Methotrexate in Osteoarthritis: Systematic Review Shows Promise for Stiffness Relief

Introduction

Osteoarthritis (OA), especially in the knee and hand, is one of the most common chronic musculoskeletal disorders worldwide. Patients often struggle with pain, stiffness, and disability, yet effective pharmacological options remain limited. Methotrexate (MTX), traditionally used in rheumatoid arthritis, is now being studied as a possible treatment for OA due to its anti-inflammatory properties.

Study Overview

The systematic review and meta-analysis, published in Inflammopharmacology (2025), was designed to evaluate the clinical efficacy of methotrexate (MTX) in osteoarthritis (OA). The authors followed PRISMA guidelines to ensure methodological rigor.

Search Strategy

• Comprehensive searches were performed in PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar up to August 2024.

• Both published and unpublished randomized controlled trials (RCTs) were considered.

• Keywords included “methotrexate,” “osteoarthritis,” “randomized controlled trial,” and “calcific joint disease.”

Inclusion & Exclusion Criteria

• Included: RCTs evaluating methotrexate in knee or hand osteoarthritis patients, with outcomes reported on pain, stiffness, or function.

• Excluded: Observational studies, case reports, animal models, and trials without a control group.

Patient Population

• 5 RCTs met the eligibility criteria, comprising a total of 465 participants.

• 229 patients received methotrexate (oral or intramuscular, 7.5–15 mg/week), while 236 received placebo or standard care.

• Mean participant age ranged from 50–70 years, reflecting typical OA demographics.

• Most patients had moderate-to-severe OA with significant baseline pain and stiffness.

Intervention Details

• Methotrexate dosing regimens varied slightly across trials (commonly 7.5–15 mg weekly, with or without folic acid supplementation).

• Treatment duration ranged from 3 months to 12 months.

• Some studies combined MTX with background analgesics or NSAIDs, while others used MTX monotherapy.

Outcome Measures

• Primary outcomes: Pain, stiffness, and physical function (measured using WOMAC, VAS, or AUSCAN scores depending on the joint studied).

• Secondary outcomes: Patient global assessment, inflammatory markers, and safety profile.

Data Analysis

• Results were pooled using a random-effects model to account for heterogeneity between studies.

• Standardized Mean Difference (SMD) with 95% Confidence Interval (CI) was reported.

• Subgroup analysis was performed for 6-month follow-up vs. end-of-study outcomes.

• Risk of bias was assessed using the Cochrane Risk of Bias tool, and overall evidence quality was graded via the GRADE system.

Risk of Bias & Evidence Strength

• Most studies were of moderate quality, with some risk of bias due to small sample sizes and variable blinding methods.

• According to GRADE, the strength of evidence for stiffness improvement was moderate, while for pain and function, it was low to very low.

Important Findings

• Stiffness Relief: MTX significantly reduced stiffness in both knee and hand OA.

  • End of follow-up: SMD = –0.36 (95% CI: –0.57 to –0.15, p < 0.01)

  • At 6 months: SMD = –0.48 (95% CI: –0.70 to –0.27, p < 0.01)

• Pain & Function: Improvements in pain and function were less consistent and not statistically robust.

• Evidence Quality: Findings are promising but limited by small sample sizes. More rigorous RCTs are required.

Why Methotrexate in Osteoarthritis Matters

Stiffness is one of the most disabling symptoms of osteoarthritis, significantly impacting daily activities. If future trials confirm methotrexate’s benefits, this widely available drug could be repurposed as a cost-effective therapy for OA management.

Future Research Needs

1. Larger, multicenter RCTs with long-term follow-up.

2. Broader outcomes, including validated pain and quality-of-life measures.

3. Safety monitoring, especially in older adults with comorbidities.

4. Mechanistic studies to clarify how methotrexate works in OA (e.g., synovitis, low-grade inflammation).

Conclusion

Methotrexate may offer clinically relevant improvements in stiffness for osteoarthritis patients, but current evidence remains preliminary. Further large-scale studies are essential before integrating MTX into OA treatment guidelines.

References

1. Gao X, Chen Z, Li Q, et al. Methotrexate for osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Inflammopharmacology. 2025;33:135–144. doi:10.1007/s10787-024-01604-x

2. Kingsbury SR, Conaghan PG, McDermott MF. The role of the NLRP3 inflammasome in osteoarthritis: a novel therapeutic target? Semin Arthritis Rheum. 2011;40(5):485-496.

3. Abou-Raya A, Abou-Raya S, Khadrawi T, Helmii M. Methotrexate in the treatment of symptomatic knee osteoarthritis: randomized placebo-controlled trial. Ann Rheum Dis. 2014;73(8):1432-1438.

4. Wenham CY, Conaghan PG. New horizons in osteoarthritis. BMJ. 2013;346:f493.

   
   

   About the Author

   Dr. Debjyoti Dutta is a consultant in Pain Medicine at Samobathi Pain Clinic and Fortis Hospital, Kolkata, and the Founder of Asian Pain Academy. He is actively involved in clinical practice, research, and education in interventional pain management, with a special interest in ultrasound-guided procedures and evidence-based pain medicine. Through his clinics and teaching initiatives, Dr. Dutta has trained doctors from across India and abroad, contributing to the growth of pain medicine as a specialty.