Leflunomide: mode of action in the treatment of rheumatoid arthritis

Leflunomide is a selective inhibitor of de novo pyrimidine synthesis. In ph ase II and III clinical trials of active rheumatoid arthritis, leflunomide was shown to improve primary and secondary outcome measures with a satisfac tory safety profile. The active metabolite of leflunomide, A77 1726, at low , therapeutically applicable doses, reversibly inhibits dihydroorotate dehy drogenase (DHODH), the rate limiting step in the de novo synthesis of pyrim idines. Unlike other cells, activated lymphocytes expand their pyrimidine p ool by approximately eightfold during proliferation; purine pools are incre ased only twofold. To meet this demand, lymphocytes must use both salvage a nd de novo synthesis pathways. Thus the inhibition of DHODH by A77 1726 pre vents lymphocytes from accumulating sufficient pyrimidines to support DNA s ynthesis. At higher doses, A77 1726 inhibits tyrosine kinases responsible f or early T cell and B cell signalling in the G(0)/G(1) phase of the cell cy cle. Because the immunoregulatory effects of A77 1726 occur at doses that i nhibit DHODH but not tyrosine kinases, the interruption of de novo pyrimidi ne synthesis may be the primary mode of action. Recent evidence suggests th at the observed anti-inflammatory effects of A77 1726 may relate to its abi lity to suppress interleukin 1 and tumour necrosis factor a selectively ove r their inhibitors in T lymphocyte/monocyte contact activation. A77 1726 ha s also been shown to suppress the activation of nuclear factor KB, a potent mediator of inflammation when stimulated by inflammatory agents. Continuin g research indicates that A77 1726 may downregulate the glycosylation of ad hesion molecules, effectively reducing cell-cell contact activation during inflammation.