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Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial
  1. Hiroya Tamai1,
  2. Kei Ikeda2,3,
  3. Toshiaki Miyamoto4,
  4. Hiroaki Taguchi5,
  5. Chang-Fu Kuo6,
  6. Kichul Shin7,
  7. Shintaro Hirata8,
  8. Yutaka Okano9,
  9. Shinji Sato10,
  10. Hidekata Yasuoka11,
  11. Masataka Kuwana12,
  12. Tomonori Ishii13,
  13. Hideto Kameda14,
  14. Toshihisa Kojima15,16,
  15. Yurie Nishi17,
  16. Masahiko Mori17,
  17. Hideaki Miyagishi18,
  18. Genta Toshima19,
  19. Yasunori Sato20,
  20. Wen-Chan Tsai21,
  21. Tsutomu Takeuchi1,22,
  22. Yuko Kaneko1
  23. MIRACLE Study Group
    1. 1Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
    2. 2Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan
    3. 3Department of Rheumatology, Dokkyo Medical University, Mibu, Japan
    4. 4Department of Rheumatology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan
    5. 5Department of Internal Medicine and Center for Arthritis and Rheumatic Disease, Kawasaki Municipal Kawasaki Hospital, Kawasaki, Japan
    6. 6Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
    7. 7Division of Rheumatology, Department of Internal Medicine, Seoul Metropolitan Government—Seoul National University Boramae Medical Center, Seoul, South Korea
    8. 8Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
    9. 9Division of Rheumatology, Department of Medicine, National Hospital Organisation Tokyo Medical Center, Tokyo, Japan
    10. 10Division of Rheumatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
    11. 11Division of Rheumatology, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Japan
    12. 12Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
    13. 13Clinical Research, Innovation and Education Center, Tohoku University Hospital, Sendai, Japan
    14. 14Division of Rheumatology, Department of Internal Medicine, Toho University Ohashi Medical Center, Tokyo, Japan
    15. 15Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
    16. 16Department of Orthopedic Surgery, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
    17. 17Medical Headquarters, Eisai Co, Ltd, Tokyo, Japan
    18. 18Clinical Data Science Department, Eisai Co, Ltd, Tokyo, Japan
    19. 19Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
    20. 20Department of Biostatistics, Keio University School of Medicine, Tokyo, Japan
    21. 21Department of Allergy, Immunology, and Rheumatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
    22. 22Saitama Medical University, Iruma, Japan
    1. Correspondence to Dr Yuko Kaneko; ykaneko.z6{at}keio.jp

    Abstract

    Objectives The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial.

    Methods The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety.

    Results The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index.

    Conclusions The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX.

    Trial registration number NCT03505008.

    • Rheumatoid Arthritis
    • Adalimumab
    • Methotrexate
    • Biological Therapy
    • Pharmacokinetics

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    Footnotes

    • Handling editor Josef S Smolen

    • Collaborators MIRACLE study collaborators: Keisuke Izumi, Yasushi Kondo, Keiko Yoshimoto, Takahisa Gono, Sung-Hwan Park, Han Joo Baek, Yun Jong Lee, In Ah Choi, Jinhyun Kim, Ping-Ning Hsu, Chun-Ming Huang, Meng-Yu Weng, Wan-Yu Sung, Tien-Tsai Cheng.

    • Contributors YK is a guarantor. HTamai and YK had full access to all data in this study and assumed responsibility for the integrity of the data and accuracy of data analysis. HTamai, YN, MM, HM, TT and YK contributed to the concept and design. Acquisition of data was done by all authors except YN, MM, HM, GT and YS. Statistical analyses of data were done by HTamai, GT and YS. Interpretation of data was done by HTamai and YK. The first draft of the manuscript was written by HTamai and YK. All authors contributed to critical revision of the manuscript for important intellectual content. Supervision was done by HTamai, TT and YK. All authors read and approved the final manuscript.

