Mechanism of action for leflunomide in rheumatoid arthritis

Leflunomide (Arava) has recently been approved by the Food and Drug Adminis tration for the treatment of rheumatoid arthritis (RA). This approval was b ased on data from a double-blind, multicenter trials in the United States ( leflunomide versus methotrexate versus placebo) in which leflunomide was su perior to placebo and similar to methotrexate (Strand ef al., Arch. Intern. Med., in press, 1999). In a multicenter European trial, leflunomide was si milar to sulfasalazine in efficacy and side effects (Smolen ct al., Lancet 353, 259-266, 1999). Both methotrexate and leflunomide retarded the rate of radiolographic progression, entitling them to qualify as disease-modifying agents (Strand et al., Arch. Intern. Med., in press, 1999). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mito chondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key ro le in the de novo synthesis of the pyrimidine ribonucleotide uridine monoph osphate (rUMP). The inhibition of human DHODH by A77 1726, the active metab olite of leflunomide, occurs at levels (approximately 600 nM) that are achi eved during treatment of RA. We propose that leflunomide prevents the expan sion of activated and autoimmune lymphocytes by interfering with the cell c ycle progression due to inadequate production of rUMP and utilizing mechani sms involving p53. The relative lack of toxicity of A77 1726 on nonlymphoid cells may be due to the ability of these cells to fulfill their ribonucleo tide requirements by use of salvage pyrimidine pathway, which makes them le ss dependent on de novo synthesis. (C) 1999 Academic Press.