Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate

Objective. Three 6-12-month, double-blind, randomized, controlled trials ha ve shown leflunomide (LEF; 20 mg/day, loading dose 100 mg X 3 days) to be e ffective and safe for the treatment of rheumatoid arthritis (RA). This anal ysis of the North American trial assessed whether the clinical benefit evid ent at month 12 was sustained over 24 months of treatment with LEF as compa red with the efficacy and safety of methotrexate (MTX), an equivalent disea se-modifying antirheumatic drug, at 24 months. Methods. The year-2 cohort, comprising patients continuing into the second year of treatment with greater than or equal to1 dose of study medication a nd greater than or equal to1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/-SD) maint enance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 1 2.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) ap proach. Statistical comparisons of the active treatments only were prospect ively defined in the protocol. Results. In total, 85% and 79% of LEF and MTX patients, respectively, who e ntered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of greater than or equal to 20% (LEF 79% versus MTX 67%; P = 0.049), greater than or e qual to 50% (LEF 56% versus MTX 43%; P = 0.053), and greater than or equal to 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the ac tive treatment groups. The mean change in total Sharp radiologic damage sco res at year 2 compared with year I and baseline (LEF 1.6 versus MTX 1.2) sh owed statistically equivalent sustained retardation of radiographic progres sion in the active treatment groups. Maximal improvements evident at 6 mont hs in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) a nd the physical component score of the Medical Outcomes Survey 36-item shor t form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF (-0.60) was statistically significantly superior to that with M TX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, seri ous treatment-related adverse events were reported in 1.6% of the LEF-treat ed patients and 3.7% of the MTX-treated patients. Frequently reported adver se 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 radiogra phic progression over 24 months. LEF was statistically significantly superi or 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 init ial treatment for active RA, with clinical benefit sustained over 2 years o f treatment without evidence of new or increased toxicity.