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Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: results from a prospective randomised controlled study (the second year of the SURPRISE study)
  1. Yuko Kaneko1,
  2. Masaru Kato2,
  3. Yoshiya Tanaka3,
  4. Masayuki Inoo4,
  5. Hitomi Kobayashi-Haraoka5,
  6. Koichi Amano6,
  7. Masayuki Miyata7,
  8. Yohko Murakawa8,
  9. Hidekara Yasuoka1,
  10. Shintaro Hirata3,9,
  11. Eiichi Tanaka10,
  12. Nobuyuki Miyasaka11,
  13. Hisashi Yamanaka10,
  14. Kazuhiko Yamamoto12,
  15. Tsutomu Takeuchi1
  16. the SURPRISE study group
    1. 1 Department of Internal Medicine, Division of Rheumatology, School of Medicine, Keio University, Tokyo, Japan
    2. 2 Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    3. 3 The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
    4. 4 Internal Medicine, Utazu Hospital, Ehime, Japan
    5. 5 Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
    6. 6 Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
    7. 7 Department of Internal Medicine, Fukushima Red Cross Hospital, Fukushima, Japan
    8. 8 Department of Rheumatology, Shimane University Faculty of Medicine, Izumo, Japan
    9. 9 Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
    10. 10 Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan
    11. 11 Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
    12. 12 Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    1. Correspondence to Professor Tsutomu Takeuchi, Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; tsutake{at}keio.jp

    Abstract

    Objective To evaluate the sustained remission and low disease activity after discontinuation of tocilizumab in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate.

    Methods The SURPRISE study was a 2-year, open-label randomised controlled study. Among patients who had been randomised to additional tocilizumab (ADD-ON) or switch to tocilizumab (SWITCH) in the first year, those who achieved remission based on the disease activity score for 28 joints (DAS28-ESR<2.6) discontinued tocilizumab at week 52 and were observed for the following 52 weeks. The endpoint of the second year included tocilizumab-free remission and low disease-activity rates, functional outcome, radiological outcomes assessed with the modified total Sharp score (mTSS) and safety. The efficacy of reinstituted tocilizumab/methotrexate was also evaluated.

    Results A total of 105 patients who achieved remission at week 52 discontinued tocilizumab; 51 in ADD-ON continued methotrexate and 54 in SWITCH received no disease-modifying antirheumatic drugs. Sustained DAS28 low disease-activity rates were significantly higher in ADD-ON than in SWITCH (55%vs27%, p=0.005). Sustained remission rates at week 104 were 24% for ADD-ON and 14% for SWITCH (p=0.29). Radiological progression was comparable between both groups (mTSS; 0.37vs0.64, p=0.36). The restart of tocilizumab induced remission in all except two patients after 36 weeks, irrespective of concomitant methotrexate.

    Conclusion Sustained low disease activity after tocilizumab discontinuation could be maintained with continued methotrexate in more than half of the patients. Retreatment with tocilizumab led to remission in more than 90% of patients.

    Trial registration number NCT01120366; Results.

    • rheumatoid arthritis
    • methotrexate
    • dmards (biologic)

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors YK, NM, HY, KY and TT designed the study and analysed and interpreted the data. YK, MK, YT, MI, HK-H, KA, MM and YM were involved in collecting data and managing their clinical research sites. YK, HY, SH and ET scored mTSS blinded to patients’ clinical information. All authors were involved in writing the manuscript and approved the final version.

    • Funding This study was supported by Specified Nonprofit Corporation Advanced Clinical Research Organization.

