How does leflunomide modulate the immune response in rheumatoid arthritis?

Leflunomide has recently been approved by the US Food and Drug Administrati on for the treatment of rheumatoid arthritis. This approval was based on da ta from double-blind multicentre trials in the US (US 301; leflunomide vers us methotrexate versus placebo) and multicentre European trials (leflunomid e versus sulfasalazine versus placebo, and leflunomide versus methotrexate versus placebo). In these trials, leflunomide was superior to placebo and s imilar to methotrexate or sulfasalazine in efficacy and adverse effects. Bo th methotrexate and leflunomide retarded the rate of radiological progressi on, entitling them to qualify as disease-modifying agents (DMARDs). Leflunomide is an immunomodulatory drug that may exert its effects by inhib iting the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH), whic h plays a key role in the de novo synthesis of the pyrimidine ribonucleotid e uridine monophosphate (rUMP). The inhibition of human DHO-DH by A77-1726, the active metabolite of leflunomide, occurs at concentrations (approximat ely 600 nmol/L) that are achieved during treatment of rheumatoid arthritis. We propose that leflunomide prevents the expansion of activated and autoim mune lymphocytes by interfering with cell cycle progression. This is mediat ed by inadequate production of rUMP and utilises mechanisms involving the s ensor protein p53. The relative lack of toxicity of A77-1726 on nonlymphoid cells may be due to the ability of these cells to fulfil their ribonucleot ide requirements by use of the salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.