Background The introduction of tumor necrosis factor inhibitors (TNFI) has dramatically improved treatments for rheumatoid arthritis (RA) during the last decade. To identify optimal use of TNFI in clinical practice, various clinical trials and all-cases postmarketing surveillance programs have been implemented in Japan1-4. However, change of benefit-risk balance of treatment with TNFI has not been investigated.
Objectives To investigate changes of safety and effectiveness of treatment with TNFI over time.
Methods This study included Japanese RA patients who started TNFI from 2005 to 2007 (2005 group, n=716, 634.2patient-years [PY]) and from 2008 to 2011 (2008 group, n=353, 270.6PY) as the first biologic therapy after their enrollment in the REAL database. Types and incidence rates of serious adverse events (SAE) during the first year of TNFI treatment were analyzed. Incidence rates (IR) were calculated with 95% confidence intervals (CI). To estimate the risk for serious infections (SI), the Cox proportional hazard model was applied. Changes in DAS28 (3/CRP) from baseline to year 1 (⊿DAS28) were compared between the two groups using Student’s t test to evaluate the effectiveness of TNFI.
Results At baseline, compared to the 2005 group, the 2008 group had shorter disease duration (p<0.001) and lower disease activity (p<0.001), and was treated with higher dosages of methotrexate (p<0.001) and lower dosage of oral corticosteroids (p<0.001). The rate of previous use of three or more non-biological DMARDs was lower in the 2008 group (p=0.001). The crude IR ratios comparing the 2008 group with the 2005 group for SAE and SI were 0.93 (95% CI 0.65-1.34) and 0.50 (0.24-1.03), respectively. The Cox proportional hazards analysis revealed that the 2008 group had significantly lower risk for SI than the 2005 group (HR: 0.45 [95% CI, 0.21-0.97]) after adjusting for baseline characteristics. Although mean DAS28 (3/CRP) at baseline and year 1 in the 2005 group was significantly higher than the 2008 group (p=0.001), no significant differences in ⊿DAS28 were observed between the two groups (p=0.770).
Conclusions The risk for SI in RA patients receiving TNFI significantly decreased after adjusting for baseline data without changes in the effectiveness. This observation could be explained, at least in part, by enlightenment of safety profile of TNFI and evidence-based risk management during treatment with TNFI.
Mod.Rheumatol 2012 DOI 10.1007/s10165-012-0702-1
Ann Rhum Dis 2009;68:1240-1246
Mod. Rheumatol 2007;17:451-458
Acknowledgements The affiliates that contributed to this work were: Hokkaido University, Juntendo University, Kagawa University, Keio University, Kobe University, Kyoto University, Nagasaki University, National Hospital Organization Nagasaki Medical Center, Ome Municipal General Hospital, Sagamihara National Hospital, Saitama Medical Center, Sasebo Chuo Hospital, The University of Tokyo, Tokyo Kyosai Hospital, Tokyo Medical University Hospital, Tokyo Metropolitan Bokutoh Hospital, Tokyo Metropolitan Geriatric Hospital, Tokyo Women’s Medical University, University of Occupational and Environmental Health, University of Tsukuba, Yokohama City Minato Red Cross Hospital, and Yokohama City University, (in alphabetical order). We sincerely thank all the rheumatologists and others caring for RA patients enrolled in the REAL registry.
Disclosure of Interest R. Sakai: None Declared, S.-K. Cho: None Declared, M. Tanaka: None Declared, T. Nanki Grant/research support from: Eisai.Co., Ltd., H. Yamazaki: None Declared, K. Watanabe: None Declared, R. Koike: None Declared, N. Miyasaka Grant/research support from: Abbott Japan Co., Ltd., Astellas Pharma Inc., MSD K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., and Teijin Pharma Ltd., M. Harigai Grant/research support from: Abbot Japan Co., Ltd., Astellas Pharma Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., LLtd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Santen Phrmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Pfizer Japan Inc., Speakers bureau: Abbot Japan Co., Ltd., Astellas Pharma Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., LLtd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Santen Phrmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Pfizer Japan Inc.