Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial.

BACKGROUND

Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate.

OBJECTIVE

To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis.

DESIGN

24-week, multicenter, randomized, double-blind, placebo-controlled trial.

SETTING

20 centers in the United States and Canada.

PATIENTS

Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months.

INTERVENTION

Leflunomide or matching placebo added to existing methotrexate therapy.

MEASUREMENTS

The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis.

RESULTS

In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate.

CONCLUSIONS

Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.