Pain Reduction with Oral Methotrexate in Knee Osteoarthritis; a Randomized Placebo-Controlled Clinical Trial

Background: Treatments for osteoarthritis are limited. Previous small studies suggest the anti-rheumatic drug methotrexate may be a potential treatment for osteoarthritis pain. Objective: To assess symptomatic benefits of methotrexate in knee osteoarthritis. Design: A multi-center, randomized, double-blind, placebo-controlled trial conducted between 13 June 2014 and 8 September 2017. Setting: Fifteen United Kingdom secondary-care musculoskeletal clinics. Participants: 207 participants with symptomatic, radiographic knee osteoarthritis, knee pain (severity ≥4/10) on most days in the last 3-months, with inadequate response to current medication were approached for inclusion. Interventions: Participants were randomized 1:1 to once-weekly oral methotrexate (6-week escalation 10mg-25mg) or matched placebo over 12-months and continued usual analgesia. Measurements: The primary endpoint was average knee pain (numerical rating scale (NRS) 0-10) at 6-months, with 12-month follow-up to assess longer-term response. Secondary endpoints included knee stiffness and function outcomes, and adverse events. Results: 155 participants (64% women, mean age 60.9 years, 50% Kellgren-Lawrence Grade 3-4) were randomized to methotrexate (n=77) or placebo (n=78). Follow-up was 86% (n=134; MTX 66, Placebo 68) at 6-months. Mean(SD) knee pain reduced from 6.4(1.80) at baseline to 5.1(2.32) at 6-months in the MTX group, and from 6.8(1.62) to 6.2(2.30) in the placebo group. The primary intention-to-treat analysis revealed a statistically significant pain reduction of 0.79 NRS points in favour of MTX (95%CI[0.08-1.51];p=0.030). There were also statistically significant treatment-group differences in favour of MTX at 6-months for WOMAC stiffness (0.60 points, 95%CI[0.01-1.18];p=0.045) and function (5.01 points, 95%CI[1.29-8.74],p=0.008). Treatment-compliance analysis supported a dose-response effect. Four unrelated serious adverse events were reported (methotrexate:2, placebo:2). Limitations: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance. Conclusions: Oral methotrexate added to usual medications demonstrated statistically significant reduction in knee osteoarthritis pain, stiffness and function at 6-months. Funding Source: Versus Arthritis 20186. Trial registration number: ISRCTN77854383 (https://doi.org/10.1186/ISRCTN77854383); EudraCT: 2013-001689-41 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number%3A2013-001689-41)