In Supportive Care Oncology

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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 12 August 214 From Research to Practice PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO Real-World Data in Rheumatoid Arthritis NEW EVIDENCE 219 DUFFERIN ST. (SOUTH BUILDING, SUITE 215C) TORONTO ON M6K 3J1 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 RITUXIMAB IN RA TREATMENT The Acquistion of Real-World Data to Confirm the Efficacy and Safety of Rituximab TOCILIZUMAB IN RA TREATMENT REGISTRY DATA IN RA Assessing the Efficacy of Tocilizumab and Rituximab Through Registry Studies Tocilizumab SC and IV: Providing Additional Benefits to Patients Interviews with Dr. Rafat Faraawi, Dr. Cem Gabay, and Dr. Janet Pope

2 In Supportive Care Oncology Publisher Paul Borlinha Managing Director Anna Christofides, MSc, RD Medical Writers Wissam Assaily, PhD Cassandra Uchida, PhD Editor Ben Fuerth, MSc Creative Director Jobet Dimaculangan Art Director Glen Cho Website Design Ronaji Naranjo Website Development Xinyu Pu New Evidence in Rheumatology is published by New Evidence 219 Dufferin St. (South Building, Suite 215C) Toronto, Ontario M6K 3J1 Correspondence should be addressed to: New Evidence 219 Dufferin St. (South Building, Suite 215C) Toronto, Ontario M6K 3J1 fax: website: To join our mailing list or to request back issues, please contact us by mail, fax: , or 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 August 214 issue summarizes and discusses the latest research in rheumatoid arthritis (RA). Key real-world studies are included that investigate the administration of rituximab in clinical practice and the effectiveness of tocilizumab monotherapy in patients with RA. In addition, registry studies of patients with RA are highlighted, which focus on confirming the efficacy of tocilizumab and rituximab in routine practice internationally. We would like to thank Dr. Janet Pope for her Canadian Perspectives, as well as Dr. Cem Gabay and Dr. Rafat Faraawi 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 August 214 1

3 Contents Tocilizumab in Rheumatoid Arthritis Treatment In Supportive Care Oncology Rituximab in Rheumatoid Arthritis Treatment 6 Real-World Data Confirm the Efficacy and Safety of Rituximab in the Treatment of Rheumatoid Arthritis The risk of serious infections in patients receiving rituximab for rheumatoid arthritis. (Silva-Fernandez L, et al. EULAR 214:OP29) Safety of rituximab infusion in rheumatoid arthritis in a single community practice. (Faraawi R, et al. EULAR 214:SAT247) Fixed versus on-flare retreatment with rituximab in RA results from the CERERRA collaboration. (Chatzidionysiou K, et al. EULAR 214:FRI328) Rituximab retention rate in clinical practice: a large multicentre Italian cohort of patients with rheumatoid arthritis. (Batticciotto A, et al. EULAR 214:FRI295) Rituximab in rheumatoid arthritis 4-year interim analysis of the non-interventional BRIDGING study. (Krause A, et al. EULAR 214:FRI297) Cost-effectiveness of abatacept, rituximab, and TNF-I after failure of the first TNF-I: results of a multicentered pragmatic randomized trial. (Manders SHM, et al. EULAR 214:SAT253) Canadian Perspective by Dr. Janet Pope Tocilizumab in Rheumatoid Arthritis Treatment 23 Tocilizumab is an Effective Option in Combination and as Monotherapy: Now Also Available as a Subcutaneous Formulation Baseline characteristics and pattern of tocilizumab use in patients with rheumatoid arthritis: interim results from the multinational, observational ACT-UP study. (Haraoui B, et al. EULAR 214:FRI3) The efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). (Burmester GR, et al. EULAR 214:FRI316) Impact of tocilizumab on fatigue and related factors in patients with rheumatoid arthritis in daily clinical practice in Spain: ACT-AXIS study. (Corominas H, et al. EULAR 214:FRI317) Biologic interactions between methotrexate and adalimumab are more extensive than those between methotrexate and tocilizumab: evidence from BioMAP profiling. (O Mahony A, et al. EULAR 214:THU526) Clinical and radiographic outcomes at two years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. (Huizinga TWJ, et al. EULAR 214:SAT255) Investigator Commentary 21 An interview with Dr. Rafat Faraawi on his study regarding the safety of rapid rituximab infusion in rheumatoid arthritis 2 New Evidence in Rheumatology August 214

4 Tocilizumab in Rheumatoid Arthritis Treatment In Supportive Care Oncology Registry Data in Rheumatoid Arthritis 47 Registry Studies Confirm the Efficacy of Tocilizumab and Rituximab in the Treatment of Rheumatoid Arthritis Tocilizumab, DMARDs, and glucocorticoids in rheumatoid arthritis interim analysis of the German noninterventional study ICHIBAN. (Specker C, et al. EULAR 214:FRI32) Investigator Commentary 64 An interview with Dr. Cem Gabay on the results of his studies on the retention rate of tocilizumab therapy in rheumatoid arthritis (RA) patients, and the effects of tocilizumab therapy on lipoprotein(a) levels in RA patients Retention of tocilizumab therapy: a comparison between tocilizumab in monotherapy and in combination with DMARDs based on the TOCERRA collaboration. (Gabay C, et al. EULAR 214:SAT36) Which biologic agent should be selected as a second choice for patients with rheumatoid arthritis treated with a TNF inhibitor? (Kunishita Y, et al. EULAR 214:SAT263) Comparative effectiveness of rituximab versus subsequent tumour necrosis factor inhibitor (TNF-I) in cumulative prednisone exposure in patients with rheumatoid arthritis with prior exposure to TNF-I. (Harrold L, et al. EULAR 214:FRI334) Canadian Perspective by Dr. Janet Pope New Evidence in Rheumatology August 214 3

5 Contributors Canadian Perspectives Janet Pope, MD, MPH, FRCPC Dr. Janet Pope is a Professor of Medicine at Western University, London, Ontario, Canada. She is a rheumatologist and epidemiologist and is the Division Head in Rheumatology at St. Joseph s Hospital, London, Ontario. She has a major interest in scleroderma research including membership in the Canadian Scleroderma Research Group (CSRG) and the Scleroderma Clinical Trials Consortium (SCTC). Dr. Pope is also co-leading the new ACR/EULAR guidelines for systemic sclerosis and has published over 25 peer-reviewed articles. In 213, she was the recipient of the Canadian Rheumatology Association s Distinguished Investigator Award and was named Rheumatologist of the Year by the Ontario Rheumatology Association. She supervises students at all levels and runs two nation-wide studentships for medical students to be exposed to clinical rheumatology or research in rheumatology. 4 New Evidence in Rheumatology August 214

6 Investigator Commentaries Rafat Faraawi, MD, FRCP(C), FACP Dr. Rafat Faraawi is an Associate Clinical Professor of Rheumatology in the Department of Medicine at McMaster University in Hamilton, Ontario, and Consultant Rheumatologist at St. Mary s Hospital, Kitchener, Ontario. Dr. Faraawi s research interests are in rheumatoid arthritis, osteoarthritis, and osteoporosis. He has been the Principal Investigator in over 3 phase II/III clinical research trials. Cem Gabay, MD Dr. Cem Gabay obtained his MD in 1985 in Geneva/Switzerland and was then trained in Internal Medicine and Rheumatology in Switzerland and France. He did his post-doctoral fellowship in basic research in the United States from 1995 to Since 21 he has been Director of the Division of Rheumatology at the Geneva University Hospitals and Professor of Medicine at the University of Geneva, Switzerland. His clinical research interests are in rheumatoid arthritis and osteoarthritis, and also leads a basic research program on the IL-1-related cytokines. New Evidence in Rheumatology August 214 5

7 Rituximab in Rheumatoid Arthritis Treatment Real-World Data Confirm the Efficacy and Safety of Rituximab in the Treatment of Rheumatoid Arthritis Rituximab is an anti-cd2 antibody that is approved for use in Canada, in combination with methotrexate, for adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response to at least one tumour necrosis factor inhibitor (TNF-I). 1 The safety and efficacy of rituximab in patients with RA have been well established in clinical trials; 2,3 however, little evidence has corroborated these findings in real-world experience. In addition, a few barriers to administration exist in real-world settings that have not been addressed in clinical trials, including lengthy infusion times, 1,4 cost, 5 and uncertainty with regards to retreatment strategies. 6 At the 214 Congress of the European League Against Rheumatism (EULAR), investigators demonstrated the safety and efficacy of rituximab in real-world settings, and presented evidence for methods to improve rituximab administration for patients with RA. This article reports on six presentations that were delivered at EULAR 214: An observational study examined the influence of rituximab on the risk of serious infections in patients with RA and found that patients who receive rituximab do not have an increased risk of serious infections compared to those who receive a TNF-I. A report on the use of a rapid infusion protocol for rituximab delivery found that rapid rituximab infusion is safe, well tolerated, and it leads to greater patient satisfaction compared with the standard infusion protocol. The CERERRA collaboration compared two rituximab retreatment strategies and found that a fixed retreatment strategy led to improved disease activity scores versus retreating at the time of flare. A large, multicentre, clinical study of rituximab retention found that approximately two-thirds of patients treated with rituximab continued treatment for 6 months. The BRIDGING study collected clinical data on the safety and efficacy of rituximab and reported that rituximab is equally as effective and safe as has been previously reported in clinical trials. The DREAM study analyzed cost-effectiveness of various second-line treatments for RA and showed that rituximab should be preferred over abatacept and a second TNF-I if costs are important in the decision-making process for treatment. References: 1. Hoffmann-La Roche Ltd. Pr RITUXAN (rituximab) Product Monograph. May 29, Volkmann E, Agrawal H, Maranian P, et al. Rituximab for rheumatoid arthritis: a meta-analysis and systematic review. Clin Med Insights Ther 21;2: van Vollenhoven RF, Emery P, Bingham III CO, et al. Long term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 213;72: Faraawi R, Roth K. Experience with accelerated rituximab infusion for rheumatoid arthritis in a single community practice. Ann Rheum Dis 21;69(Suppl 3): Benucci M, Saviola G, Baiardi P, Manfredi M. Cost-effectiveness treatment with Rituximab in patients with rheumatoid arthritis in real life. Rheumatol Int 211;31: Teng YK, Tekstra J, Breedveld FC, et al. Rituximab fixed retreatment versus on-demand retreatment in refractory rheumatoid arthritis: comparison of two B cell depleting treatment strategies. Ann Rheum Dis 29;68: New Evidence in Rheumatology August 214

8 In Supportive Care Oncology Silva-Fernandez L, et al. EULAR 214:OP29 The risk of serious infections in patients receiving rituximab for rheumatoid arthritis Background In the United Kingdom (U.K.), rituximab is used in patients with rheumatoid arthritis (RA) who have failed initial tumour necrosis factor inhibitor (TNF-I) therapy. 1 Patients with RA are at an increased risk of serious infections (SIs), and TNF-I treatment may further increase this risk in routine clinical care. Randomized controlled trial data on rituximab suggest no such increased risk of SIs; however, observational data are lacking. The aim of this study was to determine the influence of rituximab on the risk of SI in patients with RA in routine clinical practice in the U.K. Two patient populations were compared: Patients who had failed one TNF-I drug and switched to rituximab; and Patients receiving a second TNF-I drug. Study design The British Society for Rheumatology Biologics Register (BSRBR-RA) is an ongoing prospective national cohort study established in 21; there are currently more than 22, patients under active follow-up. Patients who had failed a first TNF-I and were switched to either a second TNF-I or rituximab between 21 and 212 were identified from the cohort study. The TNF-I cohort was recruited from 21 to 29. In the follow-up period subsequent treatments were captured, including rituximab. The rituximab cohort was recruited from 27 to 212, and comprised new patients starting rituximab treatment. Baseline data included previous biologic treatments. Exclusion criteria included: Patients whose first biologic was not a TNF-I; and Subsequent switches of biologic treatment. All patients were followed by physician and patient questionnaires every six months for the first three years and then by physician questionnaires annually. Deaths were identified by flagging with the U.K. National Health Service Information Centre. SIs were defined as those requiring intravenous antibiotics and/or hospitalization, or those resulting in death. Patients were followed from the start of the second biologic until one of the following occurred (whichever came first): First SI; Death; End of the first year after switch; January 31, 213. The at-risk period was defined as the time the patient was receiving treatment plus a lag window: TNF-I cohort: 9 days after first missed dose; Rituximab cohort: 9 months after last infusion. The Cox proportional hazards model was used as the statistical analysis for risk of first SI. This was adjusted for confounders using the propensity model (inverse probability of treatment weighted), using the following confounders: Age; Gender; RA-related factors; Comorbidities; and Medications. Multiple imputation was used for missing baseline data. Key findings Patient and disease characteristics at baseline are summarized in Table 1. In total, 25 subjects experienced at least one SI in the first year of follow-up after switch of treatment (158 in the TNF-I cohort vs. 47 in the rituximab cohort). (Table 2) The crude incidence rate of first SIs per 1, personyears was 6 (95% CI: 51 7) for the second TNF-I cohort and 56 (95% CI: 42 74) for the rituximab cohort. (Table 2) New Evidence in Rheumatology August 214 7

9 Table 1. Patient and disease characteristics at baseline Second TNF-I (N = 3,237) Rituximab (N = 1,18) Patient characteristics Mean age, years (SD) 55.9 (12.3) 57.8 (12.3) Female, % Diabetes, % Ever smoked, % Stopped first TNF-I for AE, % Disease characteristics Median disease duration, years (IQR) 12 (6 19) 1 (5 18) Mean DAS28 (SD) 5.6 (1.5) 6. (1.3) Mean HAQ (SD) 1.9 (.6) 2. (.6) Oral steroids, % Rheumatoid factor, % AE = adverse event; DAS28 = 28-joint disease activity score; HAQ = Health Assessment Questionnaire; IQR = interquartile range; SD = standard deviation; TNF-I = tumour necrosis factor inhibitor Table 2. First serious infection Second TNF-I (N = 3,237) Rituximab (N = 1,18) Total person-years follow-up 2, Number of first SIs Median time to infection, years (IQR) Crude incidence rate per 1, person-years, 95% CI.3 (.2.5).3 (.2.5) 6 (51 7) 56 (42 74) CI = confidence interval; IQR = interquartile range; SI = serious infection; TNF-I = tumour necrosis factor inhibitor The fully adjusted risk of SI for patients in the rituximab cohort compared to patients in the second TNF-I cohort resulted in a HR =.74 (95% CI: ). (Figure 1) HR was adjusted by age, disease duration, DAS28 and HAQ at switch, sex, smoking, use of steroids before switch, reason to stop first TNF-I, number of prior disease-modifying antirheumatic drugs, diabetes, lung involvement, heart disease, liver disease, renal disease, previous cancer, tuberculosis, and year of starting a biologic. The most common SI experienced by both cohorts was lower respiratory tract infections. (Figure 2) Figure 1. Risk of serious infection ( ).85 ( ).74 ( ) Hazard ratio 1 2nd TNF-I.5 Unadjusted TNF-I = tumour necrosis factor inhibitor *Inverse probability of treatment weighting Age & gender adjusted Fully adjusted* 8 New Evidence in Rheumatology August 214

10 In Supportive Care Oncology Figure 2. Types of infection TNF-I (n = 158) Rituximab (n = 47) Lower respiratory tract Urinary tract Skin GI infection Sepsis Bone and joint 14% 12% Other 1% GI = gastrointestinal; TNF-I = tumour necrosis factor inhibitor Key conclusions Strengths of the study included: A large national cohort; Systematic follow-up; and The study was conducted in routine clinical practice. Limitations of the study included: Non-randomized treatment selection; Missing data; and Other risk factors for infection were not captured. The data suggest that patients selected to switch to rituximab do not have an increased risk of SI compared with patients who switch to a second TNF-I. Reference: 1. Silva-Fernandez L, Lunt M, Low AS, et al. The risk of serious infections in patients receiving rituximab for rheumatoid arthritis. EULAR Abstracts 214: OP29. Faraawi R, et al. EULAR 214:SAT247 Safety of rituximab infusion in rheumatoid arthritis in a single community practice Background Rituximab is approved to be infused over four hours and 15 minutes, due to the potential for infusion reactions. 1 Recently, rapid infusion protocols (both at 6 and 9 minutes) have been shown to be well tolerated in the oncology setting. Experience with the safety of rapid infusion in patients with rheumatoid arthritis (RA) was first reported in 21. The current study reports on a safety analysis of 28 patients receiving a total of 132 rapid infusions in a single rheumatology practice. New Evidence in Rheumatology August 214 9

11 The objective of this study was to evaluate the safety, tolerability, and practicality of a rapid-infusion protocol for rituximab in patients with RA. Study design Patients who were prescribed rituximab for the treatment of moderate to severe RA were recruited from October 26 to November 213 and were given the opportunity to participate in the rapid infusion protocol. All patients provided written informed consent. All patients received premedications prior to infusion: Acetaminophen 1, mg orally; Diphenhydramine 5 mg orally; and Methylprednisolone 1 mg intravenously. Vital signs were recorded at baseline and at 15, 3, 6, 9, and 12 minutes. Each treatment course consisted of two 1, mg infusions of rituximab, administered two weeks apart: The first rituximab infusion followed the conventional infusion protocol (4 hours, 15 minutes): The initial rate was 5 mg/hr for 3 minutes, which was escalated in 5 mg/hr increments every 3 minutes to a maximum rate of 4 mg/hr. All subsequent rituximab infusions followed the rapid infusion protocol (2 hours): The initial rate was 2 mg/hr for 3 minutes, which was escalated in 2 mg/hr increments every 3 minutes to a maximum rate of 8 mg/hr. The rapid infusion protocol is summarized in Table 1. Table 1. Rapid infusion rate Time (minutes) ml/hr Infusion rate mg/hr Cumulative dose (mg) , Key findings A total of 57 patients received a combined 28 rituximab infusions between October 26 and November 213. Out of these, 5 patients met the criteria to be followed on the rapid infusion protocol, and 28 patients agreed to be followed on the accelerated rituximab infusions. Study design 5 mg/hr 1 mg/hr 15 mg/hr 2 mg/hr 25 mg/hr 3 mg/hr 35 mg/hr 4 mg/hr Initial rate 5 mg/hr escalated in 5 mg/hr increments every 3 minutes with a maximum rate of 4 mg/hr Initial rituximab infusion (day 1) Duration of first infusion: 4 hours 15 minutes 8 mg/hr 6 mg/hr 4 mg/hr 2 mg/hr Initial rate 2 mg/hr escalated in 2 mg/hr increments every 3 minutes with a maximum rate of 8 mg/hr All subsequent rituximab infusions Duration of all subsequent infusions: 2 hours 1 New Evidence in Rheumatology August 214

