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Vibeke Strand, MD; Stanley Cohen, MD; Michael Schiff, MD; Arthur Weaver, MD; Roy Fleischmann, MD; Grant Cannon, MD; Robert Fox, MD; Larry Moreland, MD; Nancy Olsen, MD; Dan Furst, MD; Jacques Caldwell, MD; Jeffrey Kaine, MD; John Sharp, MD; Frank Hurley, PhD; Iris Loew-Friedrich, MD; for the Leflunomide Rheumatoid Arthritis Investigators Group

Arch Intern Med. 1999;159:2542-2550.

Context  Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA).

Objective  To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA.

Design  Randomized, double-blind, placebo, and active-controlled 12-month study.

Setting  Forty-seven university and private rheumatology practices in the United States and Canada.

Patients  Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment.

Intervention  Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk).

Main Outcome Measures  American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population.

Results  The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P.001) and methotrexate (P=.02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy.

Conclusions  Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.

From Stanford University, Stanford, Calif (Dr Strand); the Metroplex Clinical Research Center, Dallas, Tex (Drs Cohen and Fleischmann); the Denver Arthritis Clinic, Denver, Colo (Dr Schiff); the Arthritis Center of Nebraska, Lincoln (Dr Weaver); the Veterans Affairs Medical Center and University of Utah, Salt Lake City (Dr Cannon); the Scripps Clinic, La Jolla, Calif (Dr Fox); University of Alabama at Birmingham, Birmingham (Dr Moreland); Vanderbilt University, Nashville, Tenn (Dr Olsen); the Virginia Mason Arthritis Research Center, Seattle, Wash (Dr Furst); the Halifax Clinical Research Center, Daytona Beach, Fla (Dr Caldwell); the Sarasota Arthritis Center, Sarasota, Fla (Dr Kaine); Emory University School of Medicine, Atlanta, Ga (Dr Sharp); Quintiles Transnational Corp, Arlington, Va (Dr Hurley); and Hoechst Marion Roussel, Bridgewater, NJ (Dr Loew-Friedrich).

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