Methotrexate for the treatment of osteoarthritis: a systematic review and meta-analysis of randomized controlled trials

Methotrexate (MTX) has been proposed to treat osteoarthritis (OA) because of its anti-inflammatory effects, but randomized trial results are inconsistent. We performed a systematic review and meta-analysis of randomized trials to clarify MTX’s efficacy and safety in adults with knee or hand OA. We searched MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov from inception through July 2025. Randomized controlled trials (RCTs) comparing MTX (any dose) with placebo were eligible. We pooled continuous outcomes as mean differences (MDs) and standardized mean differences (SMDs) and dichotomous outcomes as risk ratios (RRs) using random-effects models. Seven RCTs with follow-up ranging between 3 and 12 months were included. MTX did not significantly reduce overall pain compared to placebo (SMD −0.22; 95% CI, −0.48 to 0.04; I² = 62%). MTX reduced stiffness (SMD −0.29; 95% CI, −0.51 to −0.08; I² = 36%), a finding that was consistent in subgroup analyses by joint site (knee and hand). No significant benefits were observed for physical function (SMD −0.50; 95% CI, −1.14 to 0.14; I² = 93%), WOMAC total score (SMD −0.08; 95% CI, −0.33 to 0.17; I² = 93%), or quality-of-life measures (SMD −0.43; 95% CI, −1.08 to 0.22; I² = 90%). Rates of adverse events and serious adverse events were similar between groups. MTX provides a consistent reduction in stiffness but does not significantly reduce pain, improve function, or enhance quality of life. Phenotype-driven, dose-optimized, and longer-term trials that incorporate imaging or synovial biomarkers are needed to define who may benefit the most.