Single-center open-label RCT in 44 Japanese patients with rheumatic diseases (mostly RA) on stable-dose MTX, comparing folic acid 10 mg/week (ARM-1) vs. 5 mg/week (ARM-2) for 12 weeks on MTX-related toxicity and erythrocyte MTX-polyglutamate (MTX-PG) concentrations.
No significant difference in liver damage at Day 84 (OR 0.41, 95% CI 0.01–5.75, p=0.506); AST and ALT changes were nearly identical between groups (adjusted mean differences: −0.33 U/L and −0.44 U/L, both p>0.77). The only significant difference was fatigue severity, which improved more in the 10 mg arm (adjusted mean difference −0.87, 95% CI −1.71 to −0.04, p=0.041). Baseline fatigue correlated with short-chain MTX-PG1-2 concentrations.
- Small sample (n=42 completers) from a single center in Japan, with wide confidence intervals that cannot exclude clinically meaningful differences in hepatotoxicity. - Open-label design makes subjective outcomes like fatigue susceptible to placebo effects. - Patients received lower MTX doses than typical Western populations, limiting generalizability.
Routine escalation of folic acid from 5 mg to 10 mg/week does not appear to reduce MTX hepatotoxicity or most other toxicities in patients on stable-dose MTX. For patients who develop MTX-related fatigue, increasing folic acid to 10 mg/week may be worth considering, especially if short-chain MTX-PG levels are elevated.
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