RT Journal Article
SR Electronic
T1 Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP ard-2024-226350
DO 10.1136/ard-2024-226350
A1 Tamai, Hiroya
A1 Ikeda, Kei
A1 Miyamoto, Toshiaki
A1 Taguchi, Hiroaki
A1 Kuo, Chang-Fu
A1 Shin, Kichul
A1 Hirata, Shintaro
A1 Okano, Yutaka
A1 Sato, Shinji
A1 Yasuoka, Hidekata
A1 Kuwana, Masataka
A1 Ishii, Tomonori
A1 Kameda, Hideto
A1 Kojima, Toshihisa
A1 Nishi, Yurie
A1 Mori, Masahiko
A1 Miyagishi, Hideaki
A1 Toshima, Genta
A1 Sato, Yasunori
A1 Tsai, Wen-Chan
A1 Takeuchi, Tsutomu
A1 Kaneko, Yuko
A1 
YR 2024
UL http://ard.bmj.com/content/early/2024/10/03/ard-2024-226350.abstract
AB 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.