Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group.

Objective: Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months.
Methods: The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol.
Results: In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations.
Conclusion: The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.