Clinical rheumatology · 2026
Effect of different folic acid doses on methotrexate-related toxicity and its association with erythrocyte methotrexate-polyglutamates in patients with rheumatic diseases: a single-center exploratory randomized controlled trial.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Yoshida Yusuke, Hosokawa Yohei, Taogoshi Takanori, Oka Naoya, Kobayashi Hiroki, Kidoguchi Genki, Araki Kei, Ishitoku Michinori, Sugimoto Tomohiro, Mokuda Sho, Matsuo Hiroaki, Hirata Shintaro
Аннотация
INTRODUCTION: Folic acid is routinely co-administered with methotrexate (MTX) to reduce toxicity; however, the optimal dose remains unclear. This study investigated whether increasing the weekly folic acid dose from 5 to 10 mg reduces MTX-related toxicity in patients receiving stable-dose MTX therapy.
METHODS: In this single-center, open-label, randomized controlled trial, 44 patients with rheumatic diseases on stable-dose MTX either received 10 mg (ARM-1) or 5 mg (ARM-2) of folic acid per week for 12 weeks. Liver damage, other MTX-related toxicities, and erythrocyte MTX-polyglutamate (MTX-PG) concentrations were compared between groups using logistic regression analysis or analysis of covariance. Japan Registry of Clinical Trials (number: jRCT1061230085).
RESULTS: Forty-two patients completed the study. The presence of liver damage at Day 84 did not differ significantly between the two groups (OR 0.41, 95% CI, 0.01-5.75, p = 0.506). Adjusted mean differences in aspartate transaminase and alanine transaminase at Day 84 between the groups were - 0.33 U/L (95% CI, - 2.68 to 2.02; p = 0.779) and - 0.44 U/L (95% CI, - 5.39 to 4.51; p = 0.859). Comparison of outcomes between groups at Day 84 showed no significant differences in any outcomes, except for fatigue severity (adjusted mean difference, - 0.87; 95% CI, - 1.71 to - 0.04; p = 0.041). Baseline fatigue was associated with baseline MTX-PG2 or MTX-PG1-2 concentrations (OR, 1.06; p = 0.049 or OR, 1.03; p = 0.040, respectively).
CONCLUSIONS: Increasing folic acid dose to 10 mg/week showed little effect on reducing MTX-related toxicity, although it may improve fatigue in selected patients. Key Points • Increasing the weekly folic acid dose from 5 mg to 10 mg showed no additional benefit in reducing methotrexate-related toxicity in patients on stable-dose MTX. • Higher-dose folic acid was associated with improved fatigue severity, indicating a potential therapeutic option for patients who develop fatigue.
METHODS: In this single-center, open-label, randomized controlled trial, 44 patients with rheumatic diseases on stable-dose MTX either received 10 mg (ARM-1) or 5 mg (ARM-2) of folic acid per week for 12 weeks. Liver damage, other MTX-related toxicities, and erythrocyte MTX-polyglutamate (MTX-PG) concentrations were compared between groups using logistic regression analysis or analysis of covariance. Japan Registry of Clinical Trials (number: jRCT1061230085).
RESULTS: Forty-two patients completed the study. The presence of liver damage at Day 84 did not differ significantly between the two groups (OR 0.41, 95% CI, 0.01-5.75, p = 0.506). Adjusted mean differences in aspartate transaminase and alanine transaminase at Day 84 between the groups were - 0.33 U/L (95% CI, - 2.68 to 2.02; p = 0.779) and - 0.44 U/L (95% CI, - 5.39 to 4.51; p = 0.859). Comparison of outcomes between groups at Day 84 showed no significant differences in any outcomes, except for fatigue severity (adjusted mean difference, - 0.87; 95% CI, - 1.71 to - 0.04; p = 0.041). Baseline fatigue was associated with baseline MTX-PG2 or MTX-PG1-2 concentrations (OR, 1.06; p = 0.049 or OR, 1.03; p = 0.040, respectively).
CONCLUSIONS: Increasing folic acid dose to 10 mg/week showed little effect on reducing MTX-related toxicity, although it may improve fatigue in selected patients. Key Points • Increasing the weekly folic acid dose from 5 mg to 10 mg showed no additional benefit in reducing methotrexate-related toxicity in patients on stable-dose MTX. • Higher-dose folic acid was associated with improved fatigue severity, indicating a potential therapeutic option for patients who develop fatigue.