0332: Safety, Short- and Long-Term Efficacy of Methotrexate in Osteoarthritis: A Systematic Review and Meta-Analysis

Background/Purpose: Methotrexate (MTX), traditionally used for inflammatory conditions like rheumatoid arthritis, has well-established anti-inflammatory properties, recently gained interest as a potential therapeutic option for osteoarthritis (OA). Current treatments largely focus on symptom management, with limited options for altering disease course. This study aims to evaluate the safety and efficacy of MTX in reducing OA symptoms in both the short and long term.

Methods: We systematically searched PubMed, Web of Science, Embase, Ovid, and Scopus from inception to April 22, 2025. Studies evaluating the safety and efficacy of MTX in OA were included (Fig. 1). The primary outcome was pain, measured by the Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS). Outcomes were stratified by follow-up duration: short-term (less than 6 months), medium-term (6 months and 9 months), and long-term (12 months). Data were extracted and analyzed using Review Manager 5.4 (RevMan) software.

Results: This systematic review and meta-analysis included 14 studies in the qualitative synthesis and 8 in the meta-analysis, encompassing 1251 and 649 patients, respectively. MTX significantly reduced pain (SMD: –0.47; 95% CI: –0.68 to –0.26). Subgroup analyses by treatment duration showed SMDs of –0.46 (95% CI: –0.75 to –0.17) at < 6 months, –0.75 (95% CI: –1.2 to –0.29) at 6 months, –0.42 (95% CI: –1.35 to 0.51) at 9 months, and –0.06 (95% CI: –0.46 to 0.34) at 12 months. For the WOMAC score, MTX had a significant overall effect (SMD: –0.71; 95% CI: –1.2 to –0.22), with subgroup SMDs of –0.45 (95% CI: –0.88 to –0.01) at < 6 months, –1.81 (95% CI: –4.56 to 0.94) at 6 months, –0.37 (95% CI: –0.78 to 0.04) at 9 months, and –0.27 (95% CI: –0.68 to 0.13) at 12 months. For physical function, the overall effect was significant (SMD: –0.53; 95% CI: –0.84 to –0.23), with subgroup SMDs of –0.46 (95% CI: –0.76 to –0.16) at < 6 months, –0.88 (95% CI: –1.73 to –0.03) at 6 months, –0.35 (95% CI: –0.81 to 0.12) at 9 months, and –0.19 (95% CI: –0.58 to 0.19) at 12 months. On stiffness, MTX also had an overall significant effect (SMD: –0.44; 95% CI: –0.65 to –0.23). Subgroup SMDs were –0.33 (95% CI: –0.68 to 0.01) at < 6 months, –0.52 (95% CI: –0.81 to –0.24) at 6 months, –0.39 (95% CI: –1.49 to 0.72) at 9 months, and –0.34 (95% CI: –1.43 to 0.75) at 12 months (Fig. 2). Our results stated that there is an overall significant difference in adverse events (AEs) (RR, 0.75; 95% CI, 0.60 to 0.94), with a significant difference in mild AEs (RR, 0.77; 95% CI, 0.61 to 0.97) and no significant difference in serious AEs (RR, 0.65; 95% CI, 0.31 to 1.34) (Fig. 3).

Conclusion: MTX provides significant short- and medium-term improvements in pain, stiffness, and physical function in OA, with the most pronounced benefit observed at 6 months. However, its safety profile in real-world settings requires more thorough investigation. Further large-scale randomized controlled trials are needed to confirm these findings and assess long-term efficacy.