI = Health Assessment Questionnaire Disability Index; SAEs = serious adverse events Key conclusions A graphic representation of the key benefits and risks was generated to present the positive benefit-risk profile of rituximab in patients with RA who were TNF-IR. Future applications of this structured approach could include: Interpretation of the benefit-risk profile of longer-term outcomes and in other subpopulations of patients with RA; A similar assessment of other approved drugs in a consistent manner. Reference: 1. John A, Quartey G, Lehane PB, et al. A structured approach for comparative benefit-risk assessment of rituximab for the treatment of rheumatoid arthritis. ACR Annual Meeting Abstracts 214: New Evidence in Rheumatology February 215

58 In Supportive Care Oncology Canadian Perspective by Dr. John Wade The treatment of rheumatoid arthritis (RA) with biologics has undergone a generational change. Prior to the era of biologics, living with chronic pain and permanent disability was expected for many patients with moderate to severe RA. Today, biologics have allowed patients with an inadequate response to synthetic disease-modifying antirheumatic drugs to resume relatively healthy lives. Biologics available for the treatment of RA include tumour necrosis factor inhibitors (TNF-Is; e.g., etanercept), and those with alternative modes of action such as inhibitors of interleukin-6 receptor (tocilizumab) and antibodies to CD2 (rituximab). Rituximab is a monoclonal antibody designed to bind the CD2 receptor found on mature B cells. Rituximab-depletion of mature CD2-positive B cells, which are critical to the pathogenesis of RA, is responsible for the efficacy of this agent. Having a different mechanism of action has made rituximab an important alternative in patients who have an inadequate response to TNF-Is, which is how I use this biologic in my clinic. In patients who have Sjögren s syndrome, rheumatoid/ systemic lupus overlap, vasculitis, or rheumatic nodules, rituximab may be my first choice as a first-line biologic. A number of randomized clinical trials have demonstrated the efficacy and safety of rituximab in patients with moderate to severe RA. 1 In addition to controlled trials, data from real-life settings have shed more light on the role of this agent in every day practice. At last year s 214 American College of Rheumatology (ACR) conference, among the presentations were two real-life studies on efficacy and safety of rituximab. In addition, a new structured approach showing benefits and risks for biologics was also presented. The Choquette et al. study was based on the real-life RHU- MADATA registry in Quebec. 2 The objective of the study was to examine retention rates of rituximab in patients with RA who have failed TNF-Is. This real-life study confirms that rituximab is an appropriate second- or third-line treatment option after an inadequate response to TNF-Is. Although registry-based studies have limitations due to strict inclusion and exclusion criteria, they provide important insights into issues surrounding drug use in a real-world setting. An additional advantage of the RHUMADATA registry is that it is Canadian, and thus provides relevant information to Canadian healthcare professionals. The access to certain biologics, as well as the order in which biologics are given, may differ significantly from one country to another. For example, the lack of insurance coverage of some biologics in the U.S. may lead to patients being treated differently there. In Europe, strict regulations are in place about when to start which biologics, and the order in which biologics are used. In Canada, a similar treatment approach exists across all provinces, and thus, findings from a Canadian-based registry may be more relevant to rheumatology specialists in Canada. The study by Choquette et al. showed that the retention rate with rituximab was three times greater than the alternative TNF-I for up to five years, which reflects the efficacy and safety of rituximab. Consistent with this finding was that rituximab had a retention rate twice as high as an alternative TNF-I when used as a third-line treatment. The better retention rates observed when rituximab is used as both second- and third-line treatments are likely due to the different mechanism of action of this biologic. The study makes a convincing case to use rituximab as an alternative to TNF-Is in second- and third-line treatment of RA. The study by Harrold et al. was based on the Corrona database in the U.S., which has now collected data on approximately 14, patients with RA. 3 Patients included in the study (N = 215) had no psoriatic arthritis, had previously been treated with rituximab for the first time, and had switched to a subsequent biologic with an alternative mechanism of action. The objective was to examine if infection rates are impacted by rituximab dose intensity and time to switching to another biologic. The analysis showed that infection rates were low overall, indicating that neither the intensity of rituximab use nor the time to switching to another biologic had any impact on infection rates. This is especially reassuring given that the patient population was older (approximately 57 years). The observation that infection rates were not different in patients switching to another biologic in five months or less compared to those switching after 6 11 months indicates that switching to another biologic after rituximab could be done very early on. This study also shows that given as a first biologic, rituximab does not compromise patients to increased infection risk with a subsequent biologic. In addition, it is reassuring that this observation was made in a study where approximately 5% of patients had received prednisone, which is known to increase the risk of infections. Finally, the descriptive presentation by John et al. aimed to present a structured analysis of the benefits and risks of rituximab treatment from the REFLEX study. 4 REFLEX was a placebo-controlled, phase III clinical trial that examined the efficacy and safety of rituximab in RA patients who had an inadequate response to a TNF-I. Consistent with the results of the REFLEX study, the analysis showed a clear visual representation of improved efficacy outcomes in patients treated with rituximab compared with placebo. This visual method of representation may help physicians incorporate aspects of both risks and benefits in every day practice. References: 1. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 211;7: Choquette D, Bessette L, Fortin I, et al. Use of rituximab compared to anti-tnf agents as second and third line therapy in patients with rheumatoid arthritis: a report from the RHUMADATA clinical database and registry. ACR Annual Meeting Abstracts 214: Harrold LR, Reed GW, Karki C, et al. Risk of infection associated with subsequent biologic use following rituximab results from a national RA patient registry. ACR Annual Abstracts 214: John A, Quartey G, Lehane PB, et al. A structured approach for comparative benefit-risk assessment of rituximab for the treatment of rheumatoid arthritis. ACR Annual Meeting Abstracts 214:55. New Evidence in Rheumatology February

59 Other Biologics in Rheumatoid Arthritis Treatment Assessing Abatacept, Adalimumab, Etanercept, and Infliximab as First-Line Treatments in Rheumatoid Arthritis The treatment of rheumatoid arthritis (RA) changed dramatically with the arrival of biologics. Although synthetic disease-modifying antirheumatic drugs, which include steroids and methotrexate, remain the standard of care for patients with RA, these agents do not control disease activity in a significant number of patients. In such cases, monoclonal antibodies (biologics) which target components of the immune system that are critical in the pathogenesis of RA have become important in controlling disease and inducing complete remissions. A number of biologics have been developed based on knowledge of signalling pathways involved in the etiology and disease progression of RA. Biologics were first developed against the tumour necrosis factor alpha (TNF-α) signalling pathway, which explains in part the availability of several TNF inhibitors on the market today, such as adalimumab, etanercept, and infliximab. Biologics developed to target other components of the immune system include the T-cell suppressor abatacept. Although efficacy and safety of these biologics are well established, direct comparisons between various biologics regarding efficacy and safety remain poorly investigated, partly because of the absence of head-to-head trials for many of these agents. This question was recently addressed in an abstract by Choquette et al. at the 214 American College of Rheumatology (ACR) Annual Meeting. Using the RHUMADATA clinical database and registry, the study compared the five-year retention rate of abatacept with those of adalimumab, etanercept, and infliximab as firstline agents in patients with RA. Results from this study should aid clinicians in choosing the most appropriate first biologic for patients with RA. At ACR 214, investigators presented several realworld studies on first-line treatment with biologics in RA. This article reports on five presentations given at the meeting: A real-world study showed that the five-year retention rates of abatacept, adalimumab, etanercept, and infliximab following methotrexate failure were similar as first-line agents in patients with RA. In an observational study of patients with RA treated with abatacept in clinical practice, a greater proportion of bio-naïve patients had a significant clinical response and remained on treatment compared to those with a previous inadequate response to other biologics. A comparison of patient characteristics, healthcare costs, and biologic persistence between patients with RA showed that abatacept frequently had the smallest increase from baseline in healthcare costs and longest duration of biologic persistence. A study evaluating the discontinuation of biologics showed that the one-year discontinuation rate of biologics after achieving low activity disease status was high in patients with RA treated in an outpatient setting. A study on the number needed to treat (NNT) in analyzing biologics in methotrexate-naive patients showed that NNT meta-analysis can be a useful tool for determining the relative efficacy of biologics. 58 New Evidence in Rheumatology February 215

