TY - JOUR
T1 - Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose
T2 - results from the MIRACLE trial
AU - MIRACLE Study Group
AU - Tamai, Hiroya
AU - Ikeda, Kei
AU - Miyamoto, Toshiaki
AU - Taguchi, Hiroaki
AU - Kuo, Chang Fu
AU - Shin, Kichul
AU - Hirata, Shintaro
AU - Okano, Yutaka
AU - Sato, Shinji
AU - Yasuoka, Hidekata
AU - Kuwana, Masataka
AU - Ishii, Tomonori
AU - Kameda, Hideto
AU - Kojima, Toshihisa
AU - Nishi, Yurie
AU - Mori, Masahiko
AU - Miyagishi, Hideaki
AU - Toshima, Genta
AU - Sato, Yasunori
AU - Tsai, Wen Chan
AU - Takeuchi, Tsutomu
AU - Kaneko, Yuko
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2024.
PY - 2024
Y1 - 2024
N2 - 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.
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.
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U2 - 10.1136/ard-2024-226350
DO - 10.1136/ard-2024-226350
M3 - Article
C2 - 39366722
AN - SCOPUS:85207254985
SN - 0003-4967
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
M1 - 226350
ER -