Leflunomide was first "detected" in the mouse adjuvant model. Later on its mode of action was discovered to be DHODH (dihydroorotate dehydrogenase) inhibition. A 77 1726, the active metabolite of leflunomide (ARAVA^®), exhibits a unique mode of action, selectively inhibiting de novo pyrimidine synthesis in rapidly proliferating cells involved in rheumatoid arthritis (RA), such as activated lymphocytes. DHODH inhibition results in disruption of de novo pyrimidine biosynthesis, cell arrest in the G₁/S phase of mitosis, and inhibition of T cell clonal expansion, an important step in the pathogenesis of RA. A 77 1726 is highly bound to plasma proteins, displays linear pharmacokinetics and has a long elimination half-life.

A large clinical development program has proven that leflunomide is a new, very efficacious DMARD. It improves the signs and symptoms of RA rapidly and impressively. Leflunomide retards significantly the disease progression as evidenced by joint X-rays. Joint function and health-related quality of life of RA patients are considerably improved. Onset of efficacy with leflunomide is rapid (within a month), stabilizes within 6 months and is well maintained during long-term treatment. Leflunomide is a safe and well-tolerated drug.