60 In Supportive Care Oncology Choquette D, et al. ACR 214:1536 Comparing abatacept to adalimumab, etanercept, and infliximab as first-line agents in patients with rheumatoid arthritis Background The order of use of biologic agents is still a question for debate. Phase III trial data in patients with rheumatoid arthritis (RA) who have an inadequate response (IR) to methotrexate show comparable efficacy results across biologic agents. 1 In addition, a limited number of head-to-head studies has been published. Registries offer a unique opportunity to prospectively monitor the effectiveness of these agents in a clinical setting. The objective of this study was to assess if patients with RA treated with abatacept, after failure to methotrexate as a first-line treatment, have a different drug survival rate than patients similarly treated with adalimumab, etanercept, or infliximab. Study design Patients with RA prescribed a first biologic agent after January 1st, 27 were included in the present analysis. A cohort was formed of all patients who were prescribed abatacept, adalimumab, etanercept, or infliximab, as their first biologic agent. Baseline demographics for this cohort included age, disease duration, Health Assessment Questionnaire- Disability Index, fatigue and pain visual analog scale evaluation, tender joint counts, swollen joint count, Disease Activity Score in 28 joints-erythrocyte sedimentation rate, Clinical Disease Activity Index, and Simplified Disease Activity Index. Person-years of treatment were also compared across biologic agents. Statistical analysis was performed using SAS version 9.3. RHUMADATA is a clinical database and registry used daily in clinical practice at the Institut de rhumatologie de Montréal, Centre d ostéoporose et de rhumatologie de Québec, and Centre de rhumatologie de l est du Québec. Key findings A total 347 patients were included in the cohort. No clinically significant differences in baseline characteristics were noted between treatment groups. The five-year retention rates of abatacept, adalimumab, etanercept, and infliximab post methotrexate failure were 64%, 4%, 49%, and 42%, respectively. (Figure 1) There were no significant statistical differences (log-rank, p =.29). Figure 1. Drug retention of biologic agents 1. Drug retention probability Abatacept Adalimumab Etanercept Infliximab.4 Logrank, p = Time to drug failure or censoring (days) New Evidence in Rheumatology February

61 Key conclusion Abatacept, adalimumab, etanercept, and infliximab after methotrexate failure have similar five-year retention rates. Reference: 1. Choquette D, Bessette L, Fortin I, et al. Comparing abatacept to adalimumab, etanercept and infliximab as first-line agents in patients with rheumatoid arthritis. Experience from the provincial electronic database and registry RHUMADATA. ACR Annual Meeting Abstracts 214: Turesson C, et al. ACR 214:51 Bio-naïve patients with RA benefit more from abatacept treatment compared to those who are inadequate responders to other biologics Background Abatacept is a biologic disease-modifying antirheumatic drug (DMARD) used in rheumatoid arthritis (RA). 1 Data on patient characteristics, diagnosis, previous treatment, and outcomes of abatacept have been collected in the Swedish Rheumatology Quality register (SRQ), which comprises the Swedish Biologics Register (ARTIS: Arthritis Treatment In Sweden), since the drug was first available in 26. The objective of this study was to evaluate drug survival probability and the short term outcome of abatacept in clinical practice for patients with RA, using a national register. Study design Observational data from the SRQ were collected for the period from April 1, 26 to May 2, 214. Analyses were stratified by previous exposure to biologic DMARDs, regardless of the cause of discontinuation. Kaplan-Meier survival analysis with right censoring and log-rank test of equality across strata were performed and Šidák multiple-comparison adjustments applied. European League Against Rheumatism (EULAR) good or moderate response rates at 6 and 12 months were calculated and corrected for survival on drug using the Lundex method ([proportion still on drug] x [proportion responding]). Key findings A total of 1291 patients with RA starting abatacept treatment between April 26 and May 214 were included in the SRQ. The following patient groups were compared: bio-naïve (n = 2), one previous biological DMARD (n = 349), 2 previous biological DMARDs (n = 742). Baseline Disease Activity Score in 28 joints (DAS28) and disability (based on Health Assessment Questionnaire) were slightly lower in bio-naïve patients starting abatacept compared to those with inadequate response (IR) to 1 or 2 previous biologic DMARDs. The bio-naïve patients treated with abatacept had shorter disease duration, and were older at baseline, and less likely to be female compared with the other groups. Survival on drug was significantly longer in patients treated with abatacept as the first biologic DMARD compared to those with previous IR to 1 (p =.2) or 2 biologic DMARDs (p =.2). The corresponding estimated survival rates for bionaïve patients and patients treated with 1 or 2 previous biologic DMARDs were 91%/77%/78% at 6 months and 75%/6%/62% at 12 months. There was no significant difference in drug survival between those with IR to 1 vs. 2 biologic DMARDs (p =.94). Patterns of drug survival were similar with longterm follow-up. Figure 1 shows the proportion of EULAR good or moderate responders among those still on abatacept treatment at six and 12 months by previous exposure to biologic DMARDs. A greater proportion of bio-naïve patients had a Lundex-corrected EULAR good/moderate response at six months or 12 months on abatacept compared with those with previous IR to 1 or 2 biologic DMARDs. (Figure 2) 6 New Evidence in Rheumatology February 215

62 In Supportive Care Oncology Figure 1. EULAR good/moderate responders to abatacept by previous exposure to biologic DMARDs Figure 2. Lundex-corrected EULAR good/moderate responders to abatacept, by previous exposure to biologic DMARDs EULAR good/moderate responders (%) months Bio-naïve 1 previous biologic DMARD 2 previous biologic DMARDs 12 months Lundex-corrected EULAR good/moderate responders (%) months Bio-naïve 1 previous biologic DMARD 2 previous biologic DMARDs 12 months DMARDs = disease-modifying antirheumatic drugs; EULAR = European League Against Rheumatism DMARDs = disease-modifying antirheumatic drugs; EULAR = European League Against Rheumatism Key conclusion In this observational study of patients with RA treated with abatacept in clinical practice, a greater proportion of bio-naïve patients had a significant clinical response and remained on treatment compared to those with a previous IR to other biologic DMARDs. These results are compatible with reports from clinical trials, and indicate that a substantial number of RA patients treated with abatacept as their first biologic DMARD in clinical practice have a favourable outcome. Reference: 1. Turesson C, Stawiarz L, Lindblad S, Saevarsdottir S. Bio-naïve patients with rheumatoid arthritis benefit more from abatacept treatment compared to those who are inadequate responders to other biologics results from the National Swedish Rheumatology Quality Register. ACR Annual Meeting Abstracts 214:51. Johnston S, et al. ACR 214:95 Comparison of patient characteristics, healthcare costs, and biologic persistence between patients with RA initiating first- or second-line subcutaneous abatacept, adalimumab, or etanercept Background There are currently very limited comparative published data on the characteristics, healthcare costs, and biologic persistence among patients with rheumatoid arthritis (RA) who have been treated with subcutaneous (sc) abatacept in a real-world care setting. 1 The objective of this study was to compare patient characteristics, healthcare costs, and biologic persistence among patients with RA initiating sc abatacept or one of the two most commonly used sc anti-tnf-α agents, adalimumab and etanercept. Study design This was a retrospective, observational cohort study based on U.S. administrative claims data extracted from the Truven Health MarketScan Commercial Claims and Encounters (commercial) and Medicare Supplemental and Coordination of Benefits (Medicare) databases. New Evidence in Rheumatology February