12 In Supportive Care Oncology A total of 132 infusions were included in the analysis. The mean infusion interval was 9.4 months. Baseline characteristics were typical of the population of patients with RA: Mean age, years: 56.2; Sex, % female: 67.8; Mean RA disease duration, years: 11.5; Rheumatoid factor positive, %: 72.8; Concomitant methotrexate, %: 6; Mean number of previous disease-modifying antirheumatic drugs: 1.58; Mean number of previous biologics: 1.42; Number of patients who had failed or were intolerant to a tumour necrosis factor inhibitor, n (%): 26 (93); Number of patients who were biologic-naïve, n (%): 2 (7). Out of the 28 patients who agreed to the rapid infusion protocol: Four patients switched back to the conventional protocol due to mild infusion reactions (n = 2), anxiety (n = 1), or other reason (n = 1); The remaining 24 patients reported extreme satisfaction from the rapid infusion protocol. A total of seven infusion reactions were reported over 132 rapid rituximab infusions (n = 28), compared with eight infusion reactions over 148 conventional infusions (n = 22). (Table 2) There was no significant difference in the incidence of infusion reactions between the rapid and conventional infusion protocols (p =.97). None of the patients discontinued rituximab in either the rapid or conventional infusion groups due to infusion-related symptoms and reactions. Overall, all symptoms reported were mild and resolved within 24 hours after infusion. No serious infections or serious adverse events were reported in either the rapid or conventional infusion groups. Table 2. Infusion-related reactions occurring on rapid vs. conventional infusion Type of reaction Rapid infusion Conventional infusion Throat irritation/tightness 4 1 Pruritus 3 1 Face flushing 2 Fatigue 1 Chest pressure 1 Palpitations 1 Fever 1 Flu-like symptoms 1 Key conclusions The current analysis provides reassurance that rapid rituximab infusion is safe and well tolerated. The authors experience in administering this protocol over seven years proves that rapid infusion is as safe as the conventional infusion protocol. In addition to safety, patients reported greater satisfaction with the short infusion duration. These data, and previously reported data on rapid infusion in patients with RA, can assure physicians that this strategy can be safely implemented in an infusion clinic setting. Reference: 1. Faraawi R, Malik S, and Roth K. Safety of rituximab infusion in rheumatoid arthritis in a single community practice. EULAR Abstracts 214: SAT247. New Evidence in Rheumatology August

13 Chatzidionysiou K, et al. EULAR 214:FRI328 Fixed versus on-flare retreatment with rituximab in RA results from the CERERRA collaboration Background The data on how to optimally re-treat patients with rheumatoid arthritis (RA) with rituximab have been limited. 1 The objective of this study was to compare two common retreatment strategies: A fixed retreatment approach (fixed); and Retreatment when a flare occurs (on-flare). Study design Pooled data from the Collaborating European Registries for Rituximab in RA (CERERRA) project were used. Patients with RA who received at least two retreatments (three courses) with rituximab were identified from the CERERRA cohort. Information about the strategy for retreatment according to the physician s opinion was necessary for inclusion. The retreatment strategies were compared by applying an adjusted mixed model analysis. The dependent variable was 28-joint disease activity score (DAS28) improvement. Key findings Patient characteristics at the start of the first rituximab retreatment were as follows (on-flare vs. fixed): Number of patients: 442 vs. 128; Months from baseline: 1. ± 5.7 vs. 8.5 ± 7.1 (p =.2); Age, years: 49.5 ± 11.8 vs ± 12.6 (p =.2); Female, %: 88 vs. 85 (p =.5); Disease duration, years: 11. ± 7.9 vs. 11. ± 8. (p =.9); Rheumatoid factor (RF), % positive: 79 vs. 79 (p = 1.); Anti-cyclic citrullinated peptide (CCP), % positive: 78 vs. 66 (p =.7); Number of previous disease-modifying antirheumatic drugs (DMARDs): 2.4 ± 1.2 vs. 2.5 ± 1.5 (p =.4); Number of previous biologics:.5 ±.7 vs..6 ±.7 (p =.2); Baseline DAS28: 5.1 ± 1.3 vs. 4.1 ± 1.4 (p <.1); DAS28 at start of rituximab treatment: 6.3 ± 1. vs. 6.1 ± 1.2 (p =.3); Baseline Health Assessment Questionnaire (HAQ) score: 1.5 ±.7 vs. 1.3 ±.8 (p =.1); Concomitant DMARDs, %: 82 vs. 92 (p =.2); Concomitant corticosteroids, %: 58 vs. 46 (p =.4). Baseline patient characteristics at the start of the second rituximab retreatment were as follows (on-flare vs. fixed): Number of patients: 174 vs. 56; Months from baseline: 19.9 ± 7. vs ± 6.6 (p <.1); Age, years: 5.3 ± 12.3 vs ± 1.8 (p =.6); Female, %: 86 vs. 91 (p =.5); Disease duration, years: 11.7 ± 8.6 vs ± 8.6 (p =.7); RF, % positive: 82 vs. 88 (p =.5); Anti-CCP, % positive: 82 vs. 63 (p =.7); Number of previous DMARDs: 2.4 ± 1.3 vs. 2.8 ± 1.5 (p =.7); Number of previous biologics:.7 ±.7 vs..7 ±.9 (p =.7); Baseline DAS28: 5.2 ± 1.4 vs. 4. ± 1.3 (p <.1); Change in DAS28 from baseline:.7 ± 2. vs. 2.1 ± 1.4 (p <.1); DAS28 at start of rituximab treatment: 6.2 ± 1.1 vs. 6.3 ± 1.1 (p =.7); Baseline HAQ score: 1.6 ±.7 vs. 1.4 ±.7 (p =.1); Concomitant DMARDs, %: 54 vs. 54 (p = 1.); Concomitant corticosteroids, %: 81 vs. 86 (p =.4). 12 New Evidence in Rheumatology August 214

14 In Supportive Care Oncology Figure 1. Change in DAS28-ESR ΔDAS28-ESR Fixed On-flare st retreatment 2 nd retreatment 3 rd retreatment DAS28 = 28-joint disease activity score; ESR = erythrocyte sedimentation rate Patients receiving fixed retreatment had a significantly greater (in absolute number) change in DAS28-ESR (erythrocyte sedimentation rate) (p <.1) at the start of each cycle, compared to those retreated on-flare. (Figure 1) Predicted change in DAS28-ESR according to retreatment strategy was calculated using the adjusted mixed model analyses for the first (Figure 2A) and second (Figure 2B) retreatment. The models were adjusted for age, sex, and baseline characteristics that differed significantly between groups. The retreatment strategy had a significant effect on the model. A fixed retreatment yielded significantly better results than the on-flare strategy (fixed vs. on-flare): First retreatment: mean ΔDAS28 = 2.4 (95% CI: 3., 1.7) vs. 1.8 (95% CI: 3.6,.3), p <.1; Second retreatment: mean ΔDAS28 = 2.6 (95% CI: 3.1, 2.2) vs. 1.6 (95% CI: 1.8, 1.4), p <.1. Figure 2. Predicted change in DAS28-ESR in the A) first and B) second retreatment Predicted ΔDAS A p <.1 Retreatment strategy Fixed On-flare Fixed: η 2 cubic =.343 On-flare: η 2 cubic =.349 Predicted ΔDAS B p <.1 Retreatment strategy Fixed On-flare Fixed: η 2 quadratic =.275 On-flare: η 2 quadratic = Time (months) Time (months) DAS28 = 28-joint disease activity score Key conclusion A fixed retreatment strategy with rituximab in RA seems to be more effective than the on-flare retreatment strategy. Reference: 1. Chatzidionysiou K, Lie E, Nasonov E, et al. Fixed versus on-flare retreatment with rituximab in RA results from the CERERRA collaboration. EULAR Abstracts 214: FRI328. New Evidence in Rheumatology August

15 Batticciotto A, et al. EULAR 214:FRI295 Rituximab retention rate in clinical practice: a large multicentre Italian cohort of patients with rheumatoid arthritis Background Long-term extensions of randomized controlled trials in patients with rheumatoid arthritis (RA) have demonstrated that prolonged rituximab exposure of up to 9.5 years does not affect its safety, but there are no data concerning real-life clinical experiences. 1 The aim of this multicentre clinical study was to evaluate the retention of rituximab treatment in patients with RA. Study design The clinical records of 472 patients with RA treated with rituximab in 1 Italian rheumatology centres from August 26 to December 213 were reviewed. Treatment survival and the impact of selected variables (gender, age, disease duration, baseline 28-joint disease activity score [DAS28], number of previous tumour necrosis factor inhibitor [TNF-I] failures, the presence of rheumatoid factor [RF], and methotrexate treatment) were evaluated using Kaplan-Meier and Cox survival analyses. Key findings Patient characteristics were as follows: Female, %: 81.6; Mean age, years: 56.2 ± 12.8; Mean disease duration, years: 1.5 ± 8; RF-positive, %: 76.3; Anti-cyclic citrullinated peptide-positive, %: 75. Patients were treated with rituximab for a mean of 4.1 ± months (range: 122). Methotrexate was administered concomitantly in 76% of patients, and 24% of patients had previously received two or more TNF-Is. The median DAS28 at baseline was 5.7 ± 1.3. For patients completing at least 12, 24, 36, 48, and 6 months of follow-up, the retention rates were 87.9%, 78.8%, 72.5%, 67.6%, and 63.8%, respectively. (Figure 1) Treatment discontinuations due to adverse events or inefficacy had similar temporal trends. (Figure 1) Multivariate analysis (Cox regression) showed that none of the considered predictive variables were significantly associated with treatment survival: Gender: p =.399; Age: p =.486; Disease duration: p =.999; Baseline DAS28: p =.412; Number of previous TNF-I failures: p =.975; The presence of RF: p =.513; and Methotrexate treatment: p =.34. Figure 1. Treatment discontinuation Patients on treatment (%) Baseline 12 months 24 months 36 months 48 months 6 months Overall Adverse event No response Other At risk Total events New Evidence in Rheumatology August 214

16 In Supportive Care Oncology Key conclusion In this large, multicentre cohort of patients with RA, 63.8% of patients continued treatment with rituximab for 6 months. Reference: 1. Batticciotto A, Covelli M, Dinoia L, et al. Rituximab retention rate in clinical practice: a large multicentre Italian cohort of rheumatoid arthritis patients. EULAR Abstracts 214: FRI295. Krause A, et al. EULAR 214:FRI297 Rituximab in rheumatoid arthritis 4-year interim analysis of the noninterventional BRIDGING study Background Clinical routine data on the efficacy and safety of rituximab in patients suffering from severe, active rheumatoid arthritis (RA) were assessed in the German BRIDGING study. 1 The purpose of this report was to examine the following factors: Time to onset of efficacy; Correlations between time to onset and cofactors (e.g., anti-cyclic citrullinated peptide [CCP] and rheumatoid factor [RF] status, pretreatments, concomitant diseases, and age); The influence of cofactors on prognosis; and The comparison of primary therapy and retreatment. Study design The BRIDGING study is a prospective, multicentre, noninterventional study. Patients were observed for six months, or 12 months in the case of retreatment, between 21 and 214. The study planned to recruit 1,6 patients. Data to be recorded were: Treatment data; Relevant data on the course of RA (e.g., activity scores, pain intensity); and Mean adverse events (AEs). The cut-off date for the interim analysis was December 1, 213 Key findings Baseline data are summarized in Table 1. Table 1. Baseline characteristics Characteristic Value Baseline characteristics Female, % 72.4 Mean age, years 6.4 Smoker or ex-smoker, % 4.3 Anti-CCP positive, % 61.3 RF-positive, % 72.1 Mean DAS Seropositive*, n 861 Seronegative, n 12 Anti-CCP positivity by smoking status, % Non-smoker Smoker Ex-smoker Pretreatments, % DMARDs and TNF-Is 67.6 DMARDs, TNF-Is, and additional medications 7. DMARDs only 24.1 TNF-I monotherapy.8 *Seropositivity was defined as anti-ccp positive and/or RF-positive, or if the word seropositive was explicitly mentioned. CCP = cyclic citrullinated peptide; DAS28 = 28-joint disease activity score; DMARD = disease-modifying antirheumatic drug; RF = rheumatoid factor; TNF-I = tumour necrosis factor inhibitor All 996 patients received the first rituximab infusion of the first course; 91 received the second rituximab infusion of the first course. The dosage of rituximab was 1, mg in 96.7% of patients (both infusions). At week 24, DAS28 was available for 461 patients. New Evidence in Rheumatology August

17 Low disease activity was observed in 3.4% of patients (seropositive, 32.1%; seronegative, 19.1%). Remission was observed in 16.7% of patients (seropositive, 17.9%; seronegative, 8.5%). The mean improvement in DAS28 was 1.6. DAS28 improvement was not dependent on prior RA therapy, and was not affected by tuberculosis, solid tumours or lymphoma as concomitant diseases, or by smoking. A moderate/good EULAR response was observed in 73.9% of patients; a good response was observed in 27.3% of patients, and no response was found in 26.% of patients. Pain intensity scores decreased until week 18, then either plateaued or increased at week 24. (Table 2) Health Assessment Questionnaire scores decreased until week 12, and then plateaued. (Table 2) DAS28 improved continuously until week 18, but appeared to level off or even increase in some patients in week 24. (Table 2, Figure 1) This suggests that retreatment with rituximab should be considered again in some patients in week 24. The treatment response appeared to be stronger in seropositive patients than in the seronegative group. (Table 2, Figure 1) This was most pronounced in the DAS28 reduction at week 18. The highest DAS28 remission and low disease activity were observed at week 24. In total, 1,342 AEs were recorded in 541 (33%) patients. Serious adverse drug reactions (ADRs) were experienced by 112 (7%) patients. There were 22 serious infectious ADRs, representing a rate of 4. serious infectious events per 1-patient-years. There were no cases of newly acquired tuberculosis. Since the start of the study in 21, eight of 1,622 patients have died, two of whom died at least one year after the end of their observational period. Table 2. Pain intensity, HAQ, and DAS28 (mean values) Pain intensity* (VAS patient) HAQ DAS28 Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Baseline 58.8 (N = 855) 57.3 (N = 12) 1.5 (N = 751) 1.5 (N = 9) 5.6 (N = 861) 5.3 (N = 12) Day (N = 764) 5.5 (N = 98) 1.4 (N = 661) 1.4 (N = 83) 5. (N = 612) 4.8 (N = 78) Week (N = 499) 47.2 (N = 6) 1.3 (N = 434) 1.4 (N = 49) 4.5 (N = 384) 4.5 (N = 41) Week (N = 437) 45.3 (N = 54) 1.2 (N = 375) 1.3 (N = 43) 4.1 (N = 355) 4.3 (N = 4) Week (N = 385) 44.8 (N = 47) 1.2 (N = 339) 1.3 (N = 38) 3.7 (N = 29) 4.4 (N = 34) Week (N = 513) 45.8 (N = 56) 1.2 (N = 444) 1.3 (N = 45) 3.9 (N = 42) 4.2 (N = 47) *1 = intolerable pain DAS28 = 28-joint disease activity score; HAQ = Health Assessment Questionnaire; VAS = visual analogue scale 16 New Evidence in Rheumatology August 214

18 In Supportive Care Oncology Figure 1. DAS28 during observation Seropositive 4.5 Seronegative DAS28 (mean) Baseline Day 15 Week 6 Week 12 Week 18 Week 24 Error bars represent standard deviation. DAS28 = 28-joint disease activity score Key conclusions Following rituximab therapy, improvements of all activity parameters could be shown in extensively pretreated patients with severe RA. Safety data were consistent with the known safety profile of rituximab, with no new safety signals identified. The study confirms the benefit of rituximab therapy for patients with RA in daily clinical practice. Reference: 1. Krause A, Aries P-M, Lorenz H-M, et al. Rituximab in rheumatoid arthritis 4 year interim analysis of the non-interventional BRIDGING study. EULAR Abstracts 214: FRI297. Manders SHM, et al. EULAR 214:SAT253 Cost-effectiveness of abatacept, rituximab, and TNF-I after failure of the first TNF-I: results of a multicentered pragmatic randomized trial Background Various treatment options are available for patients with rheumatoid arthritis (RA) after failure of a first tumour necrosis factor inhibitor (TNF-I); however, the most cost-effective option is still unknown. 1 The objective of this randomized, open-label study was to compare the cost-effectiveness of abatacept, rituximab, and another TNF-I after failure of a first TNF-I in patients with RA. Study design The DREAM study was a pragmatic randomized trial. Inclusion criteria were as follows: Failure of a first TNF-I; A 28-joint disease activity score (DAS28) >3.2; No previous treatment with abatacept or rituximab; and No contraindications. New Evidence in Rheumatology August

19 Patients were randomized to abatacept, rituximab, or TNF-I treatment. The utility was based on the EQ5D questionnaire and was used to calculate quality-adjusted life years (QALYs). All medication costs in one year were taken into account. Incremental net monetary benefit (inmb) was performed to analyze the cost-effectiveness over one year. Key findings Patient characteristics were as follows: Total number of patients: 139; Mean age, years: 56.3; Female, %: 74.8; Median disease duration, years: 6.25; Rheumatoid factor (RF)-positive, %: 66.7; Mean DAS28: 4.8. The mean QALYs and costs over one year are illustrated in Figure 1. The inmb, corrected for gender and RF, was significantly different between rituximab and abatacept and between rituximab and a second TNF-I in favour of rituximab (p <.1 and p <.5, respectively). (Figure 2) This was true over the range of a willingness to pay from 8, euro per QALY. Figure 1. Mean QALYs and costs over one year 1. 16, Mean QALY Mean costs per year ( ) 14, 12, 1, 8, 6, 4, 2, ABA RTX TNF-I ABA RTX TNF-I ABA = abatacept; QALY = quality adjusted life year; RTX = rituximab; TNF-I = tumour necrosis factor inhibitor Figure 2. Incremental net monetary benefit analyses Mean inmb 95% CI RTX vs. TNF-I RTX vs. ABA TNF-I vs. ABA 2, 2, 15, 15, 15, 1, inmb 1, inmb 1, inmb 5, 5, 5, , Willingness to pay (*1, ) Willingness to pay (*1, ) 1, Willingness to pay (*1, ) ABA = abatacept; CI = confidence interval; inmb = incremental net monetary benefit; RTX = rituximab; TNF-I = tumour necrosis factor inhibitor 18 New Evidence in Rheumatology August 214

20 In Supportive Care Oncology Key conclusion If costs are important in the decision to choose a biological treatment, rituximab should be preferred over abatacept and a second TNF-I in patients with RA who have failed a first TNF-I. Reference: 1. Manders SHM, Kievit W, Brus HL, et al. Cost-effectiveness of abatacept, rituximab and TNFi after failure of the first TNFi: results of a multi-centered pragmatic randomized trial. EULAR Abstracts 214: SAT253. Canadian Perspective by Dr. Janet Pope The anti-cd2 antibody rituximab is well known as an effective and safe treatment for rheumatoid arthritis (RA). 1,2 It is approved in Canada, in combination with methotrexate, for patients with RA who have had an inadequate response to a tumour necrosis factor inhibitor (TNF-I). 3 I choose rituximab as a treatment for patients with RA if they do not respond to first-line TNF-I therapy, particularly if they are seropositive for rheumatoid factor (RF) and/or cyclic citrullinated peptide (CCP). While the efficacy and safety of rituximab in the treatment of RA are well established in clinical trials, 1,2 there are certain aspects of the real-world use of rituximab that remain unclear, such as the risk of serious infections over time, the appropriate retreatment strategy (when to re-treat and at what dose), and the effects of comorbidities on the efficacy of rituximab. Investigators presented studies that helped to clarify these issues at the 214 European League Against Rheumatism (EULAR) Congress. In my practice, I have not observed any differences among biologics in the incidence of serious infections, particularly after first exposure to a TNF-I; however, a large sample size is needed to observe differences, as the incidence rate is quite low. I have not been concerned about rituximab posing a higher risk of serious infections (although I am vigilant with all biologics and steroids), and there is not an increased risk of reactivating tuberculosis. 4 Silva-Fernandez et al. presented an observational, multi-site, cohort study from the U.K. that investigated the risk of serious infections in patients with RA who had failed a first-line TNF-I and then were treated with either a second TNF-I or rituximab. 5 The data collected by this registry were very comprehensive and included the tracking of important risk factors, such as disease severity, high Health Assessment Questionnaire (HAQ) scores, steroid use, duration of drug exposure, hospitalizations, and RF positivity. Another strength of this study was its large sample size with 1,18 patients on rituximab and 3,237 patients using a second TNF-I. This sample captures many patients with RA in the U.K. who are on a biological drug, and since the patients were followed very carefully, it is likely that the majority of serious infections were recorded. The rate of first serious infections was identical in both groups (6 per 1, patient-years [PY] for the second TNF-I cohort and 56 per 1, PY for rituximab, with overlapping confidence intervals). This is a bit higher than what is usually reported (35.9 per 1, PY), 6 but it is not unexpected. The rate of infections is usually higher in patients after they have failed a TNF-I, likely because these patients have more resistant disease. I believe this patient population is quite generalizable to the Canadian population of patients with RA, with the exceptions that 28-joint disease activity scores (DAS28) tend to be higher in British patients, and that steroid use is generally lower in Canada (high disease activity and steroid use are each associated with higher risk of infections). Because of these differences, it is possible that this study has a higher serious infection rate than what we would find in Canada; however, I still believe that the study provided a sound and reasonable risk estimate of serious infections with no differences between groups. It is unfortunate that the data were not randomized as we do not know why investigators chose one treatment over another. The authors concluded that patients who switch to rituximab after failing a TNF-I do not have an increased risk of serious infections compared with patients who switch to another TNF-I. The results of this study will not affect my practice, but it is reassuring to tell patients that infection rates are low (approximately 6 per 1, PY). Chatzidionysiou et al. presented a case-control study examining two retreatment strategies with rituximab: on-flare, in which patients are re-treated with rituximab when a flare occurs, and fixed, in which patients are re-treated with rituximab on a set schedule. 7 I believe there are advantages and disadvantages to both strategies. Patients on the fixed schedule may not need retreatment as often as they are receiving it, resulting in unnecessary treatments; however, this is balanced by the advantage of preventing flares. Patients on the on-flare schedule do not receive unnecessary treatment, but they also may not receive the drug in a timely manner when a flare occurs if there are access issues, resulting in unneeded pain and suffering, joint damage, potential loss of work time, etc. New Evidence in Rheumatology August

