Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial.

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.
Competing Interests: 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.
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