63 Table 1. Patient characteristics Cost analysis sample Biologic persistence sample Abatacept sc Adalimumab Etanercept Abatacept sc Adalimumab Etanercept First-line patients n = 163 n = 798 n = 8764 n = 172 n = 2517 n = 2966 Age, years 53.5 (12.1) 5.9 (12.)* 51.4 (12.4)* 53.2 (12.1) 5.6 (12.2)* 51.7 (12.3) Female, % * 75.2* * 75.1* Commercial, % * * 88.1 Medicare, % * 11.9 Non-biologic DMARDs used during baseline 1.3 (.9) 1.2 (.8) 1.3 (.8) 1.3 (.9) 1.3 (.8) 1.3 (.8) Unique 3-digit ICD-9-CM DX codes during baseline 17.1 (12.8) 14. (8.7)* 14.3 (8.9)* 17. (12.6) 14.7 (9.2)* 14.9 (9.2)* Unique NDCs during baseline 18. (1.4) 15.3 (9.3)* 15.4 (9.5)* 17.9 (1.2) 15.5 (9.6)* 15.4 (9.3)* Total health care costs during baseline, PPPM Extra-articular disease during baseline, % $225 ($2843) $1153 ($1725)* $1199 ($1944)* $1957 ($2786) $1153 ($1775)* $1152 ($21)* Second-line patients n = 256 n = 255 n = 13 n = 27 n = 739 n = 497 Age, years 55.2 (11.5) 52.8 (12.2)* 52.2 (12.4)* 55.1 (11.4) 52.5 (12.3)* 5.5 (12.5)* Female, % Commercial, % * Medicare, % * Non-biologic DMARDs used during baseline 1.2 (.8) 1.2 (.8) 1.1 (.8)* 1.2 (.8) 1.2 (.8) 1.1 (.7) Unique 3-digit ICD-9-CM DX codes during baseline 15.9 (1.4) 14.2 (8.9)* 14.3 (8.5)* 15.8 (1.4) 14.8 (9.) 14.2 (8.8)* Unique NDCs during baseline 18.7 (9.9) 17.5 (9.7) 18.1 (1.1) 18.6 (9.7) 17.5 (9.4) 17.2 (9.5)* Total health care costs during baseline, PPPM Extra articular disease during baseline, % $2663 ($2462) $2162 ($1779)* $2231 ($1941)* $2636 ($2414) $221 ($1758)* $2156 ($1982)* Data are mean (SD) unless indicated otherwise. *p <.5 vs. Abatacept sc. Hydroxychloroquine, leflunomide, methotrexate, minocycline, and sulfasalazine. Extra-articular disease includes the presence of a diagnosis for any of the following conditions: Felty s syndrome, rheumatoid lung, rheumatoid nodules, Sjögren s syndrome, vasculitis (retinal) or vasculitis (other). DX = diagnosis; ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification; NDC = National Drug Code; PPPM = per-patient per-month; sc = subcutaneous 62 New Evidence in Rheumatology February 215

64 In Supportive Care Oncology Inclusion criteria were: Patients who initiated sc abatacept, adalimumab, or etanercept between January 1, 29 and October 1, 212 (index); Patients who were continuously enrolled for 12 months before (baseline) and 3 months after index; Patients who were aged 18 years at index; Patients who had 1 baseline medical claim with an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis code for RA (714.x). First-line initiators used no biologic pre-index; second-line initiators used only one biologic pre-index. Patient characteristics were measured at baseline. Biologic persistence (follow-up) was defined as the period extending from index until the first occurrence of switch to another biologic, censoring at disenrollment from health insurance or December 31, 212. Total healthcare costs (medical and pharmacy) were measured during baseline and follow-up on a per-patientper-month (PPPM) basis. Changes in healthcare costs from baseline to end of available follow-up were compared using multivariable regression (difference-in-difference method). Biologic persistence was compared using multivariable survival analyses. Figure 1. Patient selection criteria and attrition Patients initiating a biologic DMARD (sc abatacept, iv abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, or tocilizumab) between January 1, 29 and October 1, 212 (initiation date = index) N = 96,17 Patients with continuous enrollment in medical and pharmacy benefits for at least 12 months pre-index (designated as the baseline period) and 3 months post-index n = 4,726 Patients aged 18 years of age at index n = 4,178 Patients with 1 non-diagnostic medical claim with an ICD-9-CM diagnosis code for RA (714.x) incurred within the 12 months before index n = 34,699 Patients with at least 3 days of follow-up (cost analysis sample). First-line: sc abatacept, n = 163; adalimumab, n = 798; etanercept, n = 8764 Second-line: sc abatacept, n = 256; adalimumab, n = 255; etanercept, n = 13 Patients initiating treatment after the date on which sc abatacept was available on the U.S. market (biologic persistence sample). First-line: sc abatacept, n = 172; adalimumab, n = 2517; etanercept, n = 2966 Second line: sc abatacept, n = 27; adalimumab, n = 739; etanercept, n = 497 DMARD = disease-modifying antirheumatic drug; ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification; iv = intravenous; RA = rheumatoid arthritis; sc = subcutaneous New Evidence in Rheumatology February

65 Key findings Patient characteristics are shown in Table 1. The final sample counts for each analysis is shown in Figure 1. Patients treated with sc abatacept had baseline characteristics indicative of the poorest health status (e.g., higher baseline number of unique diagnoses and baseline costs). (Table 2) Compared with patients initiating adalimumab or etanercept, those initiating sc abatacept had the numerically lowest incidence rate of non-persistence per 1 person-years. Abatacept sc had the numerically lowest hazards of nonpersistence, with differences being statistically significant in all comparisons except with first-line adalimumab. (Figure 2) Compared with patients initiating adalimumab or etanercept, those initiating sc abatacept had the lowest increase in total PPPM health care costs from pre-index to post-index. (Table 3) Abatacept sc had the numerically lowest healthcare costs according to the difference-in-difference estimator, with differences being statistically significant in all comparisons except with the second-line etanercept. Table 2. Summary of key findings First-line Second-line Abatacept sc (n = 163) Adalimumab (n = 798) Etanercept (n = 8776) Abatacept sc (n = 256) Adalimumab (n = 255) Etanercept (n = 133) Baseline number of unique diagnoses, mean (SD) 17.1 (12.8) 14. (8.7) p < (8.9) p < (1.4) 14.2 (8.9) p (8.5) p.11 Baseline number of unique medications, mean (SD) 18. (1.4) 15.3 (9.3) p < (9.5) p < (9.9) 17.5 (9.7) p (1.1) p.44 Baseline healthcare costs, mean (SD) $225 ($2843) $1153 ($1725) p <.1 $1199 ($1944) p <.1 $2663 ($2462) $2162 ($1779) p <.1 $2231 ($1941) p <.1 Adjusted healthcare cost difference* reference $64 p.12 $657 p.1 reference $12 p.425 $94 p.134 Adjusted hazard ratio of non-persistence* reference 1.54 p p.466 reference p p.57 * As calculated using difference-in-difference; positive $ value indicates lower increase from baseline in healthcare costs for sc abatacept; hazard ratio >1 indicates lower hazards of non-persistence (longer durations of persistence) for sc abatacept. sc = subcutaneous; SD = standard deviation Table 3. Unadjusted changes in healthcare cost from baseline to follow-up* Unadjusted mean total healthcare costs (PPPM, $) post-index minus pre-index Abatacept sc Adalimumab Etanercept Lower PPPM ($) values indicate lower healthcare cost increases First-line patients n = 163 n = 798 n = 8764 PPPM $1348 $154 $1575 Second-line patients n = 256 n = 255 n = 13 PPPM $66 $867 $772 * Primary analysis measured PPPM total healthcare costs from index until the first occurrence of switch to another biologic, disenrollment from health insurance, or December 31, 212. Mean (median) follow-up in days: First-line sc abatacept = 19 (162), adalimumab = 297 (21), etanercept = 252 (166); second-line sc abatacept = 194 (175); adalimumab = 269 (184), etanercept = 221 (137). PPPM = per-patient per-month; sc = subcutaneous 64 New Evidence in Rheumatology February 215

