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Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules
  1. Ryoko Sakai1,2,
  2. Michi Tanaka1,2,
  3. Toshihiro Nanki1,2,
  4. Kaori Watanabe1,2,
  5. Hayato Yamazaki1,2,
  6. Ryuji Koike1,2,3,
  7. Hayato Nagasawa4,
  8. Koichi Amano4,
  9. Kazuyoshi Saito5,
  10. Yoshiya Tanaka5,
  11. Satoshi Ito6,
  12. Takayuki Sumida6,
  13. Atsushi Ihata7,
  14. Yoshiaki Ishigatsubo7,
  15. Tatsuya Atsumi8,
  16. Takao Koike8,
  17. Atsuo Nakajima9,
  18. Naoto Tamura10,
  19. Takao Fujii11,
  20. Hiroaki Dobashi12,
  21. Shigeto Tohma13,
  22. Takahiko Sugihara14,
  23. Yukitaka Ueki15,
  24. Akira Hashiramoto16,
  25. Atsushi Kawakami17,
  26. Noboru Hagino18,
  27. Nobuyuki Miyasaka2,19,
  28. Masayoshi Harigai1,2,3,
  29. for the REAL Study Group
  1. 1Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  2. 2Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  3. 3Clinical Research Center, Tokyo Medical and Dental University Hospital, Tokyo, Japan
  4. 4Department of Rheumatology/Clinical Immunology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
  5. 5The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
  6. 6Division of Clinical Immunology, Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
  7. 7Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  8. 8Department of Internal Medicine II, Hokkaido University, Graduate School of Medicine, Sapporo, Japan
  9. 9Department of Rheumatology, Tokyo Metropolitan Police Hospital, Tokyo, Japan
  10. 10Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
  11. 11Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  12. 12Department of Internal Medicine, Division of Endocrinology and Metabolism, Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
  13. 13Department of Rheumatology, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Sagamihara, Japan
  14. 14Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
  15. 15Rheumatic and Collagen Disease Center, Sasebo Chuo Hospital, Nagasaki, Japan
  16. 16Department of Rheumatology, Kobe University Graduate School of Medicine, Kobe, Japan
  17. 17Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
  18. 18Department of Allergy and Rheumatology, The University of Tokyo, Tokyo, Japan
  19. 19Global Center of Excellence (GCOE) Program; International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, Tokyo, Japan
  1. Correspondence to Masayoshi Harigai, Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; mharigai.mpha{at}tmd.ac.jp

Abstract

Objective To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA).

Method This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan–Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied.

Results The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE.

Conclusions Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.

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Footnotes

  • Funding This work was supported by a grant-in-aid from the Ministry of Health, Labour and Welfare, Japan (H23-meneki-sitei-016 and H19-meneki-ippan-009 to NM, H22-meneki-ippann-001 to MH) and by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (#20390158 to MH, #19590530 to RK, and #50277141 to MT). This work was also supported by grants for pharmacovigilance research on biological agents from Abbott Laboratories, Bristol-Myers Japan, Eisai, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma Corp, Takeda Pharmaceutical and Pfizer Japan (to MH), and by a grant from the Japanese Ministry of Education, Global Center of Excellence (GCOE) Program, ‘International Research Center for Molecular Science in Tooth and Bone Diseases’.

  • Competing interests KA has received research support from Chugai Pharmaceutical, Mitsubishi Tanabe Pharma and Astellas Pharma. YT has received consulting fees, speaking fees, and/or honoraria from Mitsubishi-Tanabe Pharma, Chugai Pharmaceutical, Eisai, Takeda Pharmaceutical, Astellas Pharma and Abbott Japan, and has received research grant support from Mitsubishi-Tanabe Pharma, Takeda Pharmaceutical, MSD KK, Pfizer Japan, Astellas Pharma, Chugai Pharmaceutical, Abbott Japan and Eisai. TF has received grant/research support from Abbott Japan, Eisai, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Chugai Pharmaceutical, Pfizer Japan, Astellas Pharma, Bristol-Myers Squibb KK. NM has received research grants from Abbott Japan, Astellas Pharma, MSD KK, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical and Teijin Pharma. MH has received research grants from Abbott Japan, Astellas Pharma, Bristol Myers Squibb KK, Chugai Pharmaceutical, Eisai, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Santen Pharmaceutical, Takeda Pharmaceutical and Pfizer Japan.

  • Ethics approval The REAL study was approved by the ethics committees of the Tokyo Medical and Dental University Hospital and other participating institutions.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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