21 Canadian Perspective by Dr. Janet Pope In my practice, I tend to re-treat every six months until remission or a low disease state is achieved; at that point I wait until the patient feels the return of symptoms to re-treat, and then I will continue to re-treat at the observed interval of symptom recurrence minus 2 to 4 weeks. However, there is no generally accepted retreatment strategy, so studies such as this one help to inform us about what might be best for our patients. The patient characteristics were similar between groups in this study, although some differences were noted. Patients in the onflare cohort were treated slightly later than the fixed cohort (1 vs. 8.5 months from baseline), which is a consequence of the retreatment strategy being used. The number of patients who were positive for CCP was higher in the on-flare group, but this likely did not make a difference in the results observed. Baseline DAS28 was statistically different between groups, but the values were about the same from a clinical perspective. HAQ scores were slightly higher in the on-flare group. Concomitant diseasemodifying antirheumatic drug (DMARD) and steroid use were numerically different between groups; this is something that should be adjusted for when looking for differences in efficacy. DAS28 was lower after each retreatment in the fixed group; however, the time between treatments was also longer in the on-flare group (19.9 vs months from baseline in the fixed group at the start of the third cycle of rituximab). This finding is supported by previous literature. 4 The authors concluded that a fixed retreatment strategy with rituximab seems to be more effective than an on-flare strategy. I agree with this assessment; the fixed retreatment strategy maintains a low disease state in patients, and I feel this is a rational way to use rituximab. This is essentially how I use other biologics and DMARDs as well; patients are continually treated and I do not stop treatment to wait for a flare. However, I believe that individual variation should be taken into account when determining a retreatment schedule, as opposed to mandating a set schedule for all patients (e.g., every six months). Another question that needs to be addressed is how the dose of rituximab should be changed when a patient is on a fixed retreatment schedule. I usually administer the full dose (1 g intravenously and then a second dose of 1 g two weeks later) until a patient has reached a low disease state, and then I decrease the dose to 1, mg in a single infusion, based on data from previous studies. 8 Other studies have shown that two doses of 5 mg are also acceptable; 9 this re-dosing issue is something that could be clarified with further research. Krause et al. investigated the early efficacy and safety of rituximab retreatment in an observational study of German clinical centres. 1 In particular, the authors stratified patients by seropositivity status (either seropositive [RF- and/or CCP-positive] or seronegative) to investigate differences in the efficacy and safety of rituximab between these two types of patients. Rituximab is already known to be more effective in patients who are seropositive; 4 this is likely not totally unique to rituximab, but the association has been reported most often with this biologic. Seropositivity is a factor that affects my choice of treatment once a patient is eligible to receive rituximab as recommended by Health Canada (i.e., previous exposure to a TNF-I or contraindications to TNF-Is). In this situation, I am far more likely to treat patients with rituximab if they are seropositive. If a patient is seronegative, I am more likely to treat with a drug that has a different mechanism of action before trying rituximab. The sample size of this study was very large (over 1,6 patients), with a substantial number of variables collected for each patient. The patient characteristics were similar to the patients I see in my practice, with the exception that in Canada we typically do not have access to biologics until patients fail at least two DMARDs. After a follow-up period of 24 weeks following the first rituximab infusion, one-third of seropositive patients had low DAS28 compared to one-fifth of patients who were seronegative. The remission rate was twice as high in the seropositive patients compared to those who were seronegative, confirming what is already known about rituximab and seropositivity. The mean change in DAS28 after 24 weeks was clinically relevant. Smoking status and other comorbidities did not affect the efficacy of rituximab, which was reassuring to see. The rates of serious adverse drug reactions were what I would expect from a population of this size. The authors reaffirmed the benefit of rituximab therapy for patients with RA in daily clinical practice, particularly in those who are seropositive. While many patient characteristics were studied, it would have also been interesting if the investigators had looked at sex differences in the safety and efficacy of rituximab, as women generally have a worse prognosis than men. While the results of this study will not affect my own practice, some rheumatologists in Canada have been slow to adopt rituximab as treatment after a failed first TNF-I; perhaps these data will give reassurance to physicians to use rituximab earlier on in the course of treatment. References: 1. Volkmann E, Agrawal H, Maranian P, and Furst DE. Rituximab for rheumatoid arthritis: a meta-analysis and systematic review. Clin Med Insights Ther 21;2: van Vollenhoven RF, Emery P, Bingham III CO, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 213;72: Hoffmann-La Roche Ltd. Pr RITUXAN (rituximab) Product Monograph. May 29, 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: Silva-Fernandez L, Lunt M, Low AS, et al. The risk of serious infections in patients receiving rituximab for rheumatoid arthritis. EULAR Abstracts 214:OP Favalli EG, Desiati F, Atzeni F, et al. Serious infections during anti-tnfalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 29;8: Chatzidionysiou K, Lie E, Nasonov E, et al. Fixed versus on-flare retreatment with rituximab in RA results from the CERERRA collaboration. EULAR Abstracts 214: FRI Boumans MJH, Roelse AJK, Geerdink M, et al. Retreatment of rheumatoid arthritis patients with 1x1 mg rituximab results in sustained clinical response in clinical responders initially treated with 2x1 mg rituximab. Ann Rheum Dis 211;7 (Suppl 2):A81 A Emery P, Deodhar A, Rigby WF, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomized, placebo-controlled trial in patients who are biological-naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab s Efficacy in MTX inadequate responders (SERENE)). Ann Rheum Dis 21;69: Krause A, Aries P-M, Lorenz H-M, et al. Rituximab in rheumatoid arthritis 4 year interim analysis of the non-interventional BRIDGING study. EULAR Abstracts 214: FRI New Evidence in Rheumatology August 214

22 Investigator Commentary An interview with Dr. Rafat Faraawi on his study regarding the safety of rapid rituximab infusion in rheumatoid arthritis At the 214 EULAR Scientific Meeting in Paris, France, New Evidence spoke with Dr. Rafat Faraawi, Associate Clinical Professor of Rheumatology at McMaster University, Hamilton, Ontario, and Consultant Rheumatologist at St. Mary s Hospital, Kitchener, Ontario, about the results of his study on the safety of rapid rituximab infusion in rheumatoid arthritis (RA) in a single community practice. New Evidence: Which RA patient populations do you treat with rituximab in your clinic? What percentage of patients receives rituximab? Dr. Faraawi: The majority of RA patients in our clinic treated with rituximab are those who have experienced failure to tumour necrosis factor inhibitors (TNF-Is). In certain circumstances rituximab is used as a first-line biologic, particularly in those with a history of tuberculosis and malignancy, such as lymphoma. Approximately 1% of RA patients on biologics in my clinic are treated with rituximab. New Evidence: Please describe how rituximab is administered conventionally. What are the potential concerns and challenges with conventional and short infusions? Dr. Faraawi: The conventional method of rituximab administration involves the delivery of 1, mg of rituximab twice over two weeks, with the first infusion lasting four hours and 15 minutes and the second lasting three hours and 15 min. Prior to the infusion, patients are medicated with methylprednisolone, acetaminophen, and dihphenylhydramine. One of the biggest challenges with conventional infusions is the length of time patients have to stay in the clinic while receiving treatment, which can be up to six hours. The long treatment time adds to the patient s busy schedule, which is already strained by the long distances sometimes travelled for treatment. It also means that nursing staff have to stay with the patient as well, resulting in a greater burden on clinical resources. Finally, longer infusion times use up more of the physician s time, which could be diverted into other responsibilities in the clinic. Overall, short infusions are well tolerated and accepted by the majority of our patients. New Evidence: Please describe the rationale of the study. Why did you choose a two hour infusion protocol? Dr. Faraawi: There have been a number of protocols utilizing shorter infusion times with rituximab in the lymphoma setting. The success in the lymphoma setting prompted us to utilize short infusion times in the RA setting. The decision to use the two-hour infusion protocol was based on what we thought was appropriate in our setting and the experience in lymphoma setting. New Evidence in Rheumatology August

23 New Evidence: Please describe the setting of the study and the study design. What inclusion criteria did you use? What endpoints were measured? Dr. Faraawi: The objective of the study was to evaluate the safety and practicality of rapid rituximab infusion in a community setting. This is important because the results of a study from a community practice should give other community centres confidence in using rapid infusion protocols. The study was an open-label trial on moderate-to-severe RA patients who had been prescribed rituximab from October 26 to November 213. New Evidence: Please describe the key findings of the study? Dr. Faraawi: There were 28 patients who participated in the short infusion protocol during the study period, and there were a total of 132 short infusions administered. The main findings of the study were: 1) There was no significant difference in the number of infusion-related reactions (IRRs) between the conventional and the rapid infusion arm; 2) IRRs in both arms were mild, with all IRRs resolved in 24 hours or less; and 3) None of the patients discontinued treatment due to IRRs. New Evidence: How do the results of this study compare with other studies on rapid-infusion protocols in rituximab? Dr. Faraawi: The results of our study are consistent with the recently published study by Pritchard et al. 1 That study showed that infusion times can be reduced from 4.25 to two hours in in the second and subsequent infusions without increasing the rate and severity of IRRs. New Evidence: Please describe how patients felt about receiving rapid infusions. Dr. Faraawi: In general, patients prefer the short infusion protocol due to the reduced time they spend in the clinic. Patients who did not want to use the short-infusion protocol did so because they felt comfortable with the longer protocols and simply did not want to change. New Evidence: What is the conclusion and significance of the study? Dr. Faraawi: The main conclusion of the study is that the rapid infusion of rituximab in RA patients is safe and effective in a community practice setting. The results of this study are consistent with the results of the first study we reported at EULAR in This previous study, which included 1 patients who received a total of 3 infusions, showed that the short infusion protocol was safe in a community-practice setting. The results of this new study, which included 28 patients and total of 132 infusions, give us more confidence that the short infusion protocol is safe and tolerable. New Evidence: How can this infusion protocol be improved? Dr. Faraawi: Patients who receive rituximab or other biologic infusions are also given pre-medications to reduce the risk of IRRs. This may be unnecessary in some cases in which lowering or removing pre-medications altogether may be possible. Some patients may not need pre-medications like methylprednisolone, so we need to determine who these patients are so that we don t give unnecessary medications. References: 1. Pritchard CH, Greenwald MW, Kremer JM, et al. Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study. BMC Musculoskelet Disord 214;15: Faraawi R, Roth K. Experience with accelerated rituximab infusion for rheumatoid arthritis in a single community practice. EULAR Annual Meeting Abstracts 21: FRI New Evidence in Rheumatology August 214

24 In Supportive Care Oncology Tocilizumab in Rheumatoid Arthritis Treatment Tocilizumab is an Effective Option in Combination and as Monotherapy: Now Also Available as a Subcutaneous Formulation Tocilizumab is an interleukin-6 receptor inhibitor and an effective treatment for rheumatoid arthritis (RA). 1,2 Tocilizumab is approved in Canada for adult patients with moderate to severe RA who have failed at least one disease-modifying antirheumatic drug (DMARD). 3 While tocilizumab is approved for use both in monotherapy and in combination with DMARDs, the majority of patients receive such biologics as combination therapy. 3-5 However, increasing evidence suggests that tocilizumab monotherapy is superior to methotrexate monotherapy, and is equally as effective as combination therapy in patients with RA. 6,7 Additionally, tocilizumab treatment provides further benefits beyond the improvement of RA symptoms, including a subcutaneous (sc) formulation that provides ease of use for patients, and by improving fatigue symptoms that are typically associated with RA and affect quality of life. 3,8 At the 214 Congress of the European League Against Rheumatism (EULAR), investigators presented additional data to support the use of tocilizumab in monotherapy, as well as the additional benefits of tocilizumab use. This article reports on five presentations that were delivered at EULAR 214: Interim data from the ACT-UP study, an international, observational study that collected data on the use of tocilizumab in real-world clinical practice, showed that while a minority of patients with RA received tocilizumab as monotherapy, this group comprised a large proportion of patients who receive biologic monotherapy. A long-term analysis of the SUMMACTA study, comparing the efficacy and safety of the sc and intravenous (iv) formulations of tocilizumab, confirmed that the efficacy and safety profiles of tocilizumab sc remained comparable to those of tocilizumab iv after 97 weeks of treatment. Data from the prospective, observational ACT-AXIS study found that tocilizumab use improved fatigue outcomes in patients with moderate to severe RA. A cell-based profiling system was used to compare tocilizumab and adalimumab, both in combination with methotrexate and in monotherapy; the study found that the addition of methotrexate did not significantly alter the actions of tocilizumab. An extension of the ACT-RAY study, which compared tocilizumab in combination with methotrexate and in monotherapy, found that the efficacy of the two treatments was comparable and suggested that treat-to-target strategies could be used successfully to achieve sustained remission in patients with RA. References: 1. Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs 29;69: Hoffmann-La Roche Ltd. Pr ACTEMRA (tocilizumab) Product Monograph. May 6, Highlights of prescribing information: ACTEMRA (tocilizumab). Genentech, Inc. October Soliman MM, Ashcroft DM, Watson KD, et al. Impact of concomitant use of DMARDs on the persistence with anti-tnf therapies in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 211;7: Lee SJ, Chang H, Yazici Y, et al. Utilization trends of tumor necrosis factor inhibitors among patients with rheumatoid arthritis in a United States observational cohort study. J Rheumatol 29;36: Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 21;69: Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis 213;72: Burmester GR, Feist E, Kellner H, et al. Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA). Ann Rheum Dis 211;7: New Evidence in Rheumatology August

25 Haraoui B, et al. EULAR 214:FRI3 Baseline characteristics and pattern of tocilizumab use in patients with rheumatoid arthritis: interim results from the multinational, observational ACT-UP study Background Tocilizumab may be administered as combination therapy with methotrexate, or as monotherapy for patients who are unable to tolerate methotrexate (or in those for whom continued treatment with methotrexate is inappropriate). 1 Tocilizumab monotherapy has been shown to effectively treat the signs and symptoms of RA regardless of a patient s previous exposure or response to methotrexate; however, only approximately one-third of patients receiving biologic therapy for rheumatoid arthritis (RA) receive it as monotherapy. Real-life treatment patterns of tocilizumab and physicians adherence to licensed label recommendations are being examined in this observational study of patients with RA treated with tocilizumab in a routine practice setting. The objective of this report was to present interim data on baseline characteristics and patterns of intravenous tocilizumab use after six months of treatment in the ACT-UP study global population. Study design The ACT-UP study is an international, observational study with data pooled from several independent, observational, postmarketing, multicentre studies of similar design to observe routine practice patterns of tocilizumab use in different countries. Patients starting tocilizumab treatment within 8 weeks of study enrollment were observed in clinical practice for six months. Inclusion criteria were as follows: Adult patients 18 years of age or older who had moderate to severe RA, based on the 1987 American College of Rheumatology (ACR) criteria; Decision by treating physician to begin tocilizumab therapy. There were no restrictions on concomitant medications, other than that they were prescribed according to the investigator s judgment and the local label for tocilizumab. Exclusion criteria were as follows: Received tocilizumab >8 weeks before enrollment, or received tocilizumab 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. The 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. No additional study visits, study-specific medications, or interventional procedures were performed outside routine clinical practice. Patients were categorized based on whether they received tocilizumab in combination with a diseasemodifying antirheuamtic drug (DMARD) or as monotherapy at baseline. The primary objective was to observe patterns of intravenous tocilizumab use in RA patients and adherence to licensed label recommendations. The primary end point was the proportion of patients receiving tocilizumab at six months after treatment initiation. Key findings All patients receiving at least one dose of tocilizumab were included in the analysis population. As of Jan. 31, 213, 552 patients were enrolled in 14 countries and had received at least one dose of tocilizumab. At the time of tocilizumab initiation, 216 (39.1%) patients received tocilizumab as monotherapy and 336 (6.9%) received tocilizumab in combination with a DMARD. A total of 46 patients (83.3%) remained on the study at six months; 163 (75.5%) patients remained in the monotherapy group and 297 (88.4%) patients remained in the combination group. 24 New Evidence in Rheumatology August 214

26 In Supportive Care Oncology Baseline patient and disease characteristics were similar between tocilizumab treatment groups. One exception was that a higher proportion of combination therapy patients (55.1%) than monotherapy patients (35.2%) were taking corticosteroids at baseline. Disease severity was similar between the groups (28-joint disease activity score [DAS28] = 5.8 for both groups). At baseline, fewer monotherapy (51.9%; 112 patients) than combination therapy (64.9%; 218 patients) patients had previously received a biologic. (Figure 1) Among monotherapy patients, 57 (26.4%) received one biologic and 55 (25.5%) received more than one biologic before initiating tocilizumab. Among combination therapy patients, 112 (33.3%) received one biologic and 16 (31.5%) received more than one biologic before initiating tocilizumab. Reasons for stopping biologic treatment and initiating tocilizumab were similar between the groups; the primary reason was lack of efficacy, and the next was occurrence of an adverse event (AE). (Figure 1) Before starting tocilizumab, a higher proportion of monotherapy (72.2%) than combination therapy (64.9%) patients had taken and stopped a previous DMARD. (Figure 2) Previous DMARDs were stopped in monotherapy and combination therapy patients because of lack of efficacy (4.9% and 42.2%, respectively), objective intolerance (28.1% and 18.9%, respectively), and subjective intolerance (12.8% and 5.7%, respectively). (Figure 2) Most monotherapy (93.1%) and combination therapy (93.2%) patients received an initial tocilizumab dose of 8 mg/kg. (Figure 3) A total of 27 (12.5%) monotherapy and 46 (13.7%) combination therapy patients changed tocilizumab dose over six months. Dose increases occurred in 8 monotherapy and 6 combination therapy patients; Dose decreases occurred in 6 monotherapy and 15 combination therapy patients; A total of 13 monotherapy and 25 combination therapy patients had both a dose increase and a dose decrease. Reasons for changing dose included: A lack of efficacy in 18.5% (5/27) of monotherapy and 6.5% (3/46) of combination therapy patients; AEs in 29.6% (8/27) of monotherapy patients and 43.5% (2/46) of combination therapy patients. Figure 1. Previous biologic use: A) Proportion of patients who stopped a biologic before initiating tocilizumab therapy and B) Reasons for discontinuation of previous biologic therapy A B Biologic Etanercept Adalimumab Infliximab Certolizumab pegol Golimumab Abatacept Rituximab Patients (%) Monotherapy (n = 216) Combination therapy (n = 336) Treatment (%) % Monotherapy (n = 23)* Combination therapy (n = 426)* Lack of efficacy Adverse event 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. New Evidence in Rheumatology August

