Pain Reduction With Oral Methotrexate in Knee Osteoarthritis : A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND

Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain.

OBJECTIVE

To assess symptomatic benefits of methotrexate in knee OA (KOA).

DESIGN

A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41).

SETTING

15 secondary care musculoskeletal clinics in the United Kingdom.

PARTICIPANTS

A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion.

INTERVENTION

Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia.

MEASUREMENTS

The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs).

RESULTS

A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate ( = 77) or placebo ( = 78). Follow-up was 86% ( = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51;  = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18];  = 0.045) and function (5.01 points [CI, 1.29 to 8.74];  = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2).

LIMITATION

Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance.

CONCLUSION

Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months.

PRIMARY FUNDING SOURCE

Versus Arthritis.