66 In Supportive Care Oncology Figure 2. Regression-adjusted hazard ratios of nonpersistence during follow-up* Key conclusions Hazard ratio of non-persistence with 95% CI (reference = sc abatacept) First-line adalimumab First-line etanercept Second-line adalimumab Second-line etanercept In this study of patients with RA initiating first- or secondline biologics, sc abatacept was initiated in patients with poorest health status and therefore higher baseline healthcare costs compared with adalimumab or etanercept. Despite this, sc abatacept often had the lowest increase from baseline in healthcare costs and longest duration of biologic persistence. Reference: 1. Johnston S, Lobo F, McMorrow D, et al. Comparison of patient characteristics, healthcare costs, and biologic persistence between patients with rheumatoid arthritis initiating first- or second-line subcutaneous abatacept, adalimumab, or etanercept. ACR Annual Meeting Abstracts 214:95. * Primary analysis measured biologic persistence as time from index until first occurrence of switch to another biologic, censoring at disenrollment from health insurance, or December 31, 212. p <.5 vs. sc abatacept. Ochiai M, et al. ACR 214:495 Discontinuation of biologics in patients with rheumatoid arthritis after achieving low activity disease status Background Several clinical trials have reported bio-free remission or discontinuation of biologic disease-modifying antirheumatic drugs (DMARDs). However, these findings have not been confirmed in a real-world setting. The objective of this study was to evaluate the discontinuation of biologics after achieving low activity disease status among patients with rheumatoid arthritis (RA) undergoing treatment in daily practice. Study design Among 1,775 patients (infliximab, n = 418; etanercept, n = 69; adalimumab, n = 267; tocilizumab, n = 318; and abatacept, n = 82) who had been treated with biologics in the clinic between 23 and 212, data was extracted on 43 patients with RA who had discontinued biologics after their disease activity was well controlled: Infliximab: n = 26; Etanercept: n = 9; Adalimumab: n = 4; Tocilizumab: n = 2; Abatacept: n = 2. Disease Activity Score in 28 joints (DAS28) was <3.2 at the time of biologics discontinuation. Patients were divided into two groups on the basis of biologic usage one year after discontinuation: 1) bio-free group = patients who were not retreated with biologics one year after remission; 2) bio-reuse group = patients who were retreated with biologics one year after remission. Patients were also divided into bio-free success and bio-free failure groups on the basis of disease activity (DAS28 <3.2 or DAS28 3.2, respectively) one year after discontinuation. Clinical features of patients at the time of initiation and discontinuation of biologics were compared between the bio-free and bio-reuse groups and between the bio-free success and biofree failure groups. Key findings There were no significant differences in patient background characteristics between the bio-free success and bio-free failure groups. The percentages of patients who discontinued biologics due to well-controlled disease activity and in the bio-free success group among biologics users were 2.4% (43/1775) and 1.4% (25/1775), respectively. (Figure 1) New Evidence in Rheumatology February

67 The number of patients in the bio-free and bio-reuse groups were 34/43 (79.1%; infliximab, n = 2; etanercept, n = 8; adalimumab, n = 3; tocilizumab, n = 1; and abatacept, n = 2) and 9/43 (2.9%), respectively. (Figure 1) The number of patients in the bio-free success and bio-free failure groups were 25 (58.1%) (infliximab, n = 13; etanercept, n = 6; adalimumab, n = 3; tocilizumab, n = 1; and abatacept, n = 2) and 18 (41.9%), respectively. (Figure 1) There were no significant differences between the bio-free vs. bio-reuse groups with respect to: Age: 47.5 vs. 39. years; Disease duration: 3. vs. 2. years; Duration of biologics use: vs days DAS28 at initiation of biologics: 4.17 vs. 5.1; DAS28 at discontinuation of biologics: 2.9 vs. 1.8; Japanese Health Assessment Questionnaire (J-HAQ) at initiation of biologics:.75 vs..56; J-HAQ at discontinuation of biologics: vs. ; Dose of methotrexate (both at initiation and discontinuation of biologics): 8. vs. 8. mg/week; Dose of glucocorticoids at initiation of biologics: 4. vs. mg/day; p =.5. In addition, most clinical features at initiation of biologics did not differ significantly between the bio-free success and biofree failure groups. (Table 1) The median DAS28 at initiation of biologics was significantly lower in the bio-free success group than the bio-free failure group (3.95 vs. 5.4, p =.4). (Table 1) The bio-free success group received a significantly decreased average dosage of glucocorticoids during the biologics use than that in the bio-free failure group ( 3. vs. mg/day, p =.1). Figure 1. Patients and methods Discontinuation of biologics due to good patient condition n = 51 DAS28 scores were 3.2 at the time biologics were discontinued n = 8 DAS28 <3.2 n = 43 1 year after discontinuation Bio-reuse n = 9 (2.9%) Bio-free n = 34 (79.1%) Bio-free failure DAS n = 18 (41.9%) Bio-free success DAS28 <3.2 n = 25 (58.1%) Bio = biologic; DAS28 = Disease Activity Score in 28 joints Table 1. Bio-free success versus bio-free failure group (at initiation) Bio-free success (n = 25) Bio-free failure (n = 18) p-value Age (years) 52. ( ) 46. ( ).52* Female, n (%) 2. (8.) 15. (83.3).78 Disease duration (years) 3. (1. 7.) 3. (1. 8.5).55* Biologics medication period (days) 569. ( ) ( ).94* Biologics naive, n (%) 25 (1) 16 (88.9).9 DAS ( ) 5.4 ( ).4* J-HAQ.63 ( ).75 ( ).23* Dose of methotrexate (mg/week) 8. (6. 1.) 8. (8. 1.).11* Percentage of methotrexate use (%) Dose of prednisolone (mg/day) 4. (. 5.8). (. 5.).11* Percentage of prednisolone use (%) *Wilcoxon rank sum test. Pearson s chi-square test; Median (IQR). DAS28 = Disease Activity Score in 28 joints; IQR = interquartile range; J-HAQ = Japanese Health Assessment Questionnaire 66 New Evidence in Rheumatology February 215

68 In Supportive Care Oncology Key conclusions The study showed that the one-year discontinuation rate of biologics after achieving low activity disease status was high (79.1%) in patients with RA being treated in an outpatient setting. A lower DAS28 score at initiation of biologics and decreasing the dose of glucocorticoids before discontinuation of biologics were important factors leading to bio-free success in patients with RA, irrespective of biologic type. Limitations to the study included the small sample size and the fact this was a retrospective study. Reference: 1.Ochiai M, Sato E, Tanaka E, et al. Discontinuation of biologics in patients with rheumatoid arthritis after achieving low activity disease status. ACR Annual Meeting Abstracts 214:495. Yazici Y, et al. ACR 214:2528 Efficacy meta-analysis of randomized controlled trials of biologics in methotrexate-naïve patients with early rheumatoid arthritis Background The number needed to treat (NNT) analysis is a useful tool for putting randomized controlled trials (RCT) efficacy results into perspective in patient care. For clinical decision making, the NNT is a useful measure to convey statistical and clinical significance to the physician (i.e., number of patients needed to treat to achieve one additional response compared to control). The most reliable data regarding how a biologic would work comes from methotrexate-naïve RCTs, as all patients are receiving active drug for the first time and selection biases may play a lesser role in determining outcomes. The objective of the study was to perform a NNT analysis of biologics in methotrexate-naïve patients with early rheumatoid arthritis (RA). Study design PubMed was searched for randomized doubleblind, methotrexate-controlled studies of biologics in methotrexate-naïve patients with early RA from January 199 through December 213. Response rates specified by each RCT were used to assess NNT of biologic (active) versus methotrexate (control), where NNT = [1/(RR active -RR control )] x 1. Outcomes assessed included American College of Rheumatology 2 (ACR2), ACR5, and ACR7 responses, as well as Disease Activity Score in 28 joints (DAS28) remission (DAS28 <2.6). Key findings Nine published RCTs were identified: OPTIMA Kavanaugh A et al. Ann Rheum Dis 213;72:64 71; HIT HARD Detert J et al. Ann Rheum Dis 213;72:844 5; TEAR Moreland LW et al. Arth Rheum 212;64: ; IMAGE Tak PP et al. Ann Rheum Dis 211;7:39 46; COMET Emery P et al. Lancet 28; 372: ; AGREE Westhovens R et al. Ann Rheum Dis 29;68:187 77; ASPIRE St. Clair EW et al. Arth Rheum 24;5: ; GO BEFORE Emery P et al. Arth Rheum 29;6: ; PREMIER Breedveld FC et al. Arth Rheum 26;54: Baseline age was similar across the studies (average age 5.2 years, range: ), but some variability in disease duration (average duration 3.3 years, range:.7, 9.3). All biologics achieved >5% response in ACR 2, although one adalimumab trial was outperformed by methotrexate only, leading to a negative estimated NNT. (Figure 1) All biologics outperformed methotrexate only with ACR5, ACR7, and DAS28 outcomes. (Table 1) New Evidence in Rheumatology February