    • Competing interests YK has received grants or speaking fees from from AbbVie, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Hisamitsu, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi and UCB. MK has received research grants or lecture fees from GlaxoSmithKline K.K. and Actelion Pharmaceuticals. YT has received grants or speaking fees from Mitsubishi-Tanabe, Takeda, Bristol-Myers, Chugai, Astellas, AbbVie, MSD, Eli Lilly, YL Biologics, Daiichi-Sankyo, Sanofi, Janssen, Pfizer, Kyowa-Kirin, Eisai and Ono. HK-H has received speaking fees from Chugai, Astellas and Bristol-Myers Squibb. KA has received research grants from Chugai Pharmaceutical Co. and speaking fees from Daiichi-Sankyo, Eli Lilly, Pfizer Japan and Tanabe-Mitsubishi. MM is an employee of the Japanese Red Cross Society. YM has received grants, instructor fees or speaking fees from Chugai, Ono, Daiichi-Sankyo, Teijin, Eisai, Nippon Kayaku, Tanabe-Mitsubishi, Kissei, Janssen, Eisai, Astellas, Ayumi, Takeda, UCB, Sanofi and Eli- Lilly. HY has received grants or speaking fees from Bristol-Myers Squibb, Takeda, Japan Blood Products Organization, Eizai, Daiichi-Sankyo, Novartis, Chugai and Actelion. SH has received grants, lecture fees or speaking fees from AbbVie, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi and UCB. ET received speaking fees from AbbVie, Ayumi Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai Pharmaceutical, Nippon Kayaku, Pfizer, Takeda Pharmaceutical and UCB Pharma. HY has received research grants, consultant fees or speaking fees from MSD, Astellas, AbbVie, Bristol-Myers Squibb, Kaken, UCB, Ono, Ayumi, Eisai, Daiichi-Sankyo, Takeda, Tanabe-Mitsubishi, Chugai, Teijin, Torii, Nipponshinyaku, Pfizer, YL Biologics and Nipponkayaku. KY has received grants or speaking fees from Astellas Pharmaceutical, Chugai Pharmaceutical, Eizai Pharmaceutical, Immunofuture Inc, Mitsubishi Tanabe Pharma Corporation, Santen Pharmaceutical, Pfizer Japan Inc, AbbVie GK, Bristol–Myers KK, Diaichi Sankyo, Eli Lilly, Sanofi, Janssen and UCB. TT has received research grants or speaking fees from Astellas Pharma Inc, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo Co, Ltd, Takeda Pharmaceutical Co, Ltd, Teijin Pharma Ltd, AbbVie GK, Asahikasei Pharma Corp, Mitsubishi Tanabe Pharma, Astra Zeneca KK, Eli Lilly Japan KK, Novartis Pharma KK, AbbVie GK, Nipponkayaku Co, Ltd, Janssen, Pharmaceutical KK, Taiho Pharmaceutical Co, Ltd and Pfizer Japan Inc. MI and NM have nothing to declare.

    • Patient consent Obtained.

    • Ethics approval The ethics committee at each site.

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

    • Collaborators Other investigators of the SURPRISE study group: Takao Fujii (Kyoto University), Atsushi Kawakami (Nagasaki University Graduate School of Biomedical Sciences), Hideshi Yamazaki (Marunouchi Hospital), Yasuaki Okuda (Dohgo Spa Hospital), Kazuhide Tanimura (Hokkaido Medical Center for Rheumatic Diseases), Atsushi Kaneko (Nagoya Medical Center), Toshio Tanaka (Osaka University), Akira Murasawa (Niigata Rheumatic Center), Kazuhiko Ezawa (Kurashiki Sweet Hospital), Yukitaka Ueki (Sasebo Chuo Hospital), Yoshiki Shiohira (Yuuaikai Tomishiro Central Hospital), Hiroaki Dobashi (Kagawa University), Naoki Kondo (Niigata University Graduate School of Medical and Dental Sciences), Toshihiko Hidaka (Zenjinkai Shimin-no-Mori Hospital), Hajime Sano (Hyogo College of Medicine), Mitsuhiro Iwahasi (Higashi Hiroshima Memorial Hospital), Motohiro Oribe (Oribe Clinic of Rheumatism and Medicine), Shohei Nagaoka (Yokohama Minami Kyosai Hospital) and Kensei Tsuzaka (Tokyo Dental College Ichikawa General Hospital).

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