27 Figure 2. Previous DMARD stoppages: A) Proportion of patients who stopped DMARD therapy before initiating tocilizumab and B) Reasons for discontinuation of previous DMARDs A B DMARD MTX Hydroxychloroquine Leflunomide Sulfasalazine Gold Patients (%) Monotherapy (n = 216) Combination therapy (n = 336) Treatment (%) Monotherapy (n = 462)* Combination therapy (n = 578)* Lack of efficacy Subjective intolerance Objective intolerance Other Unknown DMARD = disease-modifying antirheumatic drug; MTX = methotrexate The distinction between objective and subjective intolerance as a reason for discontinuation was not specified in the protocol but was left to the discretion of the investigators. *n = number of discontinued drugs. Drugs were counted each time they were discontinued; therefore, patients might have taken an agent more than once. Six months after tocilizumab initiation, 155 (71.8%) monotherapy patients and 283 (84.2%) combination therapy patients continued to receive tocilizumab, primarily at a dose of 8 mg/kg (monotherapy, 96.1%; combination therapy, 9.5%). (Figure 3) No monotherapy patients and.7% of combination therapy patients received a tocilizumab dose greater than the approved 8 mg/kg at six months. Of the patients who did not receive a dose at six months, tocilizumab was stopped for the following reasons (monotherapy vs. combination therapy): Lack of efficacy, %: 14.8 vs. 26.4; AE, %: 24.6 vs. 26.4; Unknown reason, %: 24.6 vs. 34.; Other reason, %: 36.1 vs Other reasons for stopping treatment included withdrawal of consent, patient decision, lost to follow-up, pregnancy, disease flare, and completed study as planned. Combination therapy patients were more likely than monotherapy patients to use corticosteroids (68.2% vs. 44.4%), nonsteroidal anti-inflammatory drugs (5.6% vs. 31.%), and lipid-lowering agents (14.6% vs. 7.4%). (Figure 4) A total of 1 (4.6%) monotherapy patients began DMARD therapy after initiating tocilizumab. Figure 3. Tocilizumab dose used at initiaion and at 6 months of treatment Patients receiving TCZ dose (%) Baseline (n = 216) TCZ <8 mg/kg TCZ 8 mg/kg TCZ >8 mg/kg Monotherapy Month 6 (n = 155) Baseline (n = 336) TCZ = tocilizumab Includes only patients who received TCZ infusion in the appropriate time window. Month 6 (n = 283) Combination therapy A total of 24 (11.1%) monotherapy patients and 55 (16.4%) combination therapy patients had AEs that required dose modification or abnormal laboratory values that required follow-up. In these instances, local label or protocol recommendations were followed in 91.7% of monotherapy and 98.2% of combination therapy patients New Evidence in Rheumatology August 214

28 In Supportive Care Oncology Figure 4. Concomitant rheumatoid arthritis treatments Patients (%) DMARD MTX Hydroxychloroquine Leflunomide Sulfasalazine Monotherapy (n = 216) Combination therapy (n = 336) Corticosteroids NSAIDs Lipid-lowering agents DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug Key conclusions In this study, 39% of patients received tocilizumab as monotherapy, which is consistent with reported estimates from registry data. Tocilizumab was the first prescribed biologic for 48% of monotherapy patients and 35% of patients who received combination therapy with DMARDs. All patients who had previously stopped biologics and then initiated tocilizumab did so for similar reasons. The most common were lack of efficacy (74%) and occurrence of AEs (13%). More patients who started tocilizumab as monotherapy had previously discontinued DMARDs for reasons of intolerance (41%) compared with patients in the combination therapy group (25%). Concomitant use of corticosteroids and lipid-lowering agents was lower for patients receiving tocilizumab monotherapy than for patients receiving combination therapy. Reference: 1. Haraoui B, Casado G, Theander E, et al. Baseline characteristics and pattern of tocilizumab use in patients with rheumatoid arthritis: interim results from the multinational, observational ACT-UP study. EULAR Abstracts 214: FRI3. New Evidence in Rheumatology August

29 Burmester GR, et al. EULAR 214:FRI316 The efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA) Background Intravenous tocilizumab (TCZ-IV) is approved for use in more than 1 countries and geographic areas; subcutaneous tocilizumab (TCZ-SC) is approved for use in the U.S., Canada, Japan, and the E.U. 1 The phase III SUMMACTA study evaluated the efficacy and safety of TCZ-SC in combination with disease-modifying antirheumatic drugs (DMARDs). Long-term data has now been evaluated up to week 97. The primary objective of this study was to compare the efficacy and safety of TCZ-SC to TCZ-IV in combination with background DMARD therapy. Secondary objectives included: Long-term safety and efficacy; Pharmacokinetics and pharmacodynamics of TCZ-SC; Immunogenicity of TCZ-SC, and; The effect of switching from IV to SC. Study design All patients had rheumatoid arthritis (RA) and an inadequate response to one or more DMARDs. Up to 2% of patients had an inadequate response to tumour necrosis factor inhibitors (TNF-Is). The following biologics were discontinued prior to baseline: Infliximab, certolizumab pegol, golimumab, abatacept, and adalimumab for 8 weeks; Etanercept for 2 weeks; and Anakinra for 1 week. During the study, patients remained on a background stable dose of at least one nonbiologic DMARD. At baseline, patients were randomized 1:1 to receive TCZ-SC qw or TCZ-IV q4w. TCZ-SC and placebo-sc were administered using prefilled syringes. At week 24, all patients were re-randomized for a 72-week open-label extension: Patients who received TCZ-SC qw were re-randomized 11:1 to receive TCZ-SC qw or TCZ-IV q4w; Patients who received TCZ-IV q4w were re-randomized 2:1 to receive TCZ-IV q4w or TCZ-SC qw. The following maintenance responses were assessed at 97 weeks: The proportion of patients with American College of Rheumatology (ACR) 2, ACR5, and ACR7 responses; The proportion of patients with a 28-joint disease activity score (DAS28) <2.6 (DAS remission); The proportion of patients achieving a decrease of.3 from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI); The proportion of patients who withdrew due to lack of therapeutic response; and Safety, including immunogenicity. The intent-to-treat (ITT) population was used for all efficacy and laboratory analyses. The long-term extension ITT population included patients who had completed 24 weeks of doubleblind treatment, had been re-randomized at week 24, and had received at least one dose after rerandomization. The safety population included all patients who received at least one dose of study drug and had at least one postdose safety assessment, whether they were re-randomized at week 24 or not. Key findings Patient baseline demographics and clinical characteristics were balanced across the TCZ-SC qw and TCZ-IV q4w groups. The percentage of patients who achieved ACR2/5/7 responses, DAS28 remission, and an improvement from baseline in HAQ-DI.3 were sustained from week 24 through week 97 and comparable across all treatment groups. (Figure 1) 28 New Evidence in Rheumatology August 214

30 In Supportive Care Oncology Study design TCZ-SC 162 mg qw + Placebo-IV q4w R TCZ-SC qw TCZ-IV q4w Screening R TCZ-IV 8 mg/kg q4w + Placebo-SC qw R TCZ-SC qw TCZ-IV q4w 24-week double-blind period 72-week OLE Follow up Baseline Week 24 Week 49 Week 97 IV = intravenous; OLE = open-label extension; qw = weekly; q4w = every 4 weeks; R = randomization; SC = subcutaneous; TCZ = tocilizumab Across all treatment groups and body weight categories, ACR responses were similar between groups that continued the same route of dosing and after switching the route of administration. Lower responses were observed in the 1 kg patient subgroup; however, this phenomenon occurred across all treatment groups. The safety profile of TCZ-SC remained stable over time was comparable with that of TCZ-IV. (Table 1) Between weeks 24 and 97, four deaths occurred in the TCZ-SC to TCZ-SC group (shock, thrombosis, cerebral infarction, and unknown cause). In the TCZ-IV to TCZ-IV group, three deaths occurred (idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and ischemic infarction of the right occipital lobe). No anaphylaxis cases were identified (according to Sampson s criteria). The safety profile of switching from TCZ-IV to TCZ-SC and vice versa was similar to those of continuous TCZ-SC or TCZ- IV treatment. (Table 1) Two deaths occurred in patients who switched from TCZ- IV to TCZ-SC (pneumonia and sepsis). No deaths occurred in patients who switched from TCZ- SC to TCZ-IV. Injection-site reactions occurred more frequently in patients receiving TCZ-SC versus patients receiving TCZ-IV (treated with placebo-sc). The overall frequency of injection-site reactions decreased over time. (Table 1) The most common injection-site reaction symptom was erythema. All injection-site reactions were grade 1 or 2 and led to withdrawal in only one patient. The higher rate in the TCZ-IV to TCZ-SC arm compared with the TCZ-SC to TCZ-SC arm can be explained by multiple injection-site reaction adverse events (AEs) in five patients. One patient (.5%) who switched from TCZ-IV to TCZ-SC had a serious infection of laryngitis (grade 3) that corresponded with a grade 4 neutropenia. There was no association between grade 3 or 4 thrombocytopenia and serious bleeding events. A similar frequency of elevated liver enzymes was observed for all treatment groups; there were no reports of clinical Hy s Law cases. (Table 2) The mean tocilizumab concentrations in patients who switched from TCZ-IV to TCZ-SC and vice versa at week 25 were comparable with those in patients who received TCZ-SC to TCZ-SC or TCZ-IV to TCZ-IV throughout the study. (Figure 2) The proportion of patients who developed anti-tcz antibodies remained low and was comparable across treatment groups through week 97. No correlation of anti-tcz antibody development to clinical response or AEs was observed. (Table 3). Among patients who developed anti-tcz antibodies, one patient in the TCZ-IV to TCZ-IV arm had a clinically significant hypersensitivity reaction that led to withdrawal, and two patients experienced injection-site reactions. The two patients who tested positive for anti-tcz IgE antibody did not experience any hypersensitivity events or injection-site reactions. Among patients who developed anti-tcz antibodies with neutralizing potential, none were withdrawn from the study due to insufficient therapeutic response or met the criteria of loss of efficacy. New Evidence in Rheumatology August

31 Figure 1. Proportion of patients achieving A) ACR response, B) remission by DAS28, and C) a decrease of.3 in HAQ-DI score over 97 Weeks (ITT population)* A 1 TCZ-SC to TCZ-SC (N = 521) TCZ-IV to TCZ-IV (N = 372) Patients who achieved an ACR response (%) ACR2 ACR5 ACR TCZ-IV to TCZ-SC (N = 186) Week 97 TCZ-SC to TCZ-IV (N = 48) Week 97 ACR2, % ACR5, % ACR7, % Weeks B 1 TCZ-SC to TCZ-SC (N = 521) TCZ-IV to TCZ-IV (N = 372) 9 Patients who achieved DAS28 <2.6 (%) TCZ-IV to TCZ-SC (N = 186) Week 97 TCZ-SC to TCZ-IV (N = 48) Week 97 DAS28 <2.6, % Week 24 Week 49 Week 97 C 1 TCZ-SC to TCZ-SC (N = 521) TCZ-IV to TCZ-IV (N = 372) Patients who achieved a decrease of.3 in HAQ-DI (%) ΔHAQ-DI from baseline.3%, % TCZ-IV to TCZ-SC (N = 186) Week 97 TCZ-SC to TCZ-IV (N = 48) Week Week 24 Week 49 Week 97 *The N s refer to completer analysis. For TCZ-SC (N = 521) and TCZ-IV (N = 372), this refers to patients who continued on TCZ-SC or TCZ-IV from baseline through the open-label period; patients who switched are not included in this population and are in the boxes beside the graphs. ACR = American College of Rheumatology; DAS28 = 28-joint disease activity score; HAQ-DI = Health Assessment Questionnaire Disability Index; IV = intravenous; SC = subcutaneous; TCZ = tocilizumab 3 New Evidence in Rheumatology August 214

32 In Supportive Care Oncology Table 1. Overview of adverse events and serious adverse events (safety population) Rate/1 PY (95% CI) [No. of events] TCZ-SC to TCZ-SC TCZ-IV to TCZ-IV TCZ-IV to TCZ-SC TCZ-SC to TCZ-IV Week 24 Week 97 Week 24 Week 97 Week 97 Week 97 N Patient-years , AEs 62.8 (574.9, 631.7) [1,747] (43.4, 428.6) [4,214] (56.8, 617.1) [1,697] 48.6 (394.8, 422.7) [3,336] (37.9, 42.1) [1,1] (233.7, 314.7) [18] SAEs 11.7 (8.1, 16.4) [34] 14.6 (12.4, 17.2) [148] (1.8, 2.1) [43] 15.4 (12.9, 18.4) [126] 19.6 (14.5, 25.8) [5] 9.1 (3.3, 19.7) [6] Infections 12.1 (17.8, 133.4) [348] 18.7 (12.3, 115.3) [1,11] (112.3, 138.4) [36] 15.6 (98.6, 112.9) [862] 97. (85.3, 19.8) [248] 84.6 (63.9, 19.9) [56] Serious Infections 3.1 (1.4, 5.9) [9] 4. (2.8, 5.4) [4] 3.5 (1.7, 6.4) [1] 3.9 (2.7, 5.5) [32] 6.7 (3.9, 1.6) [17] 1.5 (.4, 8.4) [1] Opportunistic Infections*.4 (.1, 1.9) [1].4 (.11, 1.) [4] [].2 (.3,.88) [2] 1.2 (.24, 3.43) [3] [] Malignancies 1.4 (.4, 3.5) [4].9 (.4, 1.7) [9].7 (.1, 2.5) [2].7 (.3, 1.6) [6].8 (.1, 2.8) [2] 1.5 (.4, 8.4) [1] Serious hypersensitivity events.7 (.1, 2.5) [2].5 (.2, 1.2) [5] 1. (.2, 3.) [3].2 (.3,.9) [2] [] [] Patients with injection site reactions, n (%) 58. (49.5, 67.4) [168] 26.1 (23., 29.4) [264] 32.6 (26.3, 39.9) [94] 33.6 (27.1, 41.3) [91]* 93.5 (82., 16.1) [239] Deaths [].4 (.1, 1.) [4].4 (.1, 1.9) [1].5 (.1, 1.3) [4].8 (.1, 2.8) [2] [] *Excludes tuberculosis. Up to the week 97 data cut, there was 1 case of latent tuberculosis in the TCZ-SC to TCZ-SC arm and none in the other treatment groups. In the TCZ-SC to TCZ-SC arm there was 1 case each of serious atypical pneumonia, serious bronchopulmonary aspergillosis, nonserious oropharyngeal candidiasis, and serious pharyngeal abscess. In the TCZ-IV to TCZ-IV arm, events included 1 case each of nonserious genital herpes zoster and nonserious lepromatous leprosy. The events in the TCZ-IV to TCZ- SC arm were 1 case each of nonserious genital herpes zoster, nonserious oropharyngeal candidiasis, and serious burkholderia pseudomallei infection. All malignant and unspecified tumours were included. Serious adverse events occurring during or within 24 hours of the injection/infusion, excluding injection-site reactions, and that were not deemed to be unrelated to treatment by the investigator. Injection-site reaction data were not collected in the TCZ-IV to TCZ-IV group after week 24 as no SC injections were given. AE = adverse event; CI = confidence interval; IV = intravenous; PY = patient-years; SAE = serious adverse event; SC = subcutaneous; TCZ = tocilizumab New Evidence in Rheumatology August

33 Table 2. Elevations in ALT/AST (safety population) TCZ-SC to TCZ-SC TCZ-IV to TCZ-IV TCZ-IV to TCZ-SC TCZ-SC to TCZ-IV Week 24 Week 97 Week 24 Week 97 Week 97 Week 97 N Worst elevations in ALT, n Normal ( ULN), n (%) Grade 1 (ULN to 3x ULN), n (%) Grade 2 (>3 to 5x ULN), n (%) Grade 3 (>5 to 1x ULN), n (%) 264 (42.) 326 (52.) 33 (5.2) 7 (1.2) Grade 4 (>1x ULN), n (%) Consectutive elevations of ALT 3x ULN*, n (%) Consecutive elevations sustained of ALT 3x ULN, n (%) 4 (.6) 1 (.2) 139 (26.7) 38 (59.1) 65 (12.5) 8 (1.5) 1 (.2) 8 (1.5) 3 (.6) 298 (47.) 285 (45.) 39 (6.2) 8 (1.3) 124 (33.3) 198 (53.2) 47 (12.6) 3 (.8) 7 (1.) 3 (.5) 6 (1.6) 6 (32.3) 96 (51.6) 24 (12.9) 5 (2.7) 1 (.5) 4 (2.2) 15 (31.3) 24 (5.) 7 (14.6) 2 (4.2) 1 (2.1) Worst elevation in AST, n Normal ( ULN), n (%) Grade 1 (ULN to 3x ULN), n (%) Grade 2 (>3 to 5x ULN), n (%) Grade 3 (>5 to 1x ULN), n (%) 367 (58.) 254 (4.) 8 (1.3) 1 (.2) Grade 4 (>1x ULN), n (%) 212 (4.7) 283 (54.3) 21 (4.) 4 (.8) 1 (.2) 367 (58.) 243 (39.) 9 (1.5) 5 (.8) 17 (45.7) 185 (49.7) 17 (4.6) 87 (46.8) 94 (5.5) 4 (2.2) 22 (45.8) 24 (5.) 2 (4.2) 1 (.5) *Consecutive elevations are elevations in two or more consecutive samples. Consecutive elevations sustained are elevations from time of first elevation to their last record. ALT = alanine aminotransferase; AST = aspartate aminotransferase; IV = intravenous; SC = subcutaneous; TCZ = tocilizumab; ULN = upper limit of normal Figure 2. Tocilizumab serum concentration over time 7 6 TCZ-SC to TCZ-SC (N = 521) TCZ-IV to TCZ-IV (N = 372) TCZ-IV to TCZ-SC (N = 186) TCZ-SC to TCZ-IV (N = 48) Serum TCZ concentration (µg/ml) BL Time since first dose weeks* BL = baseline; IV = intravenous; SC = subcutaneous; TCZ = tocilizumab *There was a 1-week dose interruption period (week 24 25) before the first dosing in the open-label period at week 25. Baseline was considered to be the first dose of TCZ treatment. 32 New Evidence in Rheumatology August 214

