Efficacy of Methotrexate on Pain Severity Reduction and Functional Improvement in Knee Osteoarthritis: A Systematic Review and Meta-Analysis

Summary

This systematic article and meta‑analysis of four randomized controlled trials (366 participants) show that oral methotrexate moderately reduces pain, stiffness, and impairment of physical function in knee osteoarthritis compared with placebo.

Abstract

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.

Introduction

Knee osteoarthritis (KOA) is among the most prevalent degenerative joint disorders worldwide, particularly common in the elderly population, and a leading cause of pain and disability. Globally, an estimated 654.1 million individuals were living with knee osteoarthritis in 2020, with an age-standardized prevalence rate of 8.3%¹. As the condition advances, patients often experience significant pain and functional impairment, accompanied by a marked increase in the burden of treatment, accounting for 21.3 million years lived with disability²; The functional impact is profound: over 80% of patients with KOA have some degree....

Protocol

The study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines¹⁰. The study protocol was registered with PROSPERO (CRD42024584767). The databases, software, risk-of-bias tool, GRADE approach, and methodological resources used in this systematic review and meta-analysis are listed in the Table of Materials.

1. Criteria for considering studies

Studies were considered eligible if they included adults aged ≥18 years diagnosed with symptomatic knee osteoarthritis. Eligible interventions involved ....

Results

Included studies and study characteristics

Figure 1 presents the PRISMA diagram depicting the process of the meta-analysis. A total of 538 records were identified from the databases. After removing 32 duplicates, 506 records were screened. Of these, 499 were excluded based on title and abstract. The full texts of the remaining 7 articles were assessed for eligibility; 3 were excluded (1 was not a randomized controlled trial, and 2 did not report t.......

Discussion

This systematic review and meta-analysis included a total of 366 participants from four trials. The study demonstrated that oral methotrexate moderately alleviates pain and stiffness associated with knee osteoarthritis and improves functional status compared to placebo or control groups. Overall, these findings support the potential role of methotrexate in the treatment of knee osteoarthritis.

Recent randomized controlled trials^14,15

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
China National Knowledge Infrastructure (CNKI)	CNKI https://oversea.cnki.net/index/	Search date: May 1, 2026	Chinese-language literature search
Cochrane Central Register of Controlled Trials (CENTRAL)	Cochrane Library https://www.cochranelibrary.com/central/about-central	Search date: May 1, 2026	Randomized controlled trial search
Cochrane Handbook	Cochrane https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current	Current online version used by authors	Methodological guidance for systematic review and meta-analysis
Embase	Elsevier https://www.elsevier.com/products/embase https://www.embase.com/	Search date: May 1, 2026	Bibliographic database search
GRADE approach	GRADE Working Group https://www.gradeworkinggroup.org/	GRADE framework	Certainty-of-evidence assessment
Microsoft Excel	Microsoft	Microsoft Excel 2021	Data extraction and table preparation
PRISMA 2020 checklist	PRISMA https://www.prisma-statement.org/	2020 statement	Reporting checklist
PubMed	National Library of Medicine https://pubmed.ncbi.nlm.nih.gov/	Search date: May 1, 2026	Bibliographic database search
RevMan	The Cochrane Collaboration https://revman.cochrane.org/	Version 5.4	Meta-analysis and forest plots
RoB 2 tool	Cochrane https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2	Current online version used by authors	Risk-of-bias assessment
WHO International Clinical Trials Registry Platform (ICTRP)	World Health Organization https://trialsearch.who.int/	Search date: May 1, 2026	Identification of ongoing or unpublished trials