Efficacy and safety of methotrexate in osteoarthritis: A systematic review and meta-analysis of randomized controlled trials

Abstract

Objective: To evaluate the efficacy and safety of methotrexate (MTX) for osteoarthritis (OA).

Design: A systematic search of databases and clinical trial registers was conducted in September 2024 to identify randomized controlled trials (RCTs) comparing MTX with placebo. The evaluation focused on OA symptoms, including pain and function; quality of life; safety and OA-related biomarkers (biochemical and imaging markers). Meta-analysis and the minimal clinically important difference (MCID) were utilized to determine statistical and clinical significance. The risk of bias (RoB) and certainty assessment were evaluated using the RoB 1 tool, the RoB due to missing evidence tool, and the Grades of Recommendation, Assessment, Development and Evaluation Working Group framework.

Results: Six RCTs involving 602 participants were included, all with a low RoB. Compared to the placebo, MTX significantly relieved pain (standardized mean difference [SMD], -0.44; 95% confidence interval [95% CI], -0.67 to -0.20, P = 0.0003) in OA patients (knee and hand). Functional improvement with MTX was observed only in knee OA patients (weighted mean difference [WMD], -7.36; 95% CI, -14.34 to -0.38, P = 0.045). The point estimates did not exceed the upper limit of MCID, suggesting the possible clinical significance of the findings. No differences were observed for quality-of-life outcome (SMD, -0.74; 95% CI, -153 to 0.05, P = 0.07). MTX did not increase the incidence of adverse events (risk ratio, 0.88; 95% CI, 0.75 to 1.02, P = 0.09).

Conclusions: MTX can alleviate pain in patients with OA and improve functional recovery in knee OA without raising safety concerns.

Keywords: Efficacy; Meta-analysis; Methotrexate; Osteoarthritis; Safety.