Methotrexate Decreases Pain, Improves Function in Knee OA

Janis C. Kelly

April 01, 2014

Methotrexate (MTX) reduced pain, enhanced function, and produced a clinically relevant and radiologically verifiable reduction in synovitis in patients with symptomatic knee OA, according to data published online March 27 in the Annals of the Rheumatic Diseases.

The view that osteoarthritis (OA) is a "wear-and-tear" disease has largely given way to recognition that the OA disease process is more complex and includes an inflammatory component. That hypothesis hints that disease-modifying OA treatments might be able to alter disease progression, as disease-modifying antirheumatic drugs do in rheumatoid arthritis (RA).

Therefore, Anna Abou-Raya, MD, from the Rheumatology Department, University of Alexandria, and the Alexandria Regional Centre for Women's Health and Development, Egypt, and colleagues designed a randomized, placebo-controlled study to determine whether MTX would be effective at decreasing pain and inflammation in knee OA. The authors note that pain reduction and functional improvement are "of utmost importance in the treatment of knee OA" and that current treatments have limited symptomatic effect but cause significant adverse effects.

Eligible patients had clinically symptomatic primary knee OA, persistent knee pain, clinical signs of synovitis, and moderate disease severity according to Kellgren-Lawrence radiographic staging. Most were Kellgren-Lawrence grade 2 or 3. "Clinical assessment consisted of questioning about number of flares, pain, concomitant diseases and analgesics; physical examination for signs of inflammation and primary and secondary measures of disease assessment. All patients had at least two of the following four clinical signs of inflammation: warmth over the joint area, joint margin tenderness, synovial effusion, soft tissue swelling around the knee," the authors write.

The researchers randomly assigned 144 patients with primary knee OA to receive up to 25 mg/week oral MTX (n = 72) or placebo (n = 72) for 28 weeks. In addition, all participants received folic acid supplementation of 5 mg 3 times a week.

Primary outcomes were pain reduction during the previous 48 hours (measured with the visual analogue pain scale [VAS], 0 - 100 mm) and function (measured using the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] and activities of daily living [ADL] scores). The researchers measured synovitis by ultrasound imaging at baseline and at the end of the study.

The researchers defined treatment response by the Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) 2004 criteria. They classified patients as responders if the pain or physical function score was decreased by 30% or more and by 20 mm or more on the VAS.

MTX Associated With Significant OA Improvement

The authors report a clinically relevant reduction in the MTX group compared with the placebo group for knee pain, physical function, and ADL scores at 28 weeks. The mean differences were 11.4 for knee pain (95% confidence interval [CI], 2.8 - 20.0; P = .009), 9.5 for function (95% CI, 3.7 - 15.3; P = .001), and 1.2 for ADL (95% CI, 0.1 - 2.3; P = .032).

Fifty-three percent of MTX patients had a pain reduction VAS of more than 20 mm compared with 33% of placebo patients (P = .018).

The reduction in synovitis, which was considered significant both clinically and by ultrasound, was −1.4 mm with MTX vs −0.4 mm with placebo (mean difference, 1.0 mm; 95% CI, 0.4 - 0.6 mm; P = .000).

There were no serious adverse events. The MTX group had more mucositis, alopecia, gastrointestinal intolerance, and transaminitis, but the differences were not statistically significant.

"The findings of this study indicate that MTX may have dual benefit — improving pain and function, both of which influence quality of life. Improvement in WOMAC scores which reflect function, were particularly striking in patients receiving MTX compared with those receiving placebo. WOMAC scores measure physical function and their improvement indicates better functioning ability due to less pain, stiffness and/or fewer functional limitations," the researchers write.

"When interpreting the results of physical function, one needs to keep in mind the progressive nature of OA. Thus, an improvement in WOMAC scores or even a stable measure of physical function represents a treatment success. This may in itself justify the use of MTX in patients with OA. It is noteworthy, however, that the control group also improved during follow-up," the researchers conclude.

The authors have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online March 27, 2014. Abstract

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