Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases

Leflunomide (Arava(TM)) has recently been approved by the Food and Drug Adm inistration for the treatment of rheumatoid arthritis (RA). The drug, due t o its protective effects on structural joint damage, has been classified as a disease modifying anti-rheumatic drug (DMARD). Leflunomide is structural ly dissimilar from other drugs currently used to treat RA and exhibits a di fferent mechanism of action. It has shown to be protective in a variety of animal models of arthritis and autoimmunity based on its immunomodulatory a ctivity. Leflunomide is rapidly converted in vivo to its pharmacologically active metabolite A77 1726. This metabolite is a potent non-cytotoxic inhib itor of the enzyme dihydroorotate dehydrogenase (DHODH), a key enzyme in th e de novo synthesis of uridine monophosphate (UMP). Activated lymphocytes d epend on the pyrimidine dr novo syntheses to fulfill their metabolic needs for clonal expansion and terminal differentiation into effector cells. De n ovo synthesis of pyrimidines is not only essential to provide precursors fo r new RNA and DNA synthesis, but also for phospholipid synthesis and the py rimidine sugars necessary for protein glycosylation, which support the mass ive expansion in membrane biosynthesis to form daughter cells. This mechani sm likely contributes to leflunomide's action as a DMARD in RA and Ether au toimmune diseases. This review is a summary of current in vivo and in vitro data, focussing primarily on the mechanism of action of leflunomide in RA. (C) 2000 Elsevier Science B.V. All rights reserved.