Efficacy of Methotrexate on Pain Severity Reduction and Functional Improvement in Knee Osteoarthritis: A Systematic...

Knee osteoarthritis (KOA) is a prevalent degenerative joint disease among the elderly, leading to severe pain and functional impairment. Methotrexate (MTX), a disease-modifying antirheumatic drug with anti-inflammatory properties, may alleviate pain and stiffness in KOA patients and improve functional status. This meta-analysis aims to evaluate the efficacy of oral MTX in patients with KOA. A comprehensive search was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the China National Knowledge Infrastructure (CNKI) databases for literature published up to May 1, 2026, without language restrictions. Randomized controlled trials comparing oral MTX with placebo in adult patients with symptomatic KOA were included. The primary outcome was the change in the WOMAC total score. Secondary outcomes included changes in WOMAC pain, stiffness, and function. Four randomized controlled trials encompassing 366 randomized participants were included. For the primary outcome, data from 343 participants were available for analysis. Secondary outcomes (pain, stiffness, physical function) were based on three trials (281 patients), all showing improvements. MTX moderately reduced the WOMAC total score compared to placebo or control groups (mean difference [MD] = -8.69; 95% confidence interval [CI]: -16.92 to -0.46). Moderate improvements were also observed in WOMAC pain (MD = -2.66; 95% CI: -3.34 to -1.97), stiffness (MD = -0.51; 95% CI: -0.87 to -0.15), and function (MD = -7.10; 95% CI: -13.39 to -0.80). Sensitivity analyses confirmed the robustness of these findings. Oral methotrexate moderately alleviates pain and stiffness in patients with knee osteoarthritis and improves functional status. These preliminary results suggest that methotrexate may have a beneficial effect on pain and function in KOA, providing symptomatic relief without evidence of structural modification. However, the evidence is currently limited and does not support routine clinical use. Further large-scale RCTs are warranted.