69 Figure 1. ACR2 and DAS28 response ladder plots of biologics plus methotrexate versus methotrexate only ACR2 OPTIMA: adalimumab 4 mg HIT HARD: adalimumab 4 mg TEAR: etanercept 5 mg IMAGE: rituximab 2 5 mg IMAGE: rituximab 2 1 mg COMET: etanercept 5 mg AGREE: abatacept 1 mg/kg ASPIRE: infliximab 3 mg/kg ASPIRE: infliximab 6 mg/kg GOBEFORE: golimumab 5 mg GOBEFORE: golimumab 1 mg PREMIER: adalimumab 4 mg ACR2 response versus methotrexate 1.23 (1.12, 1.35).87 (.72, 1.6) 1.4 (.87, 1.24) 1.2 (1.7, 1.35) 1.25 (1.12,1.4) 1.3 (1.16, 1.45) 1.23 (1.9, 1.38) 1.16 (1.1, 1.33) 1.23 (1.8, 1.41) 1.25 (1.2, 1.52) 1.25 (1.2, 1.52) 1.23 (1.8, 1.41) 1.21 (1.16, 1.25) Relative risk (log scale) DAS28 OPTIMA: adalimumab 4 mg HIT HARD: adalimumab 4 mg TEAR: etanercept 5 mg IMAGE: rituximab 2 5 mg IMAGE: rituximab 2 1 mg COMET: etanercept 5 mg AGREE: abatacept 1 mg/kg ASPIRE: infliximab 3 mg/kg ASPIRE: infliximab 6 mg/kg GOBEFORE: golimumab 5 mg GOBEFORE: golimumab 1 mg PREMIER: adalimumab 4 mg DAS28 response versus methotrexate 2. (1.59, 2.5) 1.17 (.8, 1.69) 1.7 (.91, 1.25) 1.91 (1.3, 2.8) 2.37 (1.64, 3.43) 1.74 (1.38, 2.19) 1.78 (1.36, 2.32) 1.4 (.99, 1.98) 2.9 (1.52, 2.87) 2.24 (1.34, 3.73) 1.73 (1.1, 2.97) 1.96 (1.54, 2.51) 1.71 (1.47, 2.) Relative risk (log scale) 4. ACR = American College of Rheumatology; DAS28 = Disease Activity Score in 28 joints 68 New Evidence in Rheumatology February 215

70 In Supportive Care Oncology Table 1. Demographics, response outcome, and NNT summary by identified study Paper Medication N OPTIMA Age (Years) Duration (Years) ACR2 ACR5 ACR7 DAS28 N (%) NNT N (%) NNT N (%) NNT N (%) NNT MTX only (13.6) 4.5 (7.2) 295 (57%) 176 (34%) 88 (17%) 88 (17%) Adalimumab 4 mg + MTX (14.5) 4. (3.6) 361 (7%) (52%) 6 18 (35%) (34%) 6 HIT HARD TEAR IMAGE COMET AGREE MTX only (14.3) 1.6 (1.7) 64 (74%) 44 (51%) 3 (34%) 31 (36%) Adalimumab 4 mg + MTX (12.1) 1.8 (2.1) 57 (66%) 1 46 (53%) 9 35 (4%) 2 37 (43%) 17 MTX only (13.) 2.9 (5.6) 125 (51%) 84 (34%) 46 (19%) 135 (55%) Etanercept 5 mg + MTX (13.4) 3.5 (6.4) 124 (51%) (38%) (23%) (57%) 28 MTX only (12.7).91 (1.1) 161 (64%) 16(42%) 63 (25%) 33 (13%) Rituximab 2 5 mg + MTX Rituximab 2 1 mg + MTX (13.4).99 (1.1) 194 (77%) (59%) 6 16 (42%) 6 63 (25%) (13.3).92 (1.3) 21 (8%) (65%) (47%) 5 78 (31%) 6 MTX only (.8) 9.3 (.4) 163 (59%) 119 (43%) 69 (25%) 73(27%) Etanercept 5 mg + MTX (.9) 8.8 (.4) 22 (8%) (66%) (45%) (48%) 5 MTX only (13.) 6.7 (7.1) 157 (61%) 17 (42%) 69 (27%) 59 (23%) Abatacept 1 mg/kg + MTX (12.4) 6.2 (7.5) 195 (76%) (57%) 7 19 (43%) 7 16 (41%) 6 MTX only (13).9 (.7) 151 (42%) 91 (25%) 6 (17%) 42 (12%) ASPIRE Infliximab 3 mg/kg + MTX Infliximab 6 mg/kg + MTX (12).8 (.7) 223 (62%) (46%) (32%) 9 75 (21%) (13).9 (.8) 24 (66%) (5%) (37%) (31%) 6 MTX only (12.9) 2.9 (4.8) 79 (5%) 47 (3%) 25 (16%) 18 (11%) GOBEFORE Golimumab 5 mg + MTX Golimumab 1 mg + MTX (11.3) 3.5 (5.7) 98 (62%) 8 64 (4%) 9 38 (24%) 12 4 (25%) (11.9) 3.6 (6.1) 98 (62%) 8 58 (36%) (18%) (19%) 12 PREMIER MTX only (13.1).8 (.9) 144 (53%) 111 (41%) 72 (26%) 64 (23%) Adalimumab 4 mg + MTX (14.).7 (.8) 185 (69%) (59%) (47%) (49%) 4 ACR2/5/7 = American College of Rheumatology 2/5/7 responses; DAS28 = Disease Activity Score in 28 joints; MTX = methotrexate; NNT = number needed to treat Key conclusions In methotrexate-naïve patients with early RA, abatacept and anti-tumour necrosis factor (TNF) agents have similar efficacy when RCT endpoints, such as ACR responses, are analyzed by NNT. Differences in efficacy appeared when more aggressive treatment goals, such as major clinical response and DAS28 remission, were evaluated, suggesting that the likelihood of achieving these endpoints in patients was less with infliximab than with other anti-tnfs or abatacept. In the absence of head-to-head clinical trial data, NNT meta-analysis can be a useful tool for determining the relative efficacy of biologics in routine clinical practice. Reference: 1. Yazici Y, Luo C, Swearingen CJ. Efficacy meta-analysis of randomized controlled trials (RCTs) of biologics in methotrexate-naive patients with early rheumatoid arthritis. ACR Annual Meeting Abstracts 214: New Evidence in Rheumatology February

71 Vasculitis Predicting Relapse in Patients with ANCA-Associated Vasculitis Given Rituximab Maintenance Anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitides (AAV) is an autoimmune disorder characterized by the destruction of small blood vessels and ANCA positivity. 1 For many years, induction of remission for AAV was based on cyclophosphamide and glucocorticoids, which was effective but was also associated with frequent adverse events (AEs). 2 Recently, two randomized trials showed that rituximab was also effective in the induction of remission in patients with AAV. These studies showed that rituximab was non-inferior to daily oral or pulse cyclophosphamide for induction of remission. Rituximab has also been shown to be effective in the maintenance of remission in AAV in the MAINtenance with RITuximab in Systemic ANcaassociated vasculitis (MAINRITSAN) study by Guillevin et al. 2 The MAINRITSAN trial demonstrated that rituximab was superior to azathioprine in efficacy but was not associated with more frequent severe AEs than azathioprine. An extended followup also noted late relapses in patients treated with rituximab, raising the question of whether these relapses can be predicted. In an another follow-up of MAINTRITSAN presented at the 214 American College of Rheumatology (ACR) Annual Meeting, Terrier et al. identified two factors predictive of relapses at month 12 after starting maintenance therapy: anti-pr3-anca-positivity and persistent ANCA-positivity. 3 Identifying strong predictors of relapse would be a significant step towards reducing relapse rates in this setting. At the 214 ACR Annual Meeting, investigators identified potential predictive factors in the treatment of vasculitis, and assessed the impact of AAV and its treatment on health-related quality of life (HRQoL). The following is a report on four presentations given at the meeting: Analysis of the MAINRITSAN study identified anti-pr3 ANCA-positivity and persistent ANCApositivity as factors predictive of AAV relapse in patients given rituximab-maintenance therapy. A study on the impact of rituximab versus azathioprine for ANCA-associated vasculitis maintenance therapy on HRQoL. An analysis of employment, work disability, and quality of life of patients with ANCA-associated vasculitis showed that the quality of life of patients with AAV was impaired compared to the general population. An analysis of biomarkers of disease activity in vasculitis identified tissue inhibitor of metalloproteinase-1 (TIMP-1) as the most promising biomarker to differentiate between active and inactive giant cell arteritis. References: 1. Hamour S, Salama AD, Pusey CD. Management of ANCA-associated vasculitis: Current trends and future prospects. Ther Clin Risk Manag 21;6: Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCAassociated vasculitis. N Engl J Med 214;371: Terrier B, Pagnoux C, Geri G, et al. Factors predictive of ANCA-associated vasculitis relapse in patients given rituximab-maintenance therapy: data from the extended follow-up of MAINRITSAN trial patients. ACR Annual Meeting Abstracts 214: New Evidence in Rheumatology February 215

