Methotrexate Could Improve Pain, Management of Hand Osteoarthritis

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A 20 mg weekly oral dose of methotrexate shows potential as a low-cost treatment for reducing pain and stiffness in patients with symptomatic hand osteoarthritis, according to the results of the METHODS trial.

Results of a randomized controlled trial suggest a commonly prescribed agent for inflammatory joint conditions could be a safe, low-cost treatment for addressing painful hand osteoarthritis.

Named the METHODS trial, results of the study suggest use of a 20mg weekly oral dose of methotrexate had a moderate effect in reducing pain and stiffness in patients with symptomatic hand osteoarthritis following 6 months of treatment relative to placebo therapy.1

“In our study, as with most studies of osteoarthritis, both the placebo group and methotrexate groups’ pain improved in the first month or so,” said Flavia Cicuttini, head of the Musculoskeletal Unit and The Alfred’s Head of Rheumatology at Monash University.2 “However, pain levels stayed the same in the placebo group but continued to decrease in the methotrexate group at three and six months, when they were still decreasing. The pain improvement in the methotrexate group was twice as much as in the placebo group.”

A staple in the management of inflammatory diseases, methotrexate can be found in the treatment algorithms for hundreds of thousands of US patients. With the anti-inflammatory effects of the agent well-documented, some had begun to hypothesize about a potential role in management of hand osteoarthritis. With this in mind, Cicuttini and a team of colleagues from institutions in Australia launched the METHODS study as a multisite, parallel-group, double-blind, randomized, placebo-controlled trial to provide an overview of the efficacy and safety of methotrexate at 6 months in people with hand osteoarthritis and synovitis.1

Investigators recruited all study participants from communities in Melbourne, Hobart, Adelaide, and Perth, Australia. For inclusion in the trial, patients needed to be 40 to 75 years of age, have hand osteoarthritis, and MRI-detected synovitis of grade 1 or more. For the purpose of analysis, hand osteoarthritis was considered having a Kellgren and Lawrence grade of 2 or more in at least 1 joint. Investigators used block randomization, stratified by study site and patient sex, to randomized patients in a 1:1 ratio to receive methotrexate 20 mg or identical placebo orally once-weekly for 6 months.1

The primary outcome of interest for those included in the trial was pain reduction at 6 months, which investigators measured with a 100 mm visual analogue scale (VAS). Investigators assessed the primary outcome of interest in an intention-to-treat population. However, safety outcomes were assessed in all patients who underwent randomization.1

Upon analysis, the mean change in VAS pain at 6 months was -15.2 mm (Standard deviation [SD], 24.0) in the methotrexate group and –7.7 mm (25.3) in the placebo group, which resulted in a mean between-group difference of –9.9 (95% Confidence Interval [CI], –19.3 to –0.6; P =.037) and a standardized mean difference of 0.45 (95% CI, 0.03 to 0.87). When assessing safety, results indicated adverse events were observed among 62% of participants in the methotrexate group and 60% of the placebo group.1

“Based on these results, use of methotrexate can be considered in the management of hand osteoarthritis with an inflammatory pattern. This provides clinicians with a treatment option for this group, which tends to get more joint damage,” Cicuttini added.2

A release from Monash University pointed out Cicuttini and colleagues are planning to conduct an extension trial to address multiple questions raised by results of the current study, including whether women who develop hand osteoarthritis around menopause and often have severe pain and joint damage may benefit from methotrexate.1


  1. Wang Y, Jones G, Keen HI, et al. Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial [published online ahead of print, 2023 Oct 12]. Lancet. 2023;S0140-6736(23)01572-6. doi:10.1016/S0140-6736(23)01572-6
  2. Monash University. Common drug can improve hand osteoarthritis symptoms: Study. EurekAlert! October 12, 2023. Accessed October 19, 2023.