34 In Supportive Care Oncology Table 3. Immunogenicity at week 97 (safety population) n (%) Patients tested by screening assay at any time point, N TCZ-SC to TCZ-SC (N = 631) TCZ-IV to TCZ-IV (N = 631) TCZ-IV to TCZ-SC (N = 186) TCZ-SC to TCZ-IV (N = 48) 629 (99.7) 629 (99.7) 184 (98.9) 46 (95.8) Confirmation assay positive* 1 (1.6) 7 (1.1) 1 (.5) Neutralization assay positive* 8 (1.3) 6 (1.) 1 (.5) IgE assay positive 2 (.3) *Patients were seronegative at baseline. IgE = immunoglobulin E; IV = intravenous; SC = subcutaneous; TCZ = tocilizumab Key conclusions The long-term efficacy and safety of TCZ-SC was maintained and remained comparable with those of TCZ-IV, with the exception of injection-site reactions. Injection-site reactions were more commonly observed with TCZ-SC, but the rate was comparable to other SC RA treatments. The efficacy and safety profiles of patients who switched from TCZ-IV to TCZ-SC or TCZ-SC to TCZ-IV were comparable to those in patients who remained on TCZ-IV or TCZ-SC. The proportion of patients who developed anti-tcz antibodies remained low and was comparable across treatment groups. No correlation of anti-tcz antibody development to clinical response or AEs was observed. TCZ-SC could provide a more convenient administration option and an opportunity for home injection for patients with RA. Reference: 1. Burmester GR, Rubbert-Roth A, Cantagrel A, et al. The efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). EULAR Abstracts 214: FRI316. Corominas H, et al. EULAR 214:FRI317 Impact of tocilizumab on fatigue and related factors in patients with rheumatoid arthritis in daily clinical practice in Spain: ACT-AXIS study Background Fatigue is a common symptom experienced by patients with rheumatoid arthritis (RA) and it can negatively impact general health status and quality of life (QoL). 1 Interleukin (IL)-6 is one of the cytokines responsible for the inflammatory response in RA, which is also involved in the activation of the hypothalamic-pituitary adrenal (HPA) axis. Fatigue in RA patients is possibly a result of alterations in the HPA axis; this may also be true with other RA symptoms such as mood and sleep alterations, morning stiffness, appetite and libido suppression, and increased pain tolerance. IL-6 also induces anemia in patients with RA; this is one of the most frequent clinical manifestations whose improvement appears to be associated with disease activity, pain, and fatigue. The possible change in fatigue with tocilizumab treatment (an IL-6 receptor inhibitor) may be explained through its effect on disease activity and other RA-related factors. Study design The ACT-AXIS study was a 24-week prospective, observational, multicentre study in rheumatology units of 15 Spanish hospitals. Inclusion criteria were as follows: Patients 18 years of age; New Evidence in Rheumatology August

35 Study design Monthly treatment visits Assessments Tocilizumab Follow-up period: 24 weeks from the start of treatment Baseline visit Week 12 Week 24 The change from baseline was calculated by paired t-test and no multiple comparison method was used. Multiple regression analysis was used to determine the correlation between change in fatigue and disease-related factors, and the variance in fatigue outcomes relative to associated factors. Missing data were not considered in the analyses. Laboratory parameters (Hb, CRP, ESR) RA activity (TJC, SJC, DAS28) Patient s and physician s global assessment of disease activity by using VAS Morning stiffness (hours) Patients with moderate to severe RA, nonresponders or those intolerant to disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor inhibitors (TNF-Is), and those for whom the rheumatologist initiated treatment with tocilizumab based on clinical judgment and in accordance with local Summary of Products Characteristics; Patients who gave written informed consent. Exclusion criteria included: Pain (VAS) Fatigue (FACIT-F scale v4.) Depression (Beck inventory v2.) Sleepiness (Epworth scale) Personal aspects CRP = C-reactive protein; DAS28 = Disease Activity Score in 28 joints; ESR = erythrocyte sedimentation rate; FACIT-F = Functional Assessment Chronic Illness Therapy fatigue; Hb = hemoglobin; RA = rheumatoid arthritis; SJC = swollen joint count; TJC = tender joint count; VAS = visual analogue scale Patients who had initiated treatment with tocilizumab as clinical trial medication or as compassionate therapy; Absolute neutrophil count 2 x 1 9 /L at last available routine analysis; Inability to complete the study questionnaires, according to investigator s judgment. The primary objective of this study was to evaluate the correlation of fatigue change with evolution of related factors, including: Serum hemoglobin (Hb) levels, swollen joint count (SJC), morning stiffness, pain, sleepiness, and depression, as well as the following personal aspects: Marital status, children living at home, employment status, important events in life, physical activity, hours of sleep at night, and care for dependents. Secondary objectives included investigating changes over time in Hb and C-reactive protein (CRP) levels, SJC, morning stiffness duration, and pain, fatigue, sleepiness, and depression scores. Data were collected at the start of tocilizumab treatment (baseline visit) and at two routine follow-up visits closest to weeks 12 and 24. Characteristics of tocilizumab treatment and adverse events (AEs) were retrieved at routine monthly visits coinciding with tocilizumab administration. Key findings A total of 122 patients were enrolled in the study, 12 of whom were evaluable. Baseline patient characteristics and patient-reported outcomes are summarized in Table 1. Table 1. Baseline characteristics and patient-reported outcomes (n = 12) Characteristics Value Age, years, mean (SD) 52.2 (12.6) Female, n (%) 14 (86.7) Duration of RA, years, mean (SD) 9.1 (7.8) ESR, mm/h, mean (SD)* 45.9 (27.) CRP, mg/dl, mean (SD)* 12.5 (16.9) Hb, g/dl, mean (SD) 12.4 (1.4) Tender joint count, mean (SD) 8.6 (6.3) Swollen joint count, mean (SD) 5.9 (4.2) DAS28, mean (SD)* 5.6 (1.) Patient s global assessment (VAS), cm, mean (SD) 6.9 (2.1) Physician s global assessment (VAS), cm, mean (SD)* 6.1 (2.) Pain VAS, cm, mean (SD) 6.7 (2.3) Morning stiffness, hours, mean (SD) 1.3 (2.4) FACIT-F score, mean (SD) 23.7 (11.1) Epworth sleepiness score, mean (SD) 6.1 (4.5) Beck depression score, mean (SD) 18.5 (13.) *Missing data on variable: ESR, n = 5; CRP, n = 15; DAS28, n = 5; Physician s global assessment, n = 1. CRP = C-reactive protein; DAS28 = 28 joint disease activity score; ESR = erythrocyte sedimentation rate; FACIT-F = Functional Assessment Chronic Illness Therapy Fatigue; Hb = hemoglobin; RA = rheumatoid arthritis; SD = standard deviation; VAS = visual analogue scale DAS28 scores improved throughout the study, with mean ± SD values of 5.6 ± 1. at baseline, 3.1 ± 1.2 at week 12, and 2.9 ± 1.3 at week 24. The mean baseline DAS28 score decreased 2.5 ± 1.1 points after 12 weeks, and 2.7 ± 1.4 points after 24 weeks. (Figure 1) After 12 and 24 weeks of treatment with tocilizumab, a EULAR good response was achieved in 51% and 61% of patients, respectively. 34 New Evidence in Rheumatology August 214

36 In Supportive Care Oncology Figure 1. Mean change in DAS28 score Figure 2. DAS28 and fatigue evolution from baseline. Week 12 Week 24 DAS28 Fatigue (FACIT-F) Mean change in DAS28 score * -2.7* DAS Fatigue (FACIT-F) Baseline Week 12 Week DAS28 = Disease Activity Score in 28 joints *p <.1 vs. baseline DAS28 = Disease Activity Score in 28 joints; FACIT-F = Functional Assessment of Chronic Illness Therapy - Fatigue Along with DAS28, tocilizumab reduced fatigue outcomes. (Figure 2) Compared with baseline, the FACIT-F score was reduced at week 12 by a mean difference of 4.7 ± 9.3 points (p <.1) and at week 24 by 5.2 ± 1.9 points (p <.1). Statistically significant improvements from baseline to weeks 12 and 24 were observed in Hb and CRP levels, SJC, morning stiffness duration, and pain and depression scores. (Table 2) At week 12, the change in fatigue scores significantly correlated with changes in: Pain (r =.214, p =.27); Sleepiness (r =.374, p <.1); and Depression scores (r =.59, p <.1). At week 24, significant correlations were observed between change in fatigue and: SJC reduction (r =.26, p =.3); Pain (r =.239, p =.12); Sleepiness (r =.348, p <.1); and Depression scores (r =.514, p <.1). Multiple regression analysis showed that sleepiness and depression explained 35% of the variance in fatigue observed in the study. The remaining variables were not statistically significant. A total of 195 AEs were recorded in 77 (64.2%) patients. There were six serious AEs (3.6%), which were infectious arthritis, pilonidal cyst, respiratory failure, acute endocarditis, pyelonephritis acute, and respiratory tract infection. There were 48 AEs considered related to tocilizumab in 28/12 (23.3%) patients. Hypercholesterolemia and infusion reactions were the most common in 11 (9.2%) and 7 (5.8%) patients, respectively. Table 2. Mean changes in fatigue outcomes and related factors from baseline to 12 and 24 weeks Variable, mean (SEM) Week 12 p-value* Week 24 p-value* FACIT-F 4.7 (.9) < (1.) <.1 Serum Hb levels (g/dl).6 (.1) <.1.6 (.1) <.1 CRP levels (mg/l) 1.7 (1.9) < (2.1) <.1 SJC 3.7 (.5) < (.4) <.1 Morning stiffness (hours).9 (.3) <.1 1. (.2) <.1 Pain VAS (cm) 2.6 (.2) < (.3) <.1 Epworth sleepiness score.6 (.4) (.3) <.1 Beck depression score 3.6 (.9) < (1.1) <.5 *Based on paired samples t-test. No multiple comparison adjustment was made. CRP = C-reactive protein; FACIT-F = Functional Assessment Chronic Illness Therapy fatigue; Hb = hemoglobin; SEM = standard error of the mean; SJC = swollen joint count; VAS = visual analogue scale New Evidence in Rheumatology August

37 Key conclusions Tocilizumab improved fatigue outcomes in patients with moderate to severe RA. The beneficial effect of tocilizumab in fatigue may be mediated by its effect on disease activity, reflected in the reduction of DAS28 scores after 12 and 24 weeks of treatment. Tocilizumab reduced the concentration of acute-phase reactants and improved Hb levels, which could also contribute to decreasing fatigue. Patient-reported outcomes improved during the study, as shown by reductions in morning stiffness duration and pain, sleepiness, and depression scores. It is inconclusive if this is the result of improvement in fatigue. Fatigue was highly correlated with sleepiness and depression. This agrees with other studies concluding that improved depression outcomes contribute to a better sleep quality and, consequently, a lower sleepiness grade and fatigue. The safety profile of tocilizumab was consistent with previous observations, with no new safety signals. Reference: 1. Corominas H, Alegre de Miguel C, Rodríguez-Gómez M, et al. Impact of tocilizumab on fatigue and related factors in patients with rheumatoid arthritis in daily clinical practice in Spain: ACT-AXIS study. EULAR Abstracts 214: FRI317. O Mahony A, et al. EULAR 214:THU526 Biologic interactions between methotrexate and adalimumab are more extensive than those between methotrexate and tocilizumab: evidence from BioMAP profiling Background Biologics targeting proinflammatory cytokines represent a significant advance in the therapeutic management of rheumatoid arthritis (RA). 1 Biologics are commonly used with methotrexate since clinical trials have shown that the combination of a tumour necrosis factor inhibitor (TNF-I), such as adalimumab, and methotrexate is more effective than a TNF-I alone. This is based, in part, on the assumption that methotrexate reduces the immunogenicity of biologics. However, combining methotrexate with the interleukin (IL)-6 receptor inhibitor tocilizumab does not demonstrate the same level of incremental clinical benefit over tocilizumab monotherapy. Based on the known biologic effects of TNFα, IL-6, and methotrexate, the authors hypothesized that because IL-6 has more diverse effects on the immune system than TNFα, methotrexate may contribute less to efficacy when added to tocilizumab than when combined with a TNF-I. Using the BioMAP platform, the authors previously reported that tocilizumab, adalimumab, and methotrexate had distinct activities that led to unique BioMAP profiles for each individual agent. The objective of this study was to use the BioMAP systems platform to compare the profiles of drug combinations (adalimumab + methotrexate and tocilizumab + methotrexate) with the profiles of the individual agents to distinguish adjuvant effects. 36 New Evidence in Rheumatology August 214

38 In Supportive Care Oncology Study design Multiple primary human cell types Primary cell co-cultures Various stimulation conditions BioMAP profile Biology modeled Vascular inflammation Monocyte activation T cell activation Basal vascular immunity B cell activation Epithelial inflammation and remodeling BioMAP system 3C 4H LPS SAg HPNo BT BF4T BE3C Human primary cell types HuVEC HuVEC HuVEC + PBMC HuVEC + PBMC HuVEC + PBMC B cells + PBMC Epithelia + fibroblasts Epithelia Biology modeled Vascular inflammation Wound healing, matrix and tissue remodeling, fibrosis, and inflammation Macrophage activation BioMAP system CASM3C HDF3CGF HDFSAg KF3CT MyoF /Mphg Human primary cell types Smooth muscle cells Fibroblasts Fibroblasts + PBMC Fibroblasts + keratinocytes Myofibroblasts HuVEC + macrophages HuVEC = human umbilical vein endothelial cells; PBMC = peripheral blood mononuclear cells Study design BioMAP systems are primary human cell-based disease models developed for specific therapeutic areas, including inflammatory and autoimmune diseases. In each model system, human primary cell types from pooled healthy donors are stimulated, alone or in mixtures, such that multiple disease-relevant signaling pathways are simultaneously active. Compound or combination effects on the levels of a panel of protein readouts are measured by antibody-based detection methods. Compound effects on biomarker levels are expressed as a log ratio of drug (or combination) to dimethyl sulfoxide control, and significantly changed activities are identified using the 95% CI. Tocilizumab and adalimumab were profiled, alone and in combination with methotrexate, across a panel of 14 human cell-based BioMAP systems. BioMAP profiles, representing unique multisystem signatures for each drug or combination, were compared statistically to determine which activities were modulated differently between the combinations and their respective compounds. Three statistical measures of significance were used to determine differences in activities across the range of standard and soluble readouts. Hit scores were denoted 1 to 6, where 1 represented the most significantly different activities detected between profiles of combination treatment compared with profiles of individual agents and 6 represented no difference in standard and soluble readouts across the 14 BioMAP systems (i.e., highly similar plots). Potentiating effects of methotrexate on the effects of tocilizumab or adalimumab on all 725 markers were determined using statistical analysis to identify activities of the [Drug + methotrexate] > [Drug] under standard BioMAP stimulation conditions and under conditions of soluble IL-6 receptor (sil-6r)-trans-signaling. Activities enhanced >4%, >3%, or >2% were denoted potentiated hits, represented as a score of 1 versus for no enhancement >x%. New Evidence in Rheumatology August

39 Key findings Methotrexate alone The overlay of the methotrexate profile generated in this study and the methotrexate profile from the BioMAP database were largely similar, including antiproliferative effects on human endothelial cells, T cells, and fibroblasts. The BioMAP profile for methotrexate showed selective activity in the B cell and peripheral blood mononuclear cell (PBMC) system, with strong inhibition of secreted immunoglobulin G production. Tocilizumab with and without methotrexate Tocilizumab was profiled both alone and in combination with methotrexate, as well as in the presence and absence of sil-6r. The overlay of profiles for tocilizumab alone, methotrexate alone, and the combination of the two showed that only a limited number of standard readouts were modulated differently by the combination compared with the individual agents. Only vascular cell adhesion molecule (VCAM) in the endothelial cell and PBMC system, and macrophage colony-stimulating factor (M-CSF) in the fibroblast and PBMC system were differentially modulated by tocilizumab alone compared with tocilizumab + methotrexate. Only one readout (M-CSF in the fibroblast and PBMC system) was statistically different (p <.1, unpaired t-test) between the combination and the individual agents in a sil-6r-trans-signaling environment. Statistically, eight of 18 hits differentiated tocilizumab + methotrexate from tocilizumab alone, whereas 15 of 18 hits differentiated tocilizumab + methotrexate from methotrexate alone. Only 1 of 16 hits differentiated tocilizumab + methotrexate + sil-6r from tocilizumab + sil-6r, whereas 15 of 16 hits differentiated tocilizumab + methotrexate + sil-6r from methotrexate + sil-6r. In summary, methotrexate did not impact the selective actions of tocilizumab in the BioMAP systems, especially in the context of sil-6r-trans-signaling. Adalimumab with and without methotrexate Adalimumab was profiled both alone and in combination with methotrexate, as well as in the presence and absence of sil-6r. Overlay of the profiles showed that a markedly greater number of standard readouts were impacted in a significantly different manner by the combination compared to the individual agents. Several activities in the endothelial cell and PBMC system modeling T-cell activation responses were modulated differently by adalimumab alone compared with adalimumab + methotrexate. Under sil-6r-trans-signaling conditions, several readouts were modulated differently by adalimumab + methotrexate + sil-6r compared with adalimumab + sil-6r and methotrexate + sil-6r profiled individually. Statistically, nine of 29 hits differentiated adalimumab + methotrexate from adalimumab alone, whereas 15 of 29 hits differentiated adalimumab + methotrexate from methotrexate alone. Sixteen of 26 hits differentiated adalimumab + methotrexate + sil-6r from adalimumab + sil-6r, whereas 19 of 26 hits differentiated adalimumab + methotrexate + sil-6r from methotrexate + sil-6r. In summary, methotrexate impacted the actions of adalimumab to a greater extent than was observed with tocilizumab in the BioMAP systems. Antiproliferative effects Methotrexate contributed antiproliferative effects to the phenotypic signature of both tocilizumab and adalimumab in BioMAP systems modeling T-helper 1 (Th1) type vascular inflammation and wound healing/tissue remodeling biology, but enhanced activities when used in combination with adalimumab. In addition to the antiproliferative effects, adalimumab + methotrexate enhanced the inhibition of the following proteins outside the historical vehicle control envelope: VCAM-1 and urokinase plasminogen activator receptor in the system modeling Th1 type vascular inflammation; and IL-8 and M-CSF in the system modeling wound healing/ tissue remodeling biology. In contrast, no additional activities outside the envelope were detected with tocilizumab + methotrexate, consistent with the observations that tocilizumab and methotrexate have more overlapping effects and do not elicit further activities beyond antiproliferative effects compared with tocilizumab or methotrexate alone. Comparison of tocilizumab and adalimumab, both in combination with methotrexate A greater number of potentiated hits were consistently observed with adalimumab + methotrexate than with tocilizumab + methotrexate relative to the effects of the drugs alone. (Table 1) At the 4% threshold, methotrexate did not enhance any tocilizumab activities under standard or sil-6r stimulation conditions, whereas methotrexate enhanced the effects on adalimumab on three and four readouts under the same conditions. At >2% potentiation threshold, methotrexate enhanced the effects of adalimumab on nine and six readouts under both standard and sil-6r mediated stimulation conditions compared with two and three tocilizumab activities enhanced by methotrexate under the same conditions. 38 New Evidence in Rheumatology August 214

40 In Supportive Care Oncology Table 1. Summary of potentiated hits Potentiation hit criteria: score >x% plus modulation in the same direction 4H: xip-1 BF4T: xip-1 BF4T: xvegf BT: xgro BT: xil-17 BT: xil-5 BT: xip-1 CASMC: xegf F3CGF: xvegf FPSAg: Collagen I FPSAg: xgm-csf FPSAg: xil-1 FPSAg: xmip-1β KF3CT: xmip-1α SAg: xg-csf SAg: xil-1β SAg: xil-6 Comparsion [Drug + MTX] vs. [Drug] Hits >4% TCZ + MTX TCZ TCZ + MTX + sil-6rα TCZ + sil-6rα ADA + MTX ADA ADA + MTX + sil-6rα ADA + sil-6rα Hits >3% TCZ + MTX TCZ 1 1 TCZ + MTX + sil-6rα TCZ + sil-6rα 1 1 ADA + MTX ADA ADA + MTX + sil-6rα ADA + sil-6rα Hits >2% TCZ + MTX TCZ TCZ + MTX + sil-6rα TCZ + sil-6rα ADA + MTX ADA ADA + MTX + sil-6rα ADA + sil-6rα ADA = adalimumab; EGF = epidermal growth factor; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte macrophage colony-stimulating factor; GRO = chemokine (C-X-C motif) ligand-1; IL = interleukin; IP = interferon gamma-induced protein; MIP = macrophage inflammatory protein; MTX = methotrexate; sil-6r = soluble interleukin-6 receptor; TCZ = tocilizumab; VEGF = vascular endothelial growth factor Figure 1. Summary model Fibroblast Monocyte Macrophage T & B cells Vascular cells Fibroblast Monocyte Macrophage T & B cells Vascular cells ADA = adalimumab; MTX = methotrexate; TCZ = tocilizumab New Evidence in Rheumatology August

