Low-Dose Methotrexate for the Treatment of Inflammatory Knee Osteoarthritis

Importance A recent study reported that methotrexate may reduce joint pain in patients with inflammatory hand osteoarthritis (OA). However, it remains unknown whether methotrexate has similar effects on inflammatory knee OA. Objective To examine whether methotrexate has symptom-relieving and disease-modifying effects for participants with knee OA and effusion-synovitis. Design, Setting, and Participants This multicenter, placebo-controlled randomized clinical trial was conducted at 11 sites in China between July 18, 2019, and January 15, 2023. Community-dwelling patients with inflammatory knee OA with effusion-synovitis on magnetic resonance imaging were included. Interventions Participants were randomly assigned (1:1) to receive methotrexate, up to 15 mg weekly, or placebo using block randomization, stratified by study site. Main Outcomes and Measures The primary outcomes were knee visual analog scale (VAS) pain change and effusion-synovitis maximal area change, over 52 weeks in the intention-to-treat population. Results Of 278 participants screened, 215 participants (mean [SD] age, 60.4 [7.4] years; 191 [89%] female) were randomized (108 to the methotrexate group; 107 to the placebo group), and 175 (81%) completed the trial. Changes in VAS pain and effusion-synovitis maximal area were not significantly different between the methotrexate and placebo group over 52 weeks (between-group difference, 0.3 mm [95% CI, −6.7 to 7.3 mm] for VAS pain; 0.1 cm 2 [95% CI, −0.8 to 1.0 cm 2 ] for effusion-synovitis maximal area). No significant between-group differences were found for any of the prespecified secondary outcomes. At least 1 adverse event occurred in approximately 32 participants (29.6%) in the methotrexate group and 26 participants (24.3%) in the placebo group. Conclusions and Relevance The results of this randomized clinical trial show that, compared to placebo, low-dose methotrexate did not reduce pain or effusion-synovitis over 52 weeks in patients with knee OA and effusion-synovitis. Trial Registration ClinicalTrials.gov Identifier: NCT03815448