• Sarah R Kingsbury, Puvan Tharmanathan, Ada Keding, Fiona E Watt, David L Scott, Edward Roddy, Fraser Birrell, Nigel K Arden, Mike Bowes, Catherine Arundel, Michelle Watson, Sarah J Ronaldson, Catherine Hewitt, Michael Doherty, Robert J Moots, Terence W O'Neill, Michael Green, Gulam Patel, Toby Garrood, Christopher J Edwards, Phil J Walmsley, Tom Sheeran, David J Torgerson, and Philip G Conaghan.
• Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre, Leeds, United Kingdom (S.R.K., P.G.C.).
• Ann. Intern. Med. 2024 Sep 1; 177 (9): 114511561145-1156.

BackgroundTreatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain.ObjectiveTo assess symptomatic benefits of methotrexate in knee OA (KOA).DesignA multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41).Setting15 secondary care musculoskeletal clinics in the United Kingdom.ParticipantsA total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion.InterventionParticipants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia.MeasurementsThe primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs).ResultsA total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate (n = 77) or placebo (n = 78). Follow-up was 86% (n = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2).LimitationNot permitting oral methotrexate to be changed to subcutaneous delivery for intolerance.ConclusionOral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months.Primary Funding SourceVersus Arthritis.

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