41 Key conclusions Tocilizumab, adalimumab, and methotrexate work by markedly different mechanisms, consistent with their distinct and nonoverlapping BioMAP profiles. These results mirror the clinical finding that methotrexate in combination with the TNF-I adalimumab has more additive biologic effects than the combination of methotrexate and tocilizumab compared with either agent alone. (Figure 1) The reported efficacy of adalimumab in combination with methotrexate may reflect an overall gain of effects related to their different modes of action and enhanced effects on shared pathways/mechanisms. In contrast, the reported relatively enhanced efficacy of tocilizumab monotherapy may reflect a broader effect on the immune response, and tocilizumab + methotrexate elicits few additional activities other than antiproliferative effects compared with tocilizumab alone. Hence, though tocilizumab activities in BioMAP are distinct, they seem to cover many of the activities of methotrexate. Reference: 1. O Mahony A, Berg EL, John M, et al. Biologic interactions between methotrexate and adalimumab are more extensive than those between methotrexate and tocilizumab: evidence from BioMAP profiling. EULAR Abstracts 214: THU526. Huizinga TWJ, et al. EULAR 214:SAT255 Clinical and radiographic outcomes at two years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study Background International task force recommendations state that treatment of patients with rheumatoid arthritis (RA) should aim to reach a target of low disease activity in as short a time as possible. 1 However, once remission is achieved, there are limited guidelines on when/ if patients should discontinue biologic treatment. Initial data suggest that patients who have achieved and maintained remission may be able to discontinue treatment. The ACT-RAY study compared an add-on strategy (tocilizumab plus methotrexate) with a switch strategy (tocilizumab plus placebo) in patients with an inadequate response to methotrexate. The 24- and 52-week data have been previously reported, demonstrating relevant clinical and radiographic benefit without clinically meaningful between-arm differences for most endpoints. During years two and three, the study included a step-down strategy with the goal of achieving drug-free remission. After the first year, the objectives of ACT-RAY were: To further assess the safety and efficacy of tocilizumabbased treatment strategies; To evaluate the treat-to-target approach; and To assess the course of disease activity in patients who discontinued tocilizumab due to sustained remission. Study design ACT-RAY was a multicentre, randomized (1:1), double-blind, placebo-controlled, parallel-group, phase IIIb clinical trial. During the first 24 weeks, all patients received open-label tocilizumab 8 mg/kg intravenously every 4 weeks and were randomized to either continue oral methotrexate (Add-on strategy) or switch to tocilizumab alone with placebo (Switch strategy). Between weeks 24 and 52, treatment with tocilizumab plus blinded methotrexate or placebo continued unchanged. At week 24, if 28-joint disease activity score (DAS28) was >3.2, an open-label conventional disease-modifying antirheumatic drug (DMARD) was added at the investigator s discretion. After week 24, if DAS28 3.2, corticosteroid dose could be reduced stepwise by 2.5 mg/day at any visit; however, the dose could not be reduced to <5 mg/day during the first year. 4 New Evidence in Rheumatology August 214

42 In Supportive Care Oncology At week 36, if DAS28 was >3.2 with an added DMARD, the patient received tocilizumab 8 mg/kg every four weeks plus blinded methotrexate or placebo, plus optionally a third added DMARD. Between weeks 52 and 14, open-label treatment was adapted based on response assessment every 12 weeks. Patients continued the study in one of four treat-to-target strategies: Treatment tapering: If DAS28 was <2.6 at two consecutive assessment visits 12 weeks apart and continuously in between, tocilizumab was discontinued at the second assessment visit (tocilizumab-free remission). If DAS28 was <2.6 continuously over two consecutive assessment visits (six months) after discontinuation of tocilizumab, for patients on an open-label DMARD, the added DMARD was stopped; for patients without added DMARDs, the blinded oral treatment was stopped, and drug-free remission was achieved. For patients with an added DMARD, drug-free remission could be achieved after an additional two assessment visits (six months) with DAS28 <2.6. In patients who experienced flare, the last effective treatment or tocilizumab in combination with blinded oral treatment was restarted. Continued treatment: If DAS28 was 2.6 and 3.2, treatment was continued as before. Treatment intensification: If DAS28 was >3.2, an open-label DMARD was added if the patients had not yet received an open-label DMARD. If the patient received an open-label DMARD at the previous assessment visit, treatment was continued unchanged. Maintenance: If DAS28 was >3.2 and an open-label DMARD was added at two consecutive visits, the patient switched to tocilizumab 8 mg/kg every four weeks plus blinded methotrexate or placebo, plus the added DMARD. An additional (third) DMARD may have been added at the discretion of the investigator. For patients who stopped tocilizumab due to sustained remission before week 1, the study continued for 52 weeks after tocilizumab discontinuation; all other patients completed treatment at week 1. Patients returned four weeks after completion of the treatment for a safety follow-up visit. The main inclusion criteria were: Adults with moderate to severe, active RA experiencing an inadequate response to previous methotrexate therapy; Study design Oral MTX was blinded throughout the whole 3-year study. TCZ and the added DMARD were open label. Week 52 TCZ + MTX TCZ + MTX Added DMARD TCZ + PBO TCZ + PBO Added DMARD Sustained remission (DAS28 <2.6 at two consecutive visits 12 weeks apart) YES NO Progressive study drug discontinuation: First TCZ Sustained remission: DMARDs if present Sustained remission: MTX/PBO Drug-free remission Flare (at discretion of investigator): Restart last effective treatment or TCZ in combination with blinded oral treatment Treat-to-target Includes treat-to-target and study-drug discontinuation goals DAS28 = 28-joint disease activity score; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PBO = placebo; TCZ = tocilizumab New Evidence in Rheumatology August

43 Confirmed RA diagnosis according to the 1987 American College of Rheumatology (ACR) criteria; DAS28-ESR (erythrocyte sedimentation rate) >4.4 at baseline; Radiologic evidence of at least one joint with definite erosion; Currently receiving methotrexate for at least 12 weeks and a stable dose of methotrexate of 15 mg/week for at least six weeks prior to treatment; If the patient was receiving oral steroids, dose had to be stable and not higher than prednisone (or equivalent) 1 mg/day. The main exclusion criteria were: Prior use of DMARDs other than methotrexate one month (three months for leflunomide) before the baseline visit; Prior use of any biologics used for treating RA. The primary efficacy endpoint was the rate of DAS28 remission at week 24. Secondary endpoints included: Time to tocilizumab-free remission and time to flare after tocilizumab-free remission; Change from baseline in DAS28 and Clinical Disease Activity Index (CDAI) at each scheduled visit; Radiographic progression of joint destruction based on the Genant-modified Sharp score (GSS) at weeks 24, 52, and 14, as well as absolute change from baseline in total GSS. Adverse events (AEs) and laboratory values were monitored at each visit. Efficacy analyses were performed in the intent-to-treat (ITT) population (all randomized patients who received at least one administration of study medication), with nonresponder imputation of missing data used for binary response variables, such as DAS28 remission or ACR response. The Kaplan-Meier method was used to assess time to tocilizumab-free remission and time to flare after tocilizumab remission in years two and three. The safety analysis population included all patients who received at least one dose of study medication and had at least one postbaseline safety assessment. Key findings The ITT/safety population was composed of 277 subjects in the Add-on cohort and 276 patients in the Switch cohort (total N = 553). In the Add-on cohort, 222 subjects completed week 14, and 52 subjects extended beyond week 14; the numbers of subjects in the Switch group were 21 and 48, respectively. Baseline patient demographics and clinical characteristics were well balanced between the two groups. A total of 472 patients were potentially eligible to discontinue tocilizumab on or after week 52. Tocilizumab-free remission was achieved in 53.1% (129/243) of patients in the Add-on group, and in 47.6% (19/229) of patients in the Switch group. The median time to tocilizumab-free remission was 645 days for the Add-on group and 786 days for the Switch group. (Figure 1A) Figure 1A. Kaplan-Meier plot of time to tocilizumab-free remission A 1. Add-on Switch.9.8 Probability of TCZ-free remission n at risk Study day Add-on Switch Median = 645 days Median = 786 days TCZ = tocilizumab 42 New Evidence in Rheumatology August 214

44 In Supportive Care Oncology Within 52 weeks after achieving tocilizumab-free remission, 82.5% of patients in the Add-on group and 88.5% of patients in the Switch group experienced disease flare. The median time to flare following tocilizumab-free remission was 113 days for the Add-on group and 84 days for the Switch group. (Figure 1B) A total of 8.6% (21/243) of patients in the Add-on arm and 3.1% (7/229) of patients in the Switch arm achieved total drug-free remission (subsequent discontinuation of tocilizumab, then open-label DMARD and blinded oral treatment due to continuous achievement of DAS28 <2.6). Restarting tocilizumab treatment after flare resulted in rapid improvements in DAS28. (Figure 2) Figure 1B. Kaplan-Meier plot of time to flare after tocilizumab-free remission B Probability of no flare after TCZ-free remission Median = 84 days Median = 113 days Add-on Switch n at risk Time after TCZ-free remission (days) Add-on Switch TCZ = tocilizumab Figure 2. Mean DAS28 at and six visits after flare for patients who restarted TCZ 5. Overall Add-on Switch 4.5 Mean DAS DAS28 = DAS28 at TCZ-free remission = At flare Weeks (after flare) n = TCZ = tocilizumab Flare defined at the investigator s discretion; at flare means DAS28 evaluated on day of flare or within two weeks before flare. No imputation used for test parameters. New Evidence in Rheumatology August

45 Of the patients who flared and had a DAS28 assessment, 94.5% restarted tocilizumab. DAS28 and CDAI continued to improve until approximately week 52 and then plateaued to week 14. (Figure 3) Radiographic progression was minimal in both arms. (Figure 4) The overall safety profile was consistent with previous findings and similar for both treatment groups. (Table 1) There were 1 deaths in the study, including four in the Addon group and six in the Switch group. One death by meningitis in the Switch group was considered possibly related to methotrexate/placebo or tocilizumab treatment; AEs that led to death in all other cases were considered unrelated to methotrexate/placebo or tocilizumab. Figure 3. Mean change in A) DAS28 and B) CDAI A Add-on (N = 277) Switch (N = 276) Weeks BL Mean change from BL in DAS Parallel-arm mono vs. combo phase Treat-to-target OL DMARD step-up phase Treat-to-target and treatment step-down phase Week 14 p =.934* *p-value is from a two-sided Wilcoxon rank-sum test of no difference between the two treatment groups in change from baseline. BL = baseline; DAS28 = Disease Activity Score in 28 joints; DMARD = disease-modifying antirheumatic drug; OL = open label B Add-on (N = 277) Switch (N = 276) Weeks BL Parallel-arm mono vs. combo phase Mean change from BL in CDAI Treat-to-target OL DMARD step-up phase Treat-to-target and treatment step-down phase Week 14 p =.5* *p-value is from a two-sided Wilcoxon rank-sum test of no difference between the two treatment groups in change from baseline BL = baseline; CDAI = Clinical Disease Activity Index; DMARD = disease-modifying antirheumatic drug; OL = open label 44 New Evidence in Rheumatology August 214

46 In Supportive Care Oncology Figure 4. Radiographic results A Add-on (N = 215) Switch (N = 22) Change in GSS from BL to week SDC = 2.1 BL Cumulative probability (%) *BL = baseline; GSS = Genant-modified Sharp score; SDC = smallest detectable change B Add-on (N = 215) Switch (N = 22) Adjusted mean change from BL In total GSS Switch 9.9 Calculated mean baseline biannualized progression rate* 9. Add-on p =.34 Patients with no progression at week 14 (%) No progression = ΔGSS 2.1 (SDC) p =.98. Week 14 Week 14 *Baseline biannualized progression rate = [(GSS/RA duration) x 2]. p-value is the difference in adjusted means from the analysis of covariance. p-value is from a Cochran-Mantel-Haenszel chi-square test, with strata defined by region and baseline DAS28 ( 5.5 and >5.5). BL = baseline; DAS28 = Disease Activity Score in 28 joints; GSS = Genant-modified Sharp score; SDC = smallest detectable change A higher proportion of patients in the Add-on group had liver enzyme elevations compared with patients in the Switch group (Add-on vs. Switch): Alanine aminotransferase (ALT) elevations (% [n]): Number of patients with normal levels at baseline: 244 vs. 242; > upper limit of normal (ULN) to 1.5x ULN: 27.5 (67) vs (59); >1.5x ULN to 3x ULN: 3.3 (74) vs (42); >3x ULN to 5x ULN: 1.2 (25) vs. 4.1 (1); >5x ULN: 4.1 (1) vs. 1.2 (3). Aspartate aminotransferase (AST) elevations (% [n]): Number of patients with normal levels at baseline: 257 vs. 249 >ULN to 1.5x ULN: 32.6 (84) vs (55); >1.5x ULN to 3x ULN: 2.2 (52) vs. 7.6 (19); >3x ULN to 5x ULN: 3.9 (1) vs. 1.6 (4); >5 ULN: 1.2 (3) vs..4 (1). ULN was defined as 55 U/L for ALT and 4 U/L for AST. New Evidence in Rheumatology August

47 Table 1. Adverse events Add-on (N = 277) Switch (N = 276) Total TCZ exposure, PY AEs Total patients with 1 AE, % (n) 89.5 (248) 88.4 (244) Total no. of AEs 1,762 1,558 Rate of AEs (95% CI), per 1 PY ( ) 32.5 ( ) 1 AE leading to discontinuation, % (n) 1.1 (28) 11.2 (31) SAEs Total patients with 1 SAE, % (n) 17.7 (49) 17.4 (48) Total no. of SAEs Rate of SAEs (95% CI), per 1 PY 12.2 ( ) 15. ( ) SIs Total patients with 1 SI, % (n) 6.9 (19) 4.7 (13) Total no. of SIs Rate of SIs (95% CI), per 1 PY 4.4 ( ) 3.7 ( ) Total no. of deaths 4 6 AEs = adverse events; CI = confidence interval; no. = number; PY = patient years; SAEs = serious adverse events; SIs = serious infections; TCZ = tocilizumab Key conclusions The clinical efficacy and inhibition of structural damage progression and comparable safety shown in both the Add-on and Switch groups through weeks 24 and 52 of ACT-RAY were maintained through years two and three. Efficacy parameters were generally comparable between the two treatment arms, with some trends in favour of patients originally randomized to add-on treatment. The interpretation needs to take the multiple treatment adaptations (including tocilizumab discontinuation) into account. Year two and three results suggest that treat-to-target strategies could be successfully utilized in patients with an inadequate response to methotrexate (whether currently on methotrexate or not) to achieve sustained remission, while a subsequent step-down approach enabled some patients to reach biologic-free or all-study-drug free remission. The treatment step-down approach in patients who achieved sustained remission was associated with a high flare risk. Patients in both groups who restarted tocilizumab therapy after a flare achieved rapid improvements in DAS28. Safety outcomes were consistent with previous findings and similar between both groups at week 14. Patients in the Add-on group exhibited numerically greater marked abnormal changes for elevated transaminases than patients in the Switch group. Reference: 1. Huizinga TWJ, Conaghan PG, Martin-Mola E, et al. Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. EULAR Abstracts 214: SAT New Evidence in Rheumatology August 214

48 In Supportive Care Oncology Registry Data in Rheumatoid Arthritis Registry Studies Confirm the Efficacy of Tocilizumab and Rituximab in the Treatment of Rheumatoid Arthritis The efficacy and safety of the biologics tocilizumab and rituximab in the treatment of rheumatoid arthritis (RA) have been well established in clinical trials. 1 3 The focus of research on these drugs is now shifting from clinical trials to observational registry studies, which investigate the effectiveness of tocilizumab and rituximab in real-world populations of patients with RA. At the 214 Congress of the European League Against Rheumatism (EULAR), investigators demonstrated the real-world efficacy of tocilizumab and rituximab in the treatment of RA with multiple registry studies. This article reports on four presentations that were delivered at EULAR 214: A report of the noninterventional ICHIBAN study, which evaluated the efficacy and safety of tocilizumab in German patients with RA in clinical practice, found that tocilizumab treatment resulted in durable improvements in activity parameters and reduction of concomitant conventional synthetic disease-modifying antirheumatic drug (csdmard) and glucocorticoid use. The TOCERRA collaboration collected longitudinal tocilizumab retention data from nine registries in Europe, and found that retention of tocilizumab was comparable whether treatment was initiated as monotherapy or as combination therapy. An analysis of the Yokohama City University Rheumatic Disease Study Group registry compared clinical responses of tocilizumab in second-line therapy with a subsequent tumour necrosis factor inhibitor (TNF-I) after treatment failure with a TNF-I in first-line therapy, and found that tocilizumab was more effective than a subsequent TNF-I. A study of patients within the CORRONA registry evaluated prednisone use among patients who received rituximab after failure of a TNF-I compared with patients who were treated with a subsequent TNF-I, and found that prednisone use was comparable between the two groups. References: 1. Volkmann E, Agrawal H, Maranian P, et al. Rituximab for rheumatoid arthritis: a meta-analysis and systematic review. Clin Med Insights Ther 21;2: van Vollenhoven RF, Emery P, Bingham III CO, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 213;72: Genovese MC, Rubbert-Roth A, Smolen JS, et al. Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure. J Rheumatol 213;4: New Evidence in Rheumatology August

49 Specker C, et al. EULAR 214:FRI32 Tocilizumab, DMARDs, and glucocorticoids in rheumatoid arthritis interim analysis of the German noninterventional study ICHIBAN Background The ICHIBAN study is a single-armed, noninterventional study that evaluates the efficacy and safety of tocilizumab in patients with rheumatoid arthritis (RA) in Germany. 1 Since February 21, approximately 25 study centres have prospectively collected clinical data on RA patients, their concomitant therapies, comorbidities, therapeutic responses, patient reported outcomes, and adverse events (AEs). Patients were observed for a maximum period of two years (14 weeks), and patient recruitment ended in June 214. The objective of this report was to describe the distribution of the following parameters in daily practice during two years of tocilizumab treatment: Distribution of comedications (conventional synthetic disease-modifying antirheumatic drugs [csdmards] and glucocorticoids [GCs]); Changes in this distribution during treatment; and The efficacy in corresponding subgroups. Study design The present interim analysis included patients with completed baseline data before December 1, 213 (N = 2,373); 589 patients completed the maximal 14-week observation period. For efficacy analyses at week 14, all documented visits under tocilizumab therapy were taken into account if patients had valid data at baseline and week 14. In the case of treatment discontinuation, the last observed value was carried forward (LOCF method). Key findings As of December 1, 213, baseline data for 2,373 patients were available: Sex, male/female, %: 24.1/75.9; Mean age ± SD, years: 56.4 ± 13.3; Median duration of RA, years: 7.4; Biologics-naïve prior to treatment, % (n): 25.9 (614); Tumour necrosis factor inhibitor (TNF-I) pretreatment, % (n): 71.5 (1,696). Of the 589 patients who had completed 14 weeks of observation (W14 population), 73.9% were pretreated with TNF-Is and 24.6% were pretreated exclusively with csdmards. The total tocilizumab exposure was 4,84.8 patient-years. Subgroup analyses included patients discontinuing csdmards during observation or being continuously treated with or without csdmards. GC comedication was analysed analogously. Long-term Efficacy The long-term efficacy of tocilizumab for the W14 population is summarized in Table 1. Treatment Duration The mean tocilizumab treatment duration was 91 weeks. During the observation period, 7.7% of patients have been continuously treated with tocilizumab. (Figure 1) Among the 14 patients who discontinued treatment (29.1%), the main reasons for discontinuation were as follows, % (n): Tolerability: 5. (24); Inadequate response: 14.3 (69); Lab parameters worsened: 2.3 (11); Disease progression:.6 (3); Disease remission: 1. (5); Weight increase:.2 (1); Surgical intervention: 2.1 (1); Infection: 2.1 (1); Death of patient: 1.5 (7). At the end of observation, 46.5% of patients achieved DAS28-ESR remission (<2.6), and 27.5% and 53.8% of patients achieved a moderate or good EULAR response, respectively. During the observation period, the proportion of patients receiving tocilizumab monotherapy increased from 42.8% to 63.8%, while the proportion of patients on methotrexate combinations decreased by 14.6%. In 23.9% of patients initially being treated with csdmard combination therapy, DMARDs could be discontinued. 48 New Evidence in Rheumatology August 214