72 In Supportive Care Oncology Terrier B, et al. ACR 214:1776 Factors predictive of ANCA-associated vasculitis relapse in patients given rituximab-maintenance therapy Background The MAINtenance with RITuximab in Systemic ANcaassociated vasculitis (MAINRITSAN) trial compared rituximab to azathioprine to maintain anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remission after corticosteroid-and-cyclophosphamide induction therapy. 1 The results from this trial demonstrated that rituximab was superior to azathioprine at maintaining AAV remission. However, extended follow-up showed that late relapses could occur in patients treated with rituximab. The objective of this follow-up study was to analyze the relapses occurring after rituximab-maintenance therapy, with the aim of identifying factors that are predictive of relapse. Study design In the MAINRITSAN trial, 57 patients were randomized to the rituximab arm. For these patients, data on their relapses were recorded during the 28-month trial and extended follow-up. Factors predictive of relapse under rituximab therapy were identified with univariate and multivariate analyses. Key findings Data from 56 patients was analyzed (64% men, mean age 54 ± 13 years), with median follow-up at 5 months. In total, 15 (26%) patients experienced at least one major relapse after a median of 4 (range: 8 52) months. Three relapses occurred during the 28-month trial, while 12 relapses occurred during extended follow-up. Patients treated with rituximab maintenance in the MAINRITSAN trial had greater relapse-free survival rates than those treated with azathioprine. (Figure 1) According to univariate analysis, relapse-associated factors were: (Table 1) Granulomatosis and polyangiitis; (Wegener s) diagnosis (HR = 5.39, 95% CI: , p =.11); Anti-proteinase-3 (PR3)-ANCA at AAV diagnosis (HR = 6.29, 95% CI: , p =.8); Glomerular filtration rate <6 ml/min (HR =.43, 95% CI: , p =.15); Persistent ANCA-positivity at 6 months (HR = 2.21, 95% CI: , p =.13), and at 12 months (HR = 4.45, 95% CI: , p <.1) after starting maintenance therapy. Multivariate analysis retained anti-pr3 ANCApositivity (HR = 12.5, 95% CI: , p =.2) and persistent ANCA-positivity at 12 months (HR = 7.79, 95% CI: , p <.1), as being significantly associated with relapse. The 5-month cumulative relapse rates for patients with anti-pr3-anca and ANCA-positivity at 12 months, patients with initial anti-pr3 ANCA and ANCA negativity at 12 months, and those with antimyeloperoxidase ANCA at any time, were 82.5%, 23.4%, and %, respectively. (Figures 2, 3, 4) Study design Induction therapy Maintenance therapy Major relapse rate at 28 months 1 g x 3 iv methylprednisolone Prednisone (1 mg/kg/day) then 2 mg/day at 3 months then 1 mg/day at 6 months CYC iv.6 g/m 2 x 3 then.7 g/m 2 x 3 1:1 Randomization RTX Infusion of 5 mg on D1, D15, at 5.5 months, then every 6 months for a total of 5 infusions over 18 months AZA At the initial dose of 2 mg/kg/day then tapering, for 22 months AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies; AZA = azathioprine; CYC = cyclophosphamide; D = day; iv = intravenous; RTX = rituximab New Evidence in Rheumatology February

73 Table 1. Factors predictive of relapse in patients receiving rituximab maintenance therapy Univariate analysis Multivariate analysis HR (95% CI) p-value HR (95% CI) p-value Age 1 ( ).81 Male gender 1.48 ( ).5 GPA diagnosis 5.39 ( ).11 PR3-ANCA 6.29 ( ) ( ).2 MPO-ANCA.29 (.4 2.2).23 GFR <6 ml/min.43 ( ).15 Positive ANCA at Month ( ).13 Positive ANCA at Month ( ) < ( ) <.1 ANCA = anti-neutrophil cytoplasmic antibodies; CI = confidence interval; GFR = glomerular filtration rate; GPA = granulomatosis and polyangiitis; HR = hazard ratio; MPO = anti-myeloperoxidase; PR3 = anti-proteinase-3; RTX = rituximab Figure 1. Relapse-free survival rates for patients in the MAINRITSAN trial Figure 2. Cumulative relapse rate according to PR3-ANCA and MPO-ANCA specificity Last RTX infusion 1 Relapse-free survival (%) RTX AZA HR =.34 (.18.61) p =.4 Stop AZA Cumulative relapse rate (%) Last RTX PR3-ANCA MPO-ANCA AZA = azathioprine; HR = hazard ratio; RTX = rituximab Months Months ANCA = anti-neutrophil cytoplasmic antibodies; MPO = anti-myeloperoxidase; PR3 = anti-proteinase-3; RTX = rituximab Figure 3. Cumulative relapse rate according to ANCApositivity at month 12 Figure 4. Cumulative relapse rate according to anti- PR3 ANCA-positivity at month 12 (vs. MPO-ANCA) 1 1 PR3-ANCA/positive at M12 PR3-ANCA/negative at M12 MPO-ANCA Cumulative relapse rate (%) Last RTX Positive ANCA at M12 Negative ANCA at M12 Cumulative relapse rate (%) Last RTX Months ANCA = anti-neutrophil cytoplasmic antibodies; M12 = month 12; RTX = rituximab Months ANCA = anti-neutrophil cytoplasmic antibodies; M12 = month 12; MPO = anti-myeloperoxidase; PR3 = anti-proteinase-3; RTX = rituximab 72 New Evidence in Rheumatology February 215

74 In Supportive Care Oncology Key conclusions A quarter of AAV patients who received rituximab-maintenance therapy relapsed during extended follow-up. Factors predictive of relapse for these patients were anti-pr3-anca positivity and persistent ANCA-positivity at 12 months after starting maintenance therapy. These findings suggest that patients might benefit from rituximab-maintenance therapy to prevent relapses. Reference: 1. Terrier B, Pagnoux C, Geri G, et al. Factors predictive of ANCA-associated vasculitis relapse in patients given rituximab-maintenance therapy: data from the extended follow-up of MAINRITSAN trial patients. ACR Annual Meeting Abstracts 214:1776. Pugnet G, et al. ACR 214:1778 Rituximab versus azathioprine for ANCA-associated vasculitis maintenance therapy: impact on health-related quality of life Background Improving and preserving health-related quality of life (HRQoL) is a major goal in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). 1 Previous studies have reported that patients with AAV have decreased HRQoL. The objective of the study was to investigate the effects of rituximab versus azathioprine for AAV remissionmaintenance therapy on HRQoL and functional abilities. This analysis was based on the The MAINtenance with RITuximab in Systemic ANca-associated vasculitis (MAINRITSAN) trial, which examined rituximab versus azathioprine in the management of AAV. Study design MAINRITSAN was a phase III, non-blinded, randomized-controlled, remission-maintenance trial. Patients (N = 115) with newly diagnosed or relapsing AAV, who fulfilled the American College of Rheumatology (ACR) classification criteria and/or the Chapel Hill Consensus Conference definition classification for AAVs, were included in the trial. Once patients achieved complete remission with combined glucocorticoid and pulse cyclophosphamide induction, they were randomly assigned at a 1:1 ratio to receive either: Rituximab 5-mg infusions on day one, day 15, 5.5 months later, and then every six months for a total of five infusions over 18 months; or Azathioprine for 22 months at the initial dose of 2 mg/kg/day. Mean changes every three months of Short-Form Health Survey (SF-36) and Health Assessment Questionnaire (HAQ) scores from baseline to month 24 were analyzed. Study design Induction therapy Maintenance therapy Major relapse rate at 28 months 1 g x 3 iv methylprednisolone Prednisone (1 mg/kg/day) then 2 mg/day at 3 months then 1 mg/day at 6 months CYC iv.6 g/m 2 x 3 then.7 g/m 2 x 3 1:1 Randomization RTX Infusion of 5 mg on D1, D15, at 5.5 months, then every 6 months for a total of 5 infusions over 18 months AZA At the initial dose of 2 mg/kg/day then tapering, for 22 months AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies; AZA = azathioprine; CYC = cyclophosphamide; D = day; iv = intravenous; RTX = rituximab New Evidence in Rheumatology February

