Methotrexate Fails to Show Benefit in Knee Osteoarthritis Trial

A new study published in the Journal of American Medical Association showed that methotrexate flops to show benefit in knee osteoarthritis trial. Despite earlier signs of pain relief in hand osteoarthritis, methotrexate did not improve pain or joint inflammation in a placebo-controlled trial for knee OA.

Osteoarthritis (OA) is the leading cause of disability globally due to the population's rapid aging. Chronic joint pain and functional impairment are hallmarks of OA, which significantly lowers a person's quality of life. The absence of effective treatments to treat OA symptoms or to halt the disease process and related structural development is one of the main obstacles to lessening the burden of OA on people and society.

According to a recent study, people with inflammatory hand osteoarthritis may experience less joint discomfort while using methotrexate. Whether methotrexate has comparable effects on inflammatory knee OA is yet unclear, though. Thus, to determine if methotrexate has symptom-relieving and disease-modifying effects for individuals with knee OA and effusion-synovitis, this study was carried out.

This clinical study that took place in 11 locations in China from July 18, 2019, until January 15, 2023. The patients with inflammatory knee OA who lived in the community and had effusion-synovitis on magnetic resonance imaging were included. Stratified by trial location, participants were randomly allocated (1:1) to receive either a placebo or methotrexate up to 15 mg weekly using block randomization. Over a 52-week period, the main outcomes for the intention-to-treat group were the change in knee visual analog scale (VAS) pain and the change in effusion-synovitis maximum area.

Out of the 278 individuals who underwent screening, 215 (mean [SD] age, 60.4 [7.4] years; 191 [89%] female) were randomly assigned to one of two groups (108 to receive methotrexate, 107 to receive a placebo), and 175 (81%) finished the experiment.

Over the course of 52 weeks, there was no significant difference in the changes in VAS pain or effusion-synovitis maximum area between the methotrexate and placebo groups (between-group difference: 0.3 mm [95% CI, −6.7 to 7.3 mm] for VAS pain; 0.1 cm2 [95% CI, −0.8 to 1.0 cm2] for effusion-synovitis maximal area).

None of the predetermined secondary outcomes showed any discernible differences between groups. About 32 individuals (29.6%) in the methotrexate group and 26 participants (24.3%) in the placebo group experienced at least one adverse event. Overall, in a placebo-controlled trial for knee OA, methotrexate did not reduce pain or joint inflammation, despite prior indications of pain alleviation in hand osteoarthritis.

Source:

Zhu, Z., Yu, Q., Leng, X., Xu, J., Ren, L., Wang, K., Huang, C., Pan, Y., Zhao, Y., Li, T., Mei, Y., Guan, M., Li, X., Zhang, Z., Wu, J., Chen, Y., Qu, Y., Zhu, X., Liao, Q., … Ding, C. (2025). Low-dose methotrexate for the treatment of inflammatory knee osteoarthritis: A randomized clinical trial. JAMA Internal Medicine. https://doi.org/10.1001/jamainternmed.2025.1359