We proposed that using methotrexate to treat patients with symptomatic knee osteoarthritis (OA) could be a practical and safe treatment to reduce synovitis and, consequently, pain. Despite a moderate standard effect size, the analgesic effect was of borderline clinical meaningfulness.
Current treatments for OA are severely limited so there is an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. Methotrexate is the gold standard treatment for synovitis in other forms of arthritis. We proposed that using methotrexate to treat patients with symptomatic knee OA could be a practical and safe treatment to reduce synovitis and, consequently, pain.
We undertook a pragmatic randomised, double-blind trial of oral methotrexate compared to placebo for the reduction of pain in participants with knee OA. Participants were randomised on a 1:1 basis to methotrexate or placebo, in addition to ongoing usual care, with dose escalation over 8 weeks and a maintenance dose for the remainder of the study. The primary endpoint was average knee pain during the previous week at 6-months. Secondary endpoints included pain, quality-of-life and adverse events.
Participants with symptomatic (visual analogue scale pain 4/10) and radiographic tibiofemoral knee OA, fulfilling clinical radiology criteria, were recruited across UK primary and secondary care.
Methotrexate added to usual care demonstrated significant reduction in knee OA pain at six months, and significant improvements in pain, stiffness and function. Despite a moderate standard effect size, the analgesic effect was of borderline clinical meaningfulness.
Kingsbury SR, Tharmanathan P, Arden NK, et al. Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial. Trials. 2015 Mar 4;16:77. https://doi.org/10.1186/s13063-015-0602-8 PMID: 25872649
Kingsbury SR, Tharmanathan P, Keding A, et al. Significant pain reduction with oral methotrexate in knee osteoarthritis; results from the promote randomised controlled phase iii trial of treatment effectiveness. 2019 Osteoarthritis Research Society International (OARSI) World Congress in Toronto, Canada. Abstract. Volume 27, Supp 1, S84-S85, https://www.oarsijournal.com/issue/S1063-4584(19)X0004-7
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Department of Health Sciences, University of York, York
Division of Rheumatic and Musculoskeletal Disease and National Institute of Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds
NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Oxford
Department of Rheumatology, Maidstone and Tunbridge Wells NHS Trust, Pembury, Tunbridge Wells, Kent
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK
Academic Rheumatology, University of Nottingham, Nottingham
Department of Rheumatology and NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton
Guy’s and St Thomas’ Hospitals Foundation NHS Trust, London,
York Hospitals NHS Foundation Trust, Wigginton Road, York,
Rheumatology Department, St Peters Hospital, Guildford Road, Chertsey, Surrey,
Institute of Integrative Biology, University of Liverpool and Institute of Ageing and Chronic Disease, University Hospital Aintree, Liverpool
Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester
Research Institute for Primary Care and Health Sciences, Keele University, Keele
Department of Rheumatology, King’s College London School of Medicine, King’s College London and Department of Rheumatology, King’s College Hospital, London
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, and Imperial College London, London
The research was funded by an Arthritis Research UK Clinical Studies Grant (reference number: 20186). The project was started in October 2012 and completed in September 2016.
ISRCTN77854383 (registered: 25 October 2013).