September 09, 2025
2 min read
Key takeaways:
- Low-dose methotrexate did not relieve pain or reduce synovitis in inflammatory knee OA.
- The findings do not support use of methotrexate in inflammatory knee OA.
Low-dose methotrexate failed to improve on placebo in reducing pain or synovitis in patients with inflammatory knee osteoarthritis, according to findings published in JAMA Internal Medicine.
“Inflammation in osteoarthritis is common and an important source of both symptoms and risk for further structural progression,” David J. Hunter, PhD, Florance and Cope chair of rheumatology, and co-director of the Musculoskeletal Health Flagship, at the University of Sydney, told Healio. “At present, we have limited therapeutic options that have been approved for this particular indication. This study was conducted to determine in people with synovitis and symptomatic knee osteoarthritis if methotrexate was helpful in this particular context.”
To that end, Hunter and colleagues conducted a multicenter, placebo-controlled randomized clinical trial across 11 sites in China between July 18, 2019, and January 15, 2023. Participants were community-dwelling patients with inflammatory knee OA with effusion-synovitis on magnetic resonance imaging.
The final analysis included 215 patients from 11 sites in China. Researchers randomly assigned 108 patients to methotrexate up to 15 mg weekly, and 107 to placebo. A total of 175 patients completed the trial. Primary outcomes included change in knee visual analog scale (VAS) pain and effusion-synovitis maximal area over 52 weeks in the intention-to-treat population.
According to the researchers, no significant differences were observed in VAS pain (between-group difference, 0.3 mm; 95% CI, 6.7 to 7.3 mm). The treatment and placebo groups also were comparable in terms of effusion-synovitis maximal area (0.1 cm2; 95% CI, 0.8 to 1 cm2).
“In light of this trial and previous trials of methotrexate that have effects of uncertain clinical significance, we would not advocate for the use of methotrexate for treating inflammatory osteoarthritis based on existing data,” Hunter said. “Potentially larger methotrexate doses may have greater effects, and in particularly in persons with more severe knee pain. Whether the potential associated toxicity merits that intervention might be worthy of further investigation.”
The researchers added that adverse event rates also were comparable, with at least one event being reported in 29.6% of patients in the methotrexate group, vs. 24.3% of those in the placebo group.
“We found that compared to placebo, low-dose methotrexate did not relieve pain or reduce synovitis at 52 weeks in people with inflammatory knee osteoarthritis,” Hunter said. “While methotrexate is generally safe and well-tolerated, it does not appear to have beneficial effects.”
For more information:
David J. Hunter, PhD, can be reached at david.hunter@sydney.edu.au.
Sources/Disclosures
Collapse
Disclosures:
Hunter reports providing consulting advice on scientific advisory boards for Enlivex, Haleon, Novartis, Sanofi, TLCBio and Tissuegene.