75 Key findings Baseline demographics were similar between the two arms. The baseline AAV patient-reported outcome scores for HRQoL and global disability are shown in Table 1. The patients baseline HRQoL SF-36 item scores were significantly impaired compared with age- and sex-matched U.S. normal values. (Figure 1) The mean HRQoL SF-36 item scores for rituximab- or azathioprine-treated AAV patients at month 24 are shown in Figure 2. The mean mental component score (MCS) and physical component score (PCS) for rituximab- or azathioprinetreated AAV patients at baseline and month 24 are shown in Figure 3. The mean HAQ change, from baseline to month 24, improved significantly more for rituximab recipients (.16 points lower than the azathioprine group, p =.38). (Figure 4) The mean SF-36 PCS from baseline to month 24 tended to change more for rituximab recipients (3.95 points higher, p =.67). (Figure 5) Surprisingly, the mean SF-36 MCS from baseline to month 24 rose significantly more for the azathioprine group (4.23 points higher than rituximab, p =.41). (Figure 6) Table 1. Baseline AAV patient-reported outcome scores for HRQoL and global disability Mean ± SD AZA (n = 58) RTX (n = 57) Total (N = 115) HAQ score*.33 ± ± ±.46 SF-36 score PCS 42.7 ± ± ± 9.5 MCS 41.7 ± ± ± 1.1 *HAQ scores ranged from to 3 (higher scores indicate more severe disability). SF-36 PCS and MCS ranged from (worst) to 1 (best) status, with normal 5. AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies; AZA = azathioprine; HAQ = Health Assessment Questionnaire; HRQoL = health-related quality of life; MCS = mental component score; PCS = physical component score; RTX = rituximab; SD = standard deviation; SF-36 = Short-Form Health Survey Figure 1. Mean HRQoL SF-36 item scores for rituximab- or azathioprine-treated AAV patients at baseline 1 8 Baseline Azathioprine Rituximab Mean score Physical Function Physical Role Bodily Pain General Health Mental Health/ Emotional Well-Being Emotional Role Social Function Vitality/ Energy The + represent age- and sex-matched U.S. normal values. AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies; HRQoL = health-related quality of life; SF-36 = Short-Form Health Survey 74 New Evidence in Rheumatology February 215

76 In Supportive Care Oncology Figure 2. Mean HRQoL SF-36 item scores for rituximab- or azathioprine-treated AAV patients at month Month 24 Azathioprine Rituximab Mean score Physical Function Physical Role Bodily Pain General Health Mental Health/ Emotional Well-Being Emotional Role Social Function Vitality/ Energy The + represent age- and sex-matched U.S. normal values. AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies; HRQoL = health-related quality of life; SF-36 = Short-Form Health Survey Figure 3. Mean HRQoL SF-36 physical component and mental component scores at baseline and month Baseline Azathioprine Rituximab 6 5 Month 24 Azathioprine Rituximab 4 4 Mean score 3 2 Mean score Physical Component Score Mental Component Score Physical Component Score Mental Component Score HRQoL = health-related quality of life; SF-36 = Short-Form Health Survey New Evidence in Rheumatology February

77 Figure 4. Mean changes in HAQ scores from baseline to 24 months of follow-up Figure 5. Mean changes in PCS scores from baseline to 24 months of follow-up Azathioprine Rituximab Azathioprine Rituximab Mean HAQ score.5 Mean PCS score Azathioprine Rituximab No. of patients Months Azathioprine Rituximab No. of patients Months HAQ = Health Assessment Questionnaire PCS = physical component score Figure 6. Mean changes in MCS scores from baseline to 24 months of follow-up 7 Key conclusion 6 Azathioprine Rituximab Rituximab maintenance of AAV remission in the MAINRITSAN trial resulted in significantly attenuated global disability, although maybe not clinically meaningful improvement of physical functions. 5 Mean MCS score 4 Reference: 1. Pugnet G, Pagnoux C, Perrodeau E, et al. Rituximab versus azathioprine for ANCA-associated vasculitis maintenance therapy: impact in health-related quality of life. ACR Annual Meeting Abstracts 214: No. of patients Months Azathioprine Rituximab MCS = mental component score 76 New Evidence in Rheumatology February 215

78 In Supportive Care Oncology Benarous L, et al. ACR 214:1759 Analysis of employment, work disability, and quality of life of patients with ANCA-associated vasculitis Background Improved therapeutic strategies for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitudes (AAV) have transformed acute and life-threatening diseases into chronic ones responsible for marked morbidity that could impact employment, work disability, and quality of life (QoL). 1 The objective of the French EXPOVAS inquiry was to analyze work, handicaps, and QoL of AAV patients and to identify their determinants. Study design Patients with AAV were included in a crosssectional study assessing employment, work disability, and QoL. Specific and non-specific questionnaires, including Short-Form Health Survey (SF-36), were sent to 531 patients with AAV. QoL was compared to that of the general population, patients with end-stage renal disease (ESRD), and previously reported patients with AAV from the European Vasculitis Study Group (EUVAS) cohort. Clinical-biological data that could affect QoL were recorded, and their determinants were analyzed. Key findings Patient characteristics Questionnaires were completed by 198 patients (19 women [55%], mean age = 59 ± 14 years) diagnosed with: Granulomatosis with polyangiitis (n = 132 [67%]); Eosinophilic granulomatosis with polyangiitis (EGPA; n = 42 [21%]); and Microscopic polyangiitis (n = 24 [12%]). Analysis of employment and work disability Among 94 working-age patients (<6 years), 56% had jobs, consistent with their qualifications for 81%; 77% were stably employed, with 67% working full-time. (Figure 1) Figure 1. Analysis of employment status of working-age AAV patients Students 2% Working patients 56% Unemployed not looking for work 33% Unemployed looking for work 9% AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies New Evidence in Rheumatology February

79 Concerning the impact of AAV, 23% of workers felt that their disease qualitatively limited the nature of their work, while 43% felt it limited the quantity of work they could do; 77% of patients did not benefit from any workstation adaptation; 5% thought their disease had hindered their careers and 43% thought that it had led to a salary reduction. A third of patients were not employed and not looking for work; and 9% were looking for a job. These results were comparable with the different AAVs. (Figure 1) Analysis of QoL QoL was significantly impaired for patients with AAV compared to the general population (p <.1). (Figure 2) In contrast, QoL of patients with AAV was significantly better than that of patients with end-stage renal disease. The AAV population s QoL was similar to that of the EUVAS cohort, except for the patients physical functioning, which was better (p <.1), and their mental health, which was more impaired (p <.1). Physical health determinants for the patient population were a diagnosis with EGPA, long disease duration, and its neurological involvement. (Table 1) Mental health determinants were ocular signs (HR = 3.96 [ ], p =.14) and cardiovascular involvement (HR = 3.91 [ ], p =.32). Figure 2. Analysis of SF-36 assessed QoL in AAV patients A PF 1 B PF 1 MH RP French AAV General population MH RP French AAV EUVAS AAV 2 2 RE BP RE BP SF GH SF GH VT C VT PF 1 MH RP GPA MPA EGPA RE BP AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies; BP = bodily pain; EGPA = eosinophilic granulomatosis with polyangiitis; GH = general health; GPA = granulomatosis with polyangiitis; MH = mental health; MPA = microscopic polyangiitis; PF = physical functioning; QoL = quality of life; RE = emotional role; RP = role physical; SF = social functioning; SF-36 = Short-Form Health Survey; VT = vitality SF GH VT 78 New Evidence in Rheumatology February 215