50 In Supportive Care Oncology Table 1. Long-term efficacy of tocilizumab over two years W14 csdmard Discont.* TCZ Combi. TCZ Mono. GC Discont.* Continuous GC Continuous No GC DAS28-ESR Mean ± SD <2.6, % (n) 3.2, % (n) N BL W14 W14 W ± ± (213) 59.4 (272) ± ± (44) 54.1 (59) ± ± (75) 59. (92) ± ± (9) 63. (116) ± ± (49) 63.4 (59) ± ± (12) 56.6 (159) ± ± (35) 66.1 (41) CDAI Mean ± SD 2.8, % (n) <1, % (n) N BL W14 W14 W ± ± (81) 54.5 (229) ± ± (13) 46.4 (45) ± ± (33) 6.1 (82) ± ± (32) 59. (98) ± ± (27) 62.2 (51) ± ± (41) 5.9 (14) ± ± (11) 64.6 (31) TJC Mean ± SD N BL W ± ± ± ± ± ± ± ± ± ± ± ± ± ± 4.9 SJC Mean ± SD N BL W ± ± ± ± ± ± ± ± ± ± ± ± ± ± 3.6 FFbH Mean ± SD Improvement 1%, % (n) N BL W14 W ± ± (152) ± ± (26) ± ± (53) ± ± (72) ± ± (41) ± ± (88) ± ± (17) HAQ Mean ± SD Improvement.3, % (n) N BL W14 W ± ± (184) ± ± (37) ±.7 1. ± (62) ± ± (8) ±.8 1. ± (47) ± ± (17) ±.5.8 ± (23) *Patients discontinuing csdmards/gcs. Patients being continuously treated with csdmards/gcs during observation. Patients being continuously treated without csdmards/gcs. In case of treatment discontinuation, the LOCF method was used. Only patients with values at baseline and week 14 (or LOCF) are shown. BL = baseline; CDAI = clinical disease activity index; combi. = combination; csdmard = conventional synthetic disease-modifying antirheumatic drug; DAS28 = 28-joint disease activity score; discont. = discontinuous; ESR = erythrocyte sedimentation rate; EULAR = European League Against Rheumatism; FFbH = Funktionsfragebogen Hannover; GC = glucocorticoid; HAQ = Health Assessment Questionnaire; LOCF = last observed value was carried forward; mono. = monotherapy; SD = standard deviation; SJC = swollen joint count; TCZ = tocilizumab; TJC = tender joint count; W14 = Week 14 Figure 1. Patients under tocilizumab therapy during the observation period 1 8 Patients (%) Total TCZ monotherapy TCZ combination therapy Week n (Total)* *Without patients who discontinued therapy due to patients request, withdrawing informed consent, lost-to-follow-up, or undefined other reasons. Missing data in one case. TCZ = tocilizumab New Evidence in Rheumatology August

51 Tocilizumab monotherapy and combination therapies showed comparable efficacy: 19.3% and 22.% achieved CDAI remission ( 2.8), respectively. Clear improvement of all disease activity scores was observed. (Figure 2 and 3) After weeks, >6% of patients had reached a low disease activity state (DAS28-ESR <3.2). The response velocity and duration was comparable between the tocilizumab monotherapy and combination therapy groups. (Figure 3) The early, strong response to tocilizumab treatment allowed for substantial reduction of GC doses within the first nine months of treatment. No difference was observed between the tocilizumab monotherapy and combination therapy groups. (Figure 3) Figure 2. DAS28-ESR response after two years: tocilizumab monotherapy vs. combination therapy 8 Low disease activity (DAS28 3.2) Remission (DAS28 <2.6) Patients (%) csdmard discontinued (n = 19*) TCZ combination (n = 156*) TCZ monotherapy (n = 184*) Total (n = 458*) *Only patients with DAS28-ESR values at baseline and week 14 (or LOCF). csdmard = conventional synthetic disease-modifying antirheumatic drug; DAS28 = 28-joint disease activity score; ESR = erythrocyte sedimentation rate; LOCF = last observed value was carried forward; TCZ = tocilizumab Figure 3. DAS28-ESR response and GC dose reduction: tocilizumab monotherapy vs. combination therapy 8 12 Patients (%) GC dose (mg/d) 2 TCZ monotherapy TCZ combination therapy DAS DAS28 <2.6 GC dose Week DAS28 = 28-joint disease activity score; ESR = erythrocyte sedimentation rate; GC = glucocorticoid; TCZ = tocilizumab 5 New Evidence in Rheumatology August 214

52 In Supportive Care Oncology During the observation period, the mean daily GC dose decreased continuously from 9.4 to 5.3 mg/d. (Figure 3) Reduction of GC The proportion of patients not needing concomitant GCs increased from 11.4% to 29.% during observation, and the proportion of daily GC doses <5 mg increased from 59.7% to 76.5%. (Figure 4) During the observation period the mean daily GC dose decreased continuously from 9.4 mg/d at baseline to 5.3 mg/d at week 14. The early strong response to tocilizumab treatment allows for substantial reduction of GCs within the first nine months. No difference was observed between the tocilizumab monotherapy and combination therapy groups. In 19.2% of patients receiving GCs at baseline, GCs could be discontinued; In 52.7% of patients, GCs could be reduced; Only 1.% of patients required a GC dose increase. Tocilizumab patients continuously treated with or without GCs experienced similar DAS28-ESR responses. (Figure 5) Figure 4. Reduction of glucocorticoids during tocilizumab treatment 5 4 Patients (%) Week 14* No GC 14* 14* 14* GC > 5 mg/d GC >5 1 mg/d GC 1 mg/d *In case of treatment discontinuation the last observation was carried forward. GC = glucocorticoid; TCZ = tocilizumab Figure 5. DAS28-ESR response with tocilizumab with or without glucocorticoids 8 Low disease activity (DAS28 3.2) Remission (DAS28 <2.6) Patients (%) GC discontinued (n = 93*) continuously GC (n = 281*) continuously no GC (n = 62*) Total (n = 458*) *Only patients with DAS28-ESR values at baseline and week 14 (or LOCF). DAS28 = 28-joint disease activity score; ESR = erythrocyte sedimentation rate; GC = glucocorticoid; LOCF = last observed value was carried forward; TCZ = tocilizumab New Evidence in Rheumatology August

53 Key conclusions The results of the interim analysis of the ICHIBAN study showed clear improvements of all activity parameters with tocilizumab treatment, and a reduction of concomitant csdmard and GC use. As in controlled studies, tocilizumab monotherapy was equally effective compared to combination with csdmards in real-life conditions. This enduring efficacy was demonstrated over a long period of two years in clinical practice data. Reference: 1. Specker C, Kaufmann J, Vollmer MA, et al. Tocilizumab, DMARDs and glucocorticoids in rheumatoid arthritis interim analysis of the German non-interventional study ICHIBAN. EULAR Abstracts 214: FRI32. Gabay C, et al. EULAR 214:SAT36 Retention of tocilizumab therapy: a comparison between tocilizumab in monotherapy and in combination with DMARDs based on the TOCERRA collaboration Background Clinical trials have shown that tocilizumab is efficacious as monotherapy and in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs). 1 However, longitudinal tocilizumab retention data from large registry populations have been missing from the literature. The objective of this study was to examine the retention of tocilizumab administered alone or in combination with DMARDs in patients with rheumatoid arthritis (RA) included in the TOcilizumab Collaboration of European Registries in RA (TOCERRA) collaboration. Study design A total of 1,81 eligible treatment courses were retrieved from nine registries by the end of 213 or beginning of 214. Registries were from the following countries: Czech Republic, Denmark, Finland, Netherlands, Norway, Portugal, Slovenia, Sweden, and Switzerland. Patients with RA who were treated with tocilizumab since 29, who had a valid baseline visit, and who had not been immediately lost to follow-up were included in the analysis. Patients were considered as taking tocilizumab in monotherapy or in combination with DMARDs based on their baseline DMARD co-therapy. Time on tocilizumab was defined by the time between tocilizumab start and discontinuation, with censoring occurring at the date of last visit on tocilizumab. Unadjusted median tocilizumab retention with 95% CIs were estimated for monotherapy and combination therapy. The hazard for tocilizumab discontinuation was modeled using a country-stratified, covariateadjusted Cox proportional hazards model, applied to patients with complete baseline covariate information for the following: Sex; Age; Disease duration; Number of prior biologics; Corticosteroid use; Seropositivity (rheumatoid factor or anti-cyclic citrullinated peptide); 28-joint disease activity score (DAS28); Health Assessment Questionnaire (HAQ); Year of tocilizumab treatment initiation; and Therapy. 52 New Evidence in Rheumatology August 214

54 In Supportive Care Oncology Reported p values of baseline covariates were from Kruskal- Wallis tests for continuous or discrete covariates, or Fisher s exact tests for categorical covariates. Key findings Of the 1,81 eligible treatment courses, 52 courses (28%) were started as monotherapy and 1,38 courses were started as combination therapy. For 79% of treatment courses, DMARD co-therapy was stable over time. Tocilizumab was discontinued in 77 treatment courses (39%), of which 21 were monotherapy. The main causes of discontinuation were: Lack of effectiveness (49% and 52% for monotherapy and combination therapy, respectively); and Safety issues (32% and 28%, respectively). The unadjusted median tocilizumab retention time was 2.3 years (95% CI: ) for monotherapy and 3.7 years (95% CI: 2.9 NA) for combination therapy (p =.3, log-rank test). Baseline covariate values were as follows (total vs. monotherapy vs. combination therapy): Median age in years (interquartile range [IQR]): 57 (47 64) vs. 59 (48 67) vs. 56 (46 63), p <.1; Female, %: 79 vs. 83 vs. 78, p =.2; Median disease duration in years (IQR): 9.4 ( ) vs. 1.2 ( ) vs. 9.1 ( ), p =.1; Seropositivity, %: 81 vs. 84 vs. 8, p =.7; Number of prior biologics, % (p =.26): : 16 vs. 18 vs. 16; 1: 26 vs. 24 vs. 26; 2: 58 vs. 58 vs. 58; Corticosteroid use, %: 5 vs. 39 vs. 53, p <.1; Median DAS28 (IQR): 5. ( ) vs. 4.9 ( ) vs. 5. ( ), p =.27; Median HAQ (IQR): 1.5 (1. 2.) vs. 1.5 (1. 2.) vs. 1.5 (.9 2.), p =.11; Year of tocilizumab initiation, % (p =.5): 29: 16 vs. 11 vs. 18; 21: 23 vs. 19 vs. 24; 211: 22 vs. 19 vs. 23; 212: 23 vs. 29 vs. 21; 213: 16 vs. 22 vs. 14; Country, % (p =.5): Czech Republic: 13 vs. 11 vs. 14; Denmark: 4 vs. 45 vs. 37; Finland: 2 vs. 1 vs. 3; Netherlands: 3 vs. 3 vs. 3; Norway: 4 vs. 7 vs. 3; Portugal: 9 vs. 5 vs. 11; Slovenia: 1 vs. 6 vs. 11; Sweden: 6 vs. 7 vs. 6; Switzerland: 13 vs. 15 vs. 12. Figures 1 and 2 show Kaplan-Meier plots of tocilizumab retention by therapy and country, respectively. Figure 1. Tocilizumab retention by therapy Figure 2. Tocilizumab retention by country 1. Combination therapy (n = 1,38, events = 497) Monotherapy (n = 52, events = 21) Probability to stay on TCZ.6.4 Probability to stay on TCZ Switzerland (n = 241, events = 124) Portugal (n = 169, events = 49) Denmark (n = 716, events = 328) Slovenia (n = 171, events = 3) Czech Republic (n = 24, events = 66) Finland (n = 4, events = 8) Norway (n = 72, events = 24) Sweden (n = 112, events = 58) Netherlands (n = 49, events = 2) Time on TCZ (months) Time on TCZ (months) TCZ = tocilizumab TCZ = tocilizumab New Evidence in Rheumatology August

55 Of the 1,81 treatment courses, 1,211 were included in the country-stratified, covariate-adjusted analysis. Significant results were obtained for: Seropositivity at baseline (HR:.64 [positive vs. negative], 95% CI:.51.81, p <.1); and HAQ at baseline (HR: 1.18 [per unit increase], 95% CI: , p =.29) Therapy was not significant (HR: 1.2 [monotherapy vs. combination therapy], 95% CI: , p =.11). The differing results with respect to the effect of therapy between the unadjusted and adjusted analyses are most likely explained by confounding by covariates. Key conclusion In routine care, retention of tocilizumab seems comparable whether it is initiated as monotherapy or combination therapy. Reference: 1. Gabay C, Riek M, Hetland ML, et al. Retention of tocilizumab therapy: a comparison between tocilizumab in monotherapy and in combination with DMARDs based on the TOCERRA collaboration. EULAR Abstracts 214: SAT36. Kunishita Y, et al. EULAR 214:SAT263 Which biologic agent should be selected as a second choice for patients with rheumatoid arthritis treated with a TNF inhibitor? Background Both tumour necrosis factor inhibitors (TNF-Is) and non-tnf-i biologics can be first-line biologics for patients with rheumatoid arthritis (RA), according to 213 EULAR (European League Against Rheumatism) recommendations. 1 A definitive therapeutic algorithm does not exist for patients with RA who have failed to respond to a biologic in the first line. A recent study showed that drug retention rates are higher in patients who switched from a failed first-line TNF-I to a non-tnf-i biologic, compared to those who switched to a second TNF-I. The objective of this study was to compare clinical responses of tocilizumab with that of a TNF-I as the second biologic in patients with RA (i.e., after treatment failure with a TNF-I as first-line therapy). Study design Patients with RA who were registered in the Yokohama City University Rheumatic Disease Study Group and treated with a TNF-I in the first line were divided into two groups: Those who received a second-line TNF-I (TT group); and Those who received tocilizumab in the second line (T6 group). Clinical efficacy was assessed for 12 months after switching biologics, using the following parameters: Tender joint count (TJC); Swollen joint count (SJC); Patient s global assessment, visual analogue scale (PGH-VAS); and 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR). Key findings Baseline characteristics were as follows (TT vs. T6): Number of patients: 57 vs. 29; Age, years: 58.2 ± 9.9 vs ± 15.3, p =.2; Female, n (%): 5 (87.7) vs. 24 (82.8), p =.77; Positive for anti-citrullinated protein antibody, n (%): 12/17 (7.5) vs. 9/9 (1), p =.13; Positive for rheumatoid factor, n (%): 42/53 (79.2) vs. 19/25 (76.), p =.98; Age at onset, years: 5.1 ± 1.9 vs ± 13.3, p =.22; Concomitant methotrexate, n (%): 44 (77.2) vs. 22 (75.9), p =.9; Concomitant methotrexate dose, mg/week: 8.5 ± 1.7 vs. 9.5 ± 2.4, p =.18; Concomitant prednisolone, n (%): 4 (7.2) vs. 19 (65.5), p =.85; 54 New Evidence in Rheumatology August 214

56 In Supportive Care Oncology Concomitant prednisolone dose, mg/day: 5.7 ± 3.6 vs. 5.1 ± 2.4, p =.54; Class, n (%), p =.97: I: 7 (12.7) vs. 3 (11.5); II: 4 (72.7) vs. 2 (76.9); III: 8 (14.5) vs. 3 (11.5); IV: (.) vs. (.); Stage, n (%), p =.11; I: 8 (14.5) vs. 5 (17.9); II: 17 (3.9) vs. 14 (5.); III: 13 (23.6) vs. 4 (14.3); IV: 17 (3.9) vs. 5 (17.9). Figure 1. First and second biologics in the TT group 1 st biologic 2 nd biologic IFX 26 ADA IFX 12 ADA 1 The TNF-Is received by the TT group in both first- and second-line are illustrated in Figure 1. The TNF-Is received in the first line in the T6 group were as follows: ETN ETN 25 Infliximab: n = 16; Adalimumab: n = 3; Etanercept: n = 1. The type of TNF-I used in the first line did not differ between groups (p =.43). The reasons for switching biologics are illustrated in Figure 2. A primary non-response was defined as failing to improve DAS28 to more than a moderate response in the EULAR DAS28 improvement criteria within the first 3 6 months of starting the first TNF-I. A secondary non-response was determined by physician decision with evidence of flare and deterioration in DAS28 equal to or greater than 1.2 (after having previously demonstrated a response to a TNF-I). ADA = adalimumab; ETN = etanercept; IFX = infliximab DAS28-ESR was significantly decreased during the three months after switching biologics in both groups. (Figure 3) The reduction in DAS28-ESR was significantly larger in the T6 group from three months to 12 months post switch, compared to the TT group (4.4 ± 1.42 vs. 3.2 ± 1.7, p =.24). (Figure 4) The T6 group showed significant decreases in TJC, SJC, and PGH-VAS compared to the TT group at 12 months (2.8 ± 4.4 vs..4 ±.6, p =.7; 2.7 ± 3.7 vs..4 ±.5, p =.2; 28.1 ± 24. vs ± 17.3, p =.34, respectively). (Figure 4) Figure 2. Reasons for switching biologics TT Group T6 Group AE 1 Others 2 AE 1 PNR 17 PNR 6 SNR 37 SNR 22 p =.48 (Chi square test) AE = adverse event; PNR = primary non-response; SNR = secondary non-response; T6 = TNFi followed by tocilizumab; TNFi = tumour necrosis factor inhibitor; TT = TNFi followed by TNFi New Evidence in Rheumatology August

57 Figure 3. Disease activity parameters TT Group T6 Group 14 ** ** ** 14 ** ** ** TJC ** ** ** 14 ** ** ** SJC PGH-VAS (mm) 1 5 ** ** ** 1 5 ** ** ** ** ** ** ** ** * ** DAS28 ESR Duration (months) Duration (months) N N DAS28 = 28-joint disease activity score; ESR = erythrocyte sedimentation rate; PGH-VAS = patient s global assessment, visual analogue scale; SJC = swollen joint count; T6 = TNFi followed by tocilizumab; TJC = tender joint count; TNFi = tumour necrosis factor inhibitor; TT = TNFi followed by TNFi * p <.5, ** p <.1: Showed a significant difference between the period using t-test analysis. 56 New Evidence in Rheumatology August 214

