Methotrexate for Osteoarthritis: What Does the Evidence Say?

Osteoarthritis (OA) is a leading cause of disability worldwide, characterised by chronic pain and reduced quality of life. Despite its prevalence, pharmacotherapy options remain limited. Inflammation has emerged as a promising target, with anti-inflammatory agents used in other rheumatological conditions, such as methotrexate (MTX), being explored for OA treatment. MTX is a cornerstone therapy in rheumatoid arthritis (RA), owing to its broad immunomodulatory properties and well-established clinical efficacy. This review summarises evidence from seven randomised controlled trials and two observational studies investigating MTX in knee and hand OA. Studies varied considerably in terms of sample size, study population, MTX dosage and follow-up duration. Overall, study outcomes were conflicting in terms of MTX effect on OA symptoms. However, trials with larger sample sizes and higher MTX doses (> 15 mg/week) consistently reported benefits for pain in knee and hand OA, with a favourable safety profile, supporting MTX as a potential OA treatment. There is still a need for further research to refine dosing strategies, assess longer term use and evaluate cost-effectiveness. Given the complex heterogeneity of OA, stratification by OA phenotype, particularly consideration of local and systemic inflammation, may also be important to underpin selection of a population most likely to respond to MTX treatment. Considerations for the use of MTX in older adults, where comorbidities and polypharmacy may impact use, will also be essential for clinical implementation.