    • Funding This trial was funded by Eisai Co., Ltd. The funder of the study had no role in data collection, analysis, and interpretation.

    • Competing interests HTam received honoraria from AbbVie, Eisai; support for attending meetings from PhRMA. KI received grants from Mitsubishi-Tanabe, Eli Lilly; honoraria from AbbVie, Eisai, Pfizer, Mitsubishi-Tanabe, Janssen, Novartis, UCB, Daiichi-Sankyo, Eli Lilly, Gilead Sciences, AstraZeneca, Asahi Kasei, Chugai, Bristol-Myers Squibb. TM received consulting fees from Eisai, Gilead Sciences; honoraria from Eisai, AbbVie, Eli Lilly, Gilead Sciences, Asahi Kasei. KS received grants/research support from Novartis, Astellas, AbbVie, Bristol-Myers Squibb, Yuhan; consulting fees from KD Bio. SH received grants from AbbVie, Asahi Kasei, Chugai, Eisai, Eli Lily, Otsuka, Taisho, UCB; honoraria from AbbVie, Asahi-Kasei, Astellas, AstraZeneca, Ayumi, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Glaxo SmithKline, Janssen, Nihon-Shinyaku, Novartis, Otsuka Pharmaceutical, Pfizer, Taisho, Tanabe-Mitsubishi, UCB; participated on advisory boards of AbbVie, Astellas, Bristol Myers Squibb, Eisai, Eli Lilly, Gilead Sciences, Janssen, Taisho, UCB. SS received honoraria from AbbVie, Pfizer. HY received grants from AbbVie, Boehringer Ingelheim, Gilead Sciences, Nippon Shinyaku, Asahi Kasei, Chugai, Eisai, Mitsubishi-Tanabe, Taisho; honoraria from AbbVie, Asahi Kasei, Astellas, Daiichi Sankyo, Eisai, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer Ingelheim, Bayer, Viatris, Kissei, Takeda, Mitsubishi-Tanabe, Chugai, Novartis. MK received grants and royalties from MBL; consulting fees from Boehringer Ingelheim, Mochida, Kissei, GSK, AstraZeneca, Mitsubishi-Tanabe, Janssen, Biogen; received honoraria from Boehringer Ingelheim, Chugai, Asahi Kasei; participated on advisory board of Argenx. TI received honoraria from Asahi Kasei, GSK, Chugai, Pfizer, Eli Lilly, Boehringer-Ingelheim, AstraZeneca. HK received a grant from Pfizer, AbbVie, Asahi Kasei, Boehringer Ingelheim, Chugai, Eisai, Mitsubishi-Tanabe, Taisho; consulting fees from Sanofi; honoraria from AbbVie, Asahi Kasei, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer. TK received grant/research support from AbbVie, Astellas, Chugai; honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Pfizer, Eisai, Taisho, UCB; participated on board of JCR subcommittee on Guidelines for RA Therapeutics. YN is a shareholder and employee of Eisai. MM is a shareholder and employee of Eisai. HM is an employee of Eisai. YS received honoraria from Mochida. WT received consulting fees and honoraria from Eli Lilly, Eisai; honoraria from Pfizer. TT received consulting fees from AbbVie, Eli Lilly, Gilead Sciences, Mitsubishi-Tanabe, Taisho; honoraria from AbbVie, Astellas, AstraZeneca, Chugai, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe, Pfizer, Taisho. YK received grants from AbbVie, Asahi Kasei, Ayumi, Boehringer Ingelheim, Chugai, Eisai, Gilead Sciences, Mitsubishi-Tanabe, Taisho, UCB; consulting fees from AbbVie, Asahi Kasei, Bristol-Myers Squibb, Eli Lilly, Gilead Sciences, Pfizer, Taisho, UCB; honoraria from AbbVie, Asahi Kasei, Astellas, AstraZeneca, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Glaxo SmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Taisho, UCB. The other coauthors declare no relevant conflicts of interest.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.