58 In Supportive Care Oncology Figure 4. Comparison of disease activity parameters months 3 months 6 months 12 months ** TJC TT T6 TT T6 TT T6 TT T ** SJC TT T6 TT T6 TT T6 TT T * PGH-VAS TT T6 TT T6 TT T6 TT T6 * ** ** DAS28 ESR TT T6 TT T6 TT T6 TT T6 DAS28 = 28-joint disease activity score; ESR = erythrocyte sedimentation rate; PGH-VAS = patient s global assessment, visual analogue scale; SJC = swollen joint count; T6 = TNFi followed by tocilizumab; TJC = tender joint count; TNFi = tumour necrosis factor inhibitor; TT = TNFi followed by TNFi * p <.5, ** p <.1: Showed a significant difference between two groups using t-test analysis. New Evidence in Rheumatology August

59 Key conclusion Tocilizumab was more effective as the second biologic than an alternative TNF-I in patients with RA who had previously been treated with a TNF-I in the first line. Reference: 1. Kunishita Y, Yoshimi R, Kishimoto D, et al. Which biologic agent should be selected as a second choice for patients with rheumatoid arthritis treated with a TNF inhibitor? EULAR Abstracts 214: SAT263. Harrold L, et al. EULAR 214:FRI334 Comparative effectiveness of rituximab vs. subsequent tumour necrosis factor inhibitor (TNF-I) in cumulative prednisone exposure in patients with rheumatoid arthritis with prior exposure to TNF-I Background Up to 6% of patients with rheumatoid arthritis (RA) fail to respond to tumour necrosis factor inhibitors (TNF-Is) due to either a primary lack of response or the development of secondary drug resistance or intolerance. 1 The comparative effectiveness of rituximab to that of an alternative TNF-I in patients with RA who have previous experience with TNF-Is has been studied in several observational trials in Europe; however, data in patients from the U.S. are limited. A recent study of patients within the CORRONA registry found that patients with RA and prior exposure to a TNF-I who received rituximab were more likely to achieve low disease activity (LDA) or remission at one year compared with those who received a subsequent TNF-I. This was confirmed with a sensitivity analysis of the stratified-matched population from this cohort. 2,3 (Figure 1) The objective of this analysis was to investigate whether the increased efficacy of rituximab was associated with a greater use of prednisone. Study design The CORRONA registry is an independent, prospective, observational cohort of patients with RA recruited at more than 16 private and academic practice sites across 4 states in the U.S., with more than 6 participating rheumatologists. Figure 1. Odds ratio (95% CI) of effectiveness outcomes in the stratifiedmatched population 2,3 Stratified-matched population (N = 41) LDA/remission 1.54 ( ) macr ( ) macr ( ) macr ( ) mhaq 1.66 ( ) Favours TNF-I use Favours rituximab use CI = confidence interval; LDA = low disease activity; macr = modified American College of Rheumatology; mhaq = modified Health Assessment Questionnaire; TNF-I = tumour necrosis factor inhibitor 58 New Evidence in Rheumatology August 214

60 In Supportive Care Oncology The study population was limited to patients with RA within CORRONA (not including psoriatic arthritis) who initiated rituximab or a subsequent TNF-I on or after February 28, 26, and had the following: Prior use of at least one TNF-I and no prior use of rituximab; Moderate (Clinical Disease Activity Index [CDAI] >1 and 22) or high (CDAI >22) disease activity at baseline; A follow-up visit at one year (within a three month window); At least one visit between baseline and the one-year follow-up; and CDAI measurements at baseline and the one-year follow-up. Patients in LDA/remission (CDAI 1) at initiation or with a history of lymphoma prior to initiation were excluded. The primary outcome was a standardized measure of cumulative prednisone use (area under the curve [AUC mean ]). AUC mean was calculated as the AUC divided by the total time. The secondary outcome was the mean percentage of time patients spent receiving prednisone at a dose 1 mg, or %Time mean. Baseline data were obtained at the time of rituximab or TNF-I initiation. Patients were stratified by use of one versus 2 prior TNF-Is, and then matched based on propensity score (stratifiedmatched population). The propensity score for use of rituximab versus a TNF-I was calculated for each patient using patient demographics, disease characteristics, comorbidities, past medication history, and concurrent medications. Standardized cumulative AUC prednisone dose was plotted over time to compare trends over time between the two groups. %Time mean was computed and the distribution compared between the two groups. Differences in AUC mean were compared between the treatment groups: Using all patients (total population); and Restricted only to patients using prednisone (prednisone use population). Differences in %Time mean were compared between the treatment groups: Using all patients (total population); and Restricted only to patients using prednisone at a dose 1 mg at some time during follow-up (prednisone use 1 mg population). Cumulative prednisone over time was analyzed using a linear mixed model with a group-time interaction to test for group differences over time. Models with predictors group and time, and then time alone, were also run. Patient random effects were used to account for the correlation of multiple visits by the same patient. For AUC mean and %Time mean, unadjusted estimates were compared in the matched populations. In addition, a regression model adjusting for possible confounders of prednisone use and dose (sex, age, number of prior TNF-Is, baseline CDAI, baseline prednisone use, and baseline concomitant methotrexate use) was fit to estimate differences in AUC mean and %Time mean. Key findings Baseline patient and disease characteristics were well balanced between the rituximab and TNF-I groups, including regarding the use of prednisone (n [%]: 114 [55.6] vs. 15 [51.5], respectively; p =.43). For patients on prednisone, the median dose and interquartile range were the same. In the mixed-model analysis, there was no significant difference in trend between the two treatment groups in standardized cumulative prednisone dose by time (p =.38). (Figure 2) Figure 2. Standardized cumulative prednisone dose by time from initiation Standardized cumulative AUC prednisone Time (months) AUC = area under the curve; TNF-I = tumour necrosis factor inhibitor TNF-I (n = 25) Rituximab (n = 25) The total study population demonstrated a significant decrease in cumulative prednisone dose over time, regardless of group (p =.4). The AUC prednisone dose standardized by time was estimated for each patient; the distribution of AUC values was similar between treatment groups. (Figure 3) Among all patients, including those not on prednisone during the study period, there was no statistically significant difference in AUC mean between the rituximab and TNF-I groups. (Table 1) There was no significant difference in AUC mean by treatment group when patients with no prednisone use were excluded. 15 New Evidence in Rheumatology August

61 Figure 3. Distribution of AUC values.3 Rituximab (n = 25) TNF-I (n = 25).3 Proportion of patients.2.1 Proportion of patients Standardized AUC prednisone dose Standardized AUC prednisone dose AUC = area under the curve; TNF-I = tumour necrosis factor inhibitor The proportions of patients with no prednisone use were similar between the rituximab and TNF-I treatment groups (39% vs. 42%, respectively; p =.62). In the multivariate regression models for both the total population and the prednisone use population, the adjusted AUC mean was not significantly different between the treatment groups. (Table 1) Patients treated with rituximab spent approximately 15.% of the study period receiving 1 mg prednisone, compared with 11.3% of the study period for patients in the TNF-I group. (Table 2) The proportions of patients who received prednisone at a dose 1 mg at some time during follow-up were similar between the rituximab and TNF-I treatment groups (24% vs. 18%, respectively; p =.18). Table 1. AUC mean and difference in AUC mean between treatment groups Total population (N = 41) Prednisone-use population* (N = 244) N AUC mean N AUC mean Rituximab TNF-I Unadjusted difference (95% CI).5 (.29, 1.28).55 (.4, 1.49) Adjusted difference (95% CI).26 (.29,.82).46 (.46, 1.38) *Excludes patients with no prednisone use. Adjusted for sex, age, one or 2 prior TNF-I use, baseline Clinical Disease Activity Index, baseline prednisone use, and baseline concomitant methotrexate use. AUC = area under the curve; CI = confidence interval; TNF-I = tumour necrosis factor inhibitor 6 New Evidence in Rheumatology August 214

62 In Supportive Care Oncology Among these patients, the percentage of time spent on prednisone at a dose 1 mg was similar between the treatment groups. (Table 2) In the multivariate regression models for the total population and the prednisone use 1 mg population, the adjusted difference in %Time mean was not significant between treatment groups. Among patients with prednisone use at baseline, a total of 4 patients (18.3%) discontinued prednisone use after one year of follow-up: 16 in the rituximab group (14%) and 24 in the TNF-I group (22.9%). Table 2. Mean percentage of time spent on prednisone 1 mg (%Time mean ) and difference in %Time mean between treatment groups Total population (N = 41) Prednisone use 1 mg population* (N = 86) N %Time mean N %Time mean Rituximab TNF-I Unadjusted difference (95% CI) Adjusted difference (95% CI) 3.66 ( 2.2, 9.34) 2.79 ( 2.45, 8.3).6 ( 13.66, 13.54) 1.45 ( 14.87, 11.98) *Excludes patients with no use of prednisone 1 mg at any time. Adjusted for sex, age, one or 2 prior TNF-I use, baseline Clinical Disease Activity Index, baseline prednisone use, and baseline concomitant methotrexate use. CI = confidence interval; TNF-I = tumour necrosis factor inhibitor Key conclusions In this population of patients with RA and prior exposure to TNF-I, treatment with rituximab was associated with similar safety and a higher likelihood of achieving LDA or remission (odds ratio, 1.54; 95% CI, 1.1 to 2.35) compared with subsequent TNF-I users. Both patient groups, whether receiving rituximab or a subsequent TNF-I, demonstrated a reduction in prednisone use over time. Patients in both treatment groups demonstrated a similar cumulative use of prednisone over time and spent a similar amount of time on prednisone at a dose 1 mg. References: 1. Harrold L, Reed G, Magner R, et al. Comparative effectiveness of rituximab vs. subsequent anti-tumour necrosis factor (TNF-I) in cumulative prednisone exposure in patients with rheumatoid arthritis with prior exposure to TNF-I. EULAR Abstracts 214: FRI Harrold LR, Reed GW, Magner RP, et al. Comparative effectiveness of rituximab vs. subsequent anti-tumor necrosis factor in patients with rheumatoid arthritis with prior exposure to TNFi. Arthritis Rheum 213;65(suppl 1):S61 [abstract 1438]. 3. Harrold L, Reed G, Magner R, et al. Comparative effectiveness of rituximab versus anti-tumor necrosis factor switching for rheumatoid arthritis patients. Ann Rheum Dis 213;72(suppl 3):A46 [abstract FRI254]. New Evidence in Rheumatology August

63 Canadian Perspective by Dr. Janet Pope Tocilizumab is an interleukin-6 (IL-6) receptor antagonist that is approved in Canada for the treatment of rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. 1 In RA, tocilizumab may be used in monotherapy, or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs). 1 Approximately one-third of my patients who receive tocilizumab receive it as monotherapy, usually due to intolerance or a lack of efficacy with previous DMARDs (this is similar to registries of virtually all biologics in RA). I would not discontinue a background drug such as methotrexate when initiating tocilizumab treatment; rather, I would add tocilizumab to whatever drugs the patient is already taking and then lower the dose or discontinue the background drugs if a response or intolerance is observed. However, if a patient is already on or requires monotherapy, I would certainly consider tocilizumab because of the strong, consistent data supporting its use in monotherapy. At the 214 European League Against Rheumatism (EULAR) Congress, investigators presented new research that further demonstrates the efficacy of tocilizumab in monotherapy. Haraoui et al. investigated the characteristics of tocilizumab use in patients with RA, both in monotherapy and in combination therapy, in the multinational, observational, real-world ACT-UP study; 2 we can take pride in the fact that a Canadian led this study. All parameters that were observed showed clear signals of efficacy with tocilizumab treatment, even in patients who received concomitant glucocorticoids. It is nice to see that steroid doses were systematically collected, as steroid use is associated with a higher risk of infections. The study also found that glucocorticoid doses were reduced over the six-month observation period; this is important and beneficial as it lowers the risk of infections. A higher proportion of patients using combination therapy were also taking corticosteroids and lipid-lowering agents at baseline, and fewer monotherapy patients had received a previous biologic at baseline; therefore, patients on combination therapy may have had more severe disease. I do not believe these differences affected the results of the study since the baseline disease activity and change from baseline at 6 months were similar. The response to tocilizumab monotherapy was as effective as that with tocilizumab combination therapy; this is reassuring to see in real-world data with a large sample size. Retention rates are also important to know; after six months of tocilizumab treatment, retention rates in this study were 71.8% for monotherapy patients and 84.2% for combination therapy patients. Unfortunately, biologics do not work forever; patients who discontinue use because of a lack of efficacy usually do so in the first year, after which retention rates improve. As is generally the case with all biologics, combination therapy is often more efficacious than monotherapy, and it will likely improve retention rates; however, tocilizumab monotherapy can be considered. The reasons for changing the tocilizumab dose varied between the groups: more monotherapy patients changed dose because of a lack of efficacy, and more combination therapy patients changed dose because of an adverse event. This might mean that tocilizumab monotherapy is not ideal for patients with a high 28-joint disease activity score (DAS28). The authors concluded that the real-world response to tocilizumab is similar to that reported in clinical trials, as are the retention rates. It is also important to know that tocilizumab monotherapy and combination therapy have similar efficacies, and that glucocorticoid use can be reduced while on tocilizumab. The data show that tocilizumab combination therapy is still more likely than monotherapy to maintain a high and durable response. However, it is helpful to know that two drugs are not mandatory in the treatment of RA, and I would not introduce a second drug to a patient who was doing well on monotherapy. If a patient has to use a biologic in monotherapy, these data help to support that tocilizumab should be one of my first biologic choices. O Mahony et al. presented ex vivo data investigating the interactions between tocilizumab and methotrexate in various cell types, comparing them to the interactions between adalimumab and methotrexate. 3 It is known that adalimumab has a longer half-life in combination with methotrexate than in monotherapy. 4 This study supports this finding by showing that adalimumab monotherapy affects cells differently than the combination of adalimumab plus methotrexate. However, it is important to note that some of the interactions found in this study may not be clinically relevant. With regards to tocilizumab, the study suggests that tocilizumab monotherapy is similar in activity to the combination of tocilizumab and methotrexate, particularly with respect to IL-6 signaling. This may be why tocilizumab monotherapy and combination therapy are similar in their mechanisms of action, at least acutely. This finding may support the use of tocilizumab monotherapy; however, because it is an ex vivo experiment it is difficult to generalize the findings to a clinical setting. 62 New Evidence in Rheumatology August 214

64 In Supportive Care Oncology Specker et al. presented interim analyses from the ICHIBAN study, which collected efficacy, safety, and comorbidity data from patients using tocilizumab for two years from multiple sites in Germany. 5 German rheumatologists were early adopters of tocilizumab, so the German population of patients with RA is a good population to study for tocilizumab use because of the large sample size available (almost 2,4 patients). The results of this study were reassuring because they were similar to those reported in the Haraoui study; tocilizumab monotherapy was equally as effective as combination therapy, and steroid doses were reduced in both groups (as were DMARD doses in the combination therapy group). This is important to know as it reflects real-world practice. DAS28-ESR (erythrocyte sedimentation rate) responses were similar regardless of background glucocorticoid status; this was to be expected, as tocilizumab will cause a certain response irrespective of background medications used. The two-year retention rate reported in this study was 7.7%. This number is similar to other databases of patients who are on tumour necrosis factor inhibitors (TNF-Is); 6 in general, about 2 25% of patients discontinue use in the first year, and another 2 25% are lost in the second year. The fact that the tocilizumab retention rate is similar to that of TNF-Is is a good thing, as it gives us more options for our patients. This is beneficial since not all drugs work in all patients. Monotherapy use of tocilizumab increased during the observation period. This could mean that some patients on combination therapy were able to discontinue their background DMARD, or it might mean that more patients on monotherapy were enrolled in the study over time as more literature with monotherapy accumulated over time, or both. Observational studies are important because they can answer questions in patient populations that are more similar to the patients in my practice. Patients in clinical trials typically have higher compliance/adherence, fewer comorbidities, and higher disease activity than the patients I see. Also, patients in randomized controlled trials do not pay for treatment, so it is particularly interesting to look at drug retention rates in observational studies when co-pay costs occur for some patients. Another difference between observational studies and clinical trials is that background drug doses can be changed or eliminated in observational studies, which is more similar to real-world practice. These studies also allow for patients to be followed for longer periods of time and can obtain larger sample sizes allowing for rare events to be observed. Because of these factors, observational studies are more generalizable to my practice. The similarities between the Specker et al. and Haraoui et al. studies provide me with additional reassurance of the efficacy and durability of tocilizumab, both in combination therapy and monotherapy. They also show that background DMARDs and particularly glucocorticoids can be lowered with tocilizumab therapy, which is important for our patients because of the risk of infections with glucocorticoid use. While efficacy is generally higher with combination therapy, particularly in the first six months of treatment, the combination of two drugs also has more adverse events; so, lowering the dose of background drugs in some patients, such as those who experience side effects, may be beneficial. References: 1. Hoffmann-La Roche Ltd. Pr ACTEMRA (tocilizumab) Product Monograph. May 6, Haraoui B, Casado G, Theander E, et al. Baseline characteristics and pattern of tocilizumab use in patients with rheumatoid arthritis: interim results from the multinational, observational ACT-UP study. EULAR Abstracts 214: FRI3. 3. O Mahony A, Berg EL, John M, et al. Biologic interactions between methotrexate and adalimumab are more extensive than those between methotrexate and tocilizumab: evidence from BioMAP profiling. EULAR Abstracts 214: THU Pouw MF, Krieckaert CL, Nurmohamed MT, et al. Key findings towards optimizing adalimumab treatment: the concentration-effect curve. Ann Rheum Dis 213;Dec.1: doi:1.1136/annrheumdis [Epub ahead of print]. 5. Specker C, Kaufmann J, Vollmer MA, et al. Tocilizumab, DMARDs and glucocorticoids in rheumatoid arthritis interim analysis of the German non-interventional study ICHIBAN. EULAR Abstracts 214: FRI Frazier-Mironer A, Dougados M, Mariette X, et al. Retention rates of adalimumab, etanercept and infliximab as first and second-line biotherapy in patients with rheumatoid arthritis in daily practice. Joint Bone Spine 214;81: New Evidence in Rheumatology August

65 Investigator Commentary An interview with Dr. Cem Gabay on the results of his studies on the retention rate of tocilizumab therapy in rheumatoid arthritis (RA) patients, and the effects of tocilizumab therapy on lipoprotein(a) levels in RA patients At the 214 EULAR Scientific Meeting in Paris, France, New Evidence spoke with Dr. Cem Gabay, Professor of Medicine and Head of the Department of Rheumatology at the University Hospital of Geneva, Switzerland, on his studies regarding the retention of tocilizumab therapy in RA patients based on the TOCERRA registry, and the effects of tocilizumab therapy on lipoprotein levels in RA patients. Abstract SAT36: Retention of tocilizumab therapy: a comparison between tocilizumab in monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) based on the TOCERRA collaboration New Evidence: When do you treat RA patients with tocilizumab monotherapy in your clinic? Dr. Gabay: Most RA patients treated with tocilizumab are treated with a combination of tocilizumab and synthetic DMARDs, mainly methotrexate. However, RA patients intolerant to methotrexate, other DMARDs, or who have comorbidities which make methotrexate a poor choice are treated with tocilizumab monotherapy. Although most patients receive tocilizumab in combination with DMARDs, the number of RA patients receiving tocilizumab monotherapy has been increasing. New Evidence: How do retention rates of tocilizumab monotherapy with and without DMARDs compare to other biologic monotherapies? Dr. Gabay: The retention rate of tocilizumab monotherapy compared with other biologics has not been determined yet, although it is an important question. What we have examined so far is the retention rate of tocilizumab with and without conventional DMARDs. We know that the efficacy of tumour necrosis factor alpha inhibitors (TNF-Is) increases when combined with methotrexate, and that this increase is not observed when methotrexate is combined with tocilizumab. Therefore, one could hypothesize that the retention rate would be better with tocilizumab monotherapy than with TNF-I monotherapy. 64 New Evidence in Rheumatology August 214