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 of movement limitation, and 25% cannot perform major activities of daily living. While KOA has traditionally been regarded as a non-inflammatory disease driven by mechanical wear and tear, recent studies have highlighted the pivotal role of synovitis in KOA pathogenesis^3,4,5. Synovitis is not only closely associated with pain and stiffness in KOA patients but also accelerates cartilage deterioration and the progression of the disease. Thus, targeting synovitis has emerged as a promising therapeutic strategy for KOA management.

The current clinical guidelines for the American College of Rheumatology⁶ primarily focus on symptom relief, including topical treatments (e.g., NSAID gels), oral analgesics (e.g., acetaminophen and NSAIDs), and non-pharmacological interventions such as physical therapy and weight management. Although these approaches provide short-term relief, they do not effectively halt the persistent inflammatory processes. Although NSAIDs are currently the most commonly recommended treatment for KOA in international guidelines and clinical practice, their potential adverse effects and contraindications make them unsuitable for many patients⁷. This has led to a growing need for novel therapeutic options that can both alleviate symptoms.

Methotrexate, as a disease-modifying antirheumatic drug, is the standard therapy for treating inflammatory arthritis. MTX inhibits dihydrofolate reductase, thereby reducing the synthesis of purines and pyrimidines, which suppresses the proliferation and activation of inflammatory cells⁸. Additionally, MTX increases adenosine concentrations, further modulating immune responses and reducing the production of pro-inflammatory cytokines (e.g., TNF-α and IL-6)⁹. These actions effectively inhibit synovitis, a key pathological component of KOA. Given the central role of synovitis in KOA, MTX holds the potential for reducing pain, alleviating stiffness, and improving joint function by modulating inflammation.

Despite the well-established efficacy of MTX in the treatment of rheumatoid arthritis, its effectiveness in managing KOA remains a topic of ongoing debate. Some randomized controlled trials have failed to demonstrate moderate clinical benefits of MTX over placebo, while other studies have shown notable improvements in pain relief, stiffness reduction, and functional improvement. In adult patients with symptomatic knee osteoarthritis, does oral methotrexate compared with placebo or non‑methotrexate control improve pain, stiffness, and physical function as measured by the WOMAC scale.

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 the use of methotrexate administered orally, irrespective of formulation, dose, or treatment duration. Studies were included only if any concomitant medications or cointerventions were administered equally across all study groups. The comparison intervention was placebo, and studies were eligible when the only difference between the intervention and control groups was the addition of methotrexate. If additional treatments such as nonsteroidal anti-inflammatory drugs were used, they had to be identical in both groups to avoid confounding effects.

The primary outcome of interest was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score. Secondary efficacy outcomes included changes in WOMAC pain, WOMAC stiffness, and WOMAC physical function scores. All included studies reported outcomes using the same standardized WOMAC 0–100 scale; therefore, no score conversion was required. For studies reporting multiple follow-up time points, the time point closest to 24 weeks was selected because this represented the most common treatment duration among the included trials. The available follow-up durations were 16 and 24 weeks, and when both were reported, the 24-week data were preferentially included in the analysis. Only randomized controlled trials were considered eligible for inclusion, whereas crossover trials were excluded.

2. Search strategy

One reviewer (YT) conducted systematic searches in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Infrastructure (CNKI) from inception to May 1, 2026, without language restrictions. The core search terms combined “Knee Osteoarthritis” (MeSH and free‑text: knee osteoarthritis, knee OA, gonarthrosis) and “Methotrexate” (MeSH and free‑text: methotrexate, MTX, rheumatrex) using the Boolean operator AND. A randomized controlled trial filter and a human studies filter were applied. All searches were performed in the title, abstract, and keyword fields. Database‑specific adaptations were made: PubMed used MeSH and Title/Abstract syntax; Embase used EMTREE terms; CENTRAL used the standard Cochrane RCT filter; CNKI used Chinese keywords. In addition, the WHO International Clinical Trials Registry Platform (ICTRP) was searched using the terms “knee osteoarthritis” AND “methotrexate” to identify ongoing or unpublished trials (grey literature). The exact execution date for all databases was May 1, 2026. To ensure thoroughness, the reference lists of identified trials and systematic reviews were manually reviewed. The complete search strategy is provided in Supplementary Table 1.

3. Study selection

After eliminating duplicate studies, the relevance of all titles and abstracts was independently evaluated by two reviewers (YT and NW). Moreover, full texts of the selected articles were obtained to assess their eligibility for inclusion. Disagreements among the reviewers were resolved either through consensus or by consulting a third reviewer (SH).

4. Data collection process

Two reviewers (YT and NW) employed a standardized form for data extraction from the included trials independently. When change SDs were not reported, they were imputed using the formula SD_change = √(SD_baseline² + SD_final² – 2r·SD_baseline·SD_final) with a conservative correlation coefficient r = 0.5. Corresponding authors were additionally contacted via email to acquire any necessary missing data. Discrepancies were resolved either through consensus or by inviting a third reviewer (SH) for assistance.

5. Safety outcomes

Safety outcomes were additionally extracted from each included trial, including adverse events, serious adverse events, treatment discontinuations or withdrawals, liver-function abnormalities, blood-count abnormalities, and other reported laboratory abnormalities. These outcomes were summarized in a structured descriptive table because the included trials differed in safety-outcome definitions, reporting formats, and completeness of laboratory-abnormality data.

6. Quality assessment

Two independent reviewers (YT and NW) assessed the risk of bias according to the Cochrane tool in randomized clinical trials¹¹, which consists of five domains. Each trial was assigned a study-level risk for each domain, indicating the level of bias risk as low, high, or some concerns. The certainty of evidence in the meta-analysis was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, based on established guidelines¹². Any disagreements in the assessments were resolved by consensus or by inviting a third reviewer (SH) to make the final decision when consensus could not be reached.

7. Data synthesis 

Data synthesis was conducted using RevMan (The Cochrane Collaboration). To maintain consistency and account for potential biases, all analyses were conducted by the intention-to-treat principle, which includes all randomized participants regardless of their adherence to the intervention. For continuous variables, the inverse variance random-effects model was used to pool the data. The between-study variance (τ²) was estimated using the DerSimonian-Laird estimator¹³, the default method in RevMan 5.4. All four included trials reported WOMAC scores on a standardized 0–100 scale; therefore, mean differences (MD) were used instead of standardized mean differences (SMD), as MD is more clinically interpretable when the same metric is used. The results are reported as MD with the corresponding 95% confidence intervals (CI). A p-value below 0.05 was considered statistically significant. Heterogeneity was quantified using the I² test. Because only four studies were included (k < 10), publication bias was not formally assessed (e.g., funnel plot or Egger’s test), as such tests lack sufficient power and are not recommended by Cochrane guidance in this setting. These rigorous statistical methods and principles were adopted to provide a comprehensive and robust analysis of the available data. Additionally, as only four studies were included, formal publication bias tests (e.g., funnel plot asymmetry or Egger’s test) were not performed, which are unreliable when the number of studies is less than 10 and could lead to misleading conclusions.

8. Subgroup analysis

Subgroup analyses were conducted according to follow-up duration (<6 months and ≥6 months).

9. Sensitivity analyses

Sensitivity analyses were performed in this meta-analysis through (1) using fixed-effects models, (2) excluding trials with a high or unknown risk of bias, (3) excluding trials with less than or equal to 6 months, and (4) only including English literature. These analyses aimed to assess the robustness of the findings and enhance the reliability of the results.

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