Methotrexate and leflunomide: Biochemical basis for combination therapy inthe treatment of rheumatoid arthritis

Objectives: Methotrexate is currently one of the most widely prescribed dis ease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA). Combination therapy of methotrexate with other DMARDs incr eases the clinical success of low-dose methotrexate treatment. Leflunomide is a new DMARD that may have a high potential for success in combination th erapy with methotrexate, This review compares the mode of action of methotr exate and leflunomide and speculates on how this contributes to therapeutic efficacy in RA when these agents are used singly or in combination. Methods: A literature review of the biochemical mechanisms considered to be the basis for the therapeutic efficacy of methotrexate and leflunomide in treating RA is presented. Results: Low-dose methotrexate inhibits cytokine production, purine biosynt hesis, and, in an animal model, causes the release of adenosine, a potent a ntiinflammatory agent. Leflunomide, through inhibition of de novo pyrimidin e biosynthesis, can regulate lymphocyte proliferation. Conclusions: The biochemical mechanisms underlying the therapeutic efficacy of low-dose methotrexate and leflunomide in the treatment of RA are quite different. The potentially complementary mechanisms of action of these two effective DMARDs should provide a rationale for their use in combination th erapy for patients whose condition no longer responds to methotrexate alone . Semin Arthritis Rheum 29: 14-26. Copyright (C) 1999 by W.B. Saunders Comp any.