IngentaConnect Mechanism of Action for Leflunomide in Rheumatoid Arthritis

Authors: Fox R.I.¹; Herrmann M.L.²; Frangou C.G.²; Wahl G.M.³; Morris R.E.⁴; Strand V.⁵; Kirschbaum B.J.²

Source: Clinical Immunology, Volume 93, Number 3, December 1999 , pp. 198-208(11)

Abstract:

Leflunomide (Arava) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). This approval was based on data from a double-blind, multicenter trials in the United States (leflunomide versus methotrexate versus placebo) in which leflunomide was superior to placebo and similar to methotrexate (Strand et al., Arch. Intern. Med., in press, 1999). In a multicenter European trial, leflunomide was similar to sulfasalazine in efficacy and side effects (Smolen et 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 mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of RA. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with the cell cycle progression due to inadequate production of rUMP and utilizing mechanisms 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 ribonucleotide requirements by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis. Copyright 1999 Academic Press.

Language: English

Document Type: Review article

Affiliations: 1: Division of Rheumatology, Scripps Memorial and Research Institutes, La Jolla, California, 92037 2: DG Rheumatology, Hoechst Marion Roussel, Wiesbaden, D-65174, Germany 3: Gene Expression Laboratory, The Salk Institute, La Jolla, California, 92037 4: Department of Cardiovascular Surgery 5: Department of Cardiovascular Surgery, Department of Rheumatology, Stanford University School of Medicine, Stanford, California, 94305

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