Methotrexate Shows No Benefit in Reducing Pain or Inflammation in Inflammatory Knee Osteoarthritis
A multicenter randomized clinical trial published in JAMA Internal Medicine, has found that methotrexate does not improve pain or reduce effusion-synovitis in patients with inflammatory knee osteoarthritis (OA). Conducted across 11 sites in China, the trial offers critical insight into the lack of efficacy of methotrexate in managing symptoms and inflammation in this specific OA phenotype.
The study included 215 participants with inflammatory knee OA and effusion-synovitis confirmed by MRI. Participants were randomly assigned to receive either low-dose methotrexate (up to 15 mg weekly) or placebo and were followed over 52 weeks. The primary endpoints were changes in knee pain, as measured by visual analog scale (VAS), and effusion-synovitis maximal area.
Results demonstrated no statistically significant differences between the two groups. The between-group difference in VAS pain was 0.3 mm (95% CI, −6.7 to 7.3 mm), and the difference in effusion-synovitis maximal area was 0.1 cm² (95% CI, −0.8 to 1.0 cm²). “Changes in VAS pain and effusion-synovitis maximal area were not significantly different between the methotrexate and placebo group over 52 weeks,” the study reported.
Secondary outcomes, including functional scores and other imaging parameters, also failed to show any meaningful benefit with methotrexate therapy. The consistency of findings across multiple endpoints strengthens the conclusion that methotrexate lacks clinical utility in this OA subtype.
The safety profile was comparable between groups. At least one adverse event occurred in 29.6% of participants in the methotrexate group and 24.3% in the placebo group. These rates align with the known tolerability of low-dose methotrexate, but without evidence of efficacy, the risk-benefit ratio does not favor its use in this context.
“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,” the authors concluded.
For practicing rheumatologists, this study underscores the need to distinguish between inflammatory mechanisms in hand OA, where methotrexate may have benefit, versus knee OA, where this trial indicates it does not. Treatment decisions should remain guided by robust evidence of disease-specific efficacy.
Reference
Zhu Z, Yu Q, Leng X, et al. Low-dose methotrexate for the treatment of inflammatory knee osteoarthritis: a randomized clinical trial. JAMA Intern Med. Published online June 2, 2025. doi:10.1001/jamainternmed.2025.1359