80 In Supportive Care Oncology Table 1. Physical health determinants for AAV patients Physical health Multivariate analysis Variable Altered n = 36 Non-altered n = 153 Univariate analysis, p-value HR (95% CI) p-value Demographic Age, mean ± SD, years 6.1 ± ± Male sex, n (%) 15 (42) 66 (43) 1. AAV duration, mean ± SD, months ± ± (1. 1.1).39 AAV diagnosis, n (%) (1.6 6.).37 GPA 17 (47) 19 (71) MPA 4 (11) 18 (12) EGPA 15 (42) 26 (17) Baseline manifestation, n/n (%) Weight loss 16/28 (57) 53/121 (44).21 Myalgias 11/27 (41) 42/123 (34).51 Arthralgias 14/28 (5) 54/121 (45).68 Skin 7/27 (26) 36/124 (29).82 Eye 3/27 (11) 33/124 (27).13 Ear, nose, and throat 2/28 (71) 94/124 (76).63 Lung 2/27 (74) 77/12 (64).38 Cardiovascular 5/27 (19) 16/122 (13).54 Gastrointestinal 5/27 (19) 14/12 (12).35 Kidney 1/27 (37) 45/122 (37) 1. Neuropathy 17/27 (63) 5/128 (39).3 BVAS, mean ± SD 17.8 ± ± Baseline biology Positive ANCA, n/n (%) 11/23 (48) 97/124 (78).4 Serum creatinine, mean ± SD, µmol/l 11 ± ± AAV = ANCA-associated vasculitides; ANCA = anti-neutrophil cytoplasmic antibodies; BVAS = Birmingham Vasculitis Activity Score; CI = confidence interval; EGPA = eosinophilic granulomatosis with polyangiitis; GPA = granulomatosis and polyangiitis; HR = hazard ratio; MPA = microscopic polyangiitis; SD = standard deviation Key conclusions The study showed that the QoL of patients with AAV was impaired compared to that of the general population, mainly for patients with EGPA and long-standing disease. In contrast, the study showed that normal employment seemed to be preserved. Reference: 1. Benarous L, Terrier B, Berezne A, et al. Analysis of employment, work disability and quality of life of patients with ANCA-associated vasculitis. ACR Annual Meeting Abstracts 214:1759. New Evidence in Rheumatology February

81 Rodriguez-Pla A, et al. ACR 214:88 Biomarkers of disease activity in vasculitis Background Many serum proteins that reflect levels of inflammation, injury, and repair are elevated in severe active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and decline with treatment. However, fewer promising biomarkers have been identified in other forms of vasculitis. The objective of this study was to identify circulating proteins that distinguish between active vasculitis and remission in giant cell arteritis (GCA), Takayasu s arteritis (TA), polyarteritis nodosa (PAN), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), using a panel of markers known to be elevated in AAV. Study design The following 22 serum proteins linked to possible pathways relevant to vasculitis were measured using a microarray platform: matrix metalloproteinase-3 (MMP-3), NGAL, angiotensin-converting enzyme (ACE), soluble interleukin-6 receptor, osteopontin, plasminogen activator inhibitor-1, platelet-derived growth factor-ab, RANTES, soluble intercellular adhesion molecule-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), B-cell attracting chemokine-1, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon γ (INF-γ) interleukin-15 (IL-15), interleukin-18, interleukin-18bpa, soluble interleukin-2ra, interleukin-6, interleukin-8, INF-γ inducible protein-1 (IP-1), and soluble tumour necrosis factor receptor II. Disease activity during the past 28 days was classified by physician global assessment (PGA), where remission is indicated by PGA = and active disease by PGA = 1 1. The association between serum proteins and erythrocyte sedimentation rate (ESR) was studied using Spearman s correlation. Three analyses were done to determine statistical significance and estimate effect size in comparing marker levels in active vasculitis and remission: Mixed effects models were used to account for repeated measures with unequal spacing between visits. Fold-change in marker values between active and the mean of a patient s remission values was calculated for each patient. Conditional logistic regression was used to calculate odds ratios and their 95% confidence intervals (95% CI), associating marker level (independent variable) with prediction of active disease vs. remission. J48 classification tree using WEKA Data Mining Software was used to find cut-off points of the most relevant markers to differentiate between active and inactive GCA. Key findings A total of 479 samples from 174 patients (GCA, n = 66; TA, n = 35; PAN, n = 31; EGPA, n = 42) were tested, with one active visit sample and 1 3 remission visit samples per patient. While the patients were on treatment, 44 samples (92%) were obtained. Disease activity ranged from PGA 1 to 9. The correlation of ESR with the majority of the protein markers was weak; the highest correlation was observed in GCA with IL-6 (r =.34, p <.1). (Table 1) Fold-change and p-values were similar when use of prednisone and other immune-suppressive drugs were included in the models. The odds ratios of the significant markers are shown in Table 2. Cut-off points of the most relevant markers to differentiate between active and inactive GCA are shown in Figure 1. 8 New Evidence in Rheumatology February 215

82 In Supportive Care Oncology Table 1. Fold change of the blood protein biomarkers associated with disease activity in the mixed model analysis GCA Serum protein Fold change p-value BCA IP sil-2ra TIMP PAN MMP CSS ACE BCA G-CSF GM-CSF IL CSS = Churg-Strauss syndrome; GCA = giant cell arteritis; PAN = panarteritis nodosa Table 2. Conditional logistic regression of the significant biomarkers for GCA disease activity in the mixed model analysis GCA Serum protein Odds ratio 95% CI BCA IP sil-2ra TIMP PAN MMP CSS ACE BCA G-CSF GM-CSF IL CI = confidence interval; CSS = Churg-Strauss syndrome; GCA = giant cell arteritis; PAN = panarteritis nodosa Figure 1. J48 classification tree for GCA biomarkers TIMP > IL6 TNFRII > >27.88 INFg ACE Remission (3) ESR.59 > > >25 MMP3 Remission (8) Remission (2) Active (6) Osteopontin Active (13.48/.48) > > Remission (127/27) Active (7/1) Active (6) TIMP1 ESR = erythrocyte sedimentation rate; GCA = giant cell arteritis > Active (3) Remission (5.52) Key conclusions This study identifies several potential biomarkers of disease activity in GCA, PAN, and EGPA, although effect sizes were modest in this partially treated cohort. Promising markers included several cytokines (IL-15, IP-1, G-CSF, G-CMSF, BCA-1), soluble cytokine receptors (sil-2ra), enzymes (MMP-3, ACE), and the metalloproteinase inhibitor TIMP-1. Among all the biomarkers studied in these patients, TIMP-1 seems the most promising biomarker to differentiate between active and inactive GCA. Larger studies are needed to test the utility of these biomarkers for disease monitoring as well as confirmation in an independent cohort. Reference: 1. Rodriguez-Pla A,Warner RL, Cuthbertson D, et al. Biomarkers of disease activity in vasculitis. ACR Annual Meeting Abstracts 214:88. New Evidence in Rheumatology February

83 Investigator Commentary An interview with Dr. Christian Pagnoux on the role of rituximab in maintenance therapy of ANCA-associated vasculitis At the ACR/ARHP 214 Annual Meeting, New Evidence spoke with Dr. Christian Pagnoux, faculty member of the Division of Rheumatology at Mount Sinai Hospital, Toronto, about a sub-study of the MAINtenance with RITuximab in Systemic ANcaassociated vasculitis (MAINRITSAN) study. MAINRITSAN investigators examined rituximab for maintenance therapy in ANCA-associated vasculitis compared with conventional treatment. Abstract Terrier, et al. Factors Predictive of ANCA-Associated Vasculitis Relapse in Patients Given Rituximab-Maintenance Therapy: Data from the Extended Follow-up of MAINRITSAN Trial Patients New Evidence: This study was a follow-up on the MAINRITSAN study which examined the efficacy and safety of rituximab compared with azathioprine for maintenance in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). What were the key findings of the MAINRITSAN study? Dr. Pagnoux: The MAINRITSAN study was one of the most important studies conducted in systemic vasculitis over the past four years. 1 The aim of the study was to compare rituximab with azathioprine for the maintenance of remission in AAV. The key finding was that relapse rates were significantly reduced to 5% at 28 months in the rituximab arm compared to 29% in the azathioprine group. There were no differences in the rates of adverse events between the two treatment arms. However, it must be emphasized that the dose of rituximab used in this study (5 mg every 6 months) is lower than that used for induction. Based on the results of MAINRITSAN, several groups have concluded that rituximab should be the new standard of care for remission after induction with cyclophosphamide. It is also very likely that rituximab should be the standard of care for maintenance after induction with rituximab, based on the RAVE (Rituximab in ANCA-Associated Vasculitis) study, which showed that rituximab was safe and effective for induction of remission. 2 New Evidence: What is the purpose of finding an alternative treatment to conventional maintenance therapies? Dr. Pagnoux: Immunosuppressants such as methotrexate and azathioprine have been considered the standard of care for maintenance of remission in this setting for a long time. However, their use has been associated with high relapse rates (3% at three years, and 5% 7% at 5 7 years). Immunosuppressants have also been associated with an increased risk of infections and some cases of cancer. 3-5 Therefore, there is a need to identify a better option for the maintenance of remission. 82 New Evidence in Rheumatology February 215