Leflunomide: A New Disease Modifying Anti-Rheumatic Drug

Park, Yong Beom; Lee, Soo Kon

Abstract

Leflunomide is a novel, isoxazol based disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Its mechanism differs from other DMARDs in that it inhibits de novo pyrimidine synthesis by inhibiting the enzyme dihydroorotate dehydrogenase (DHODH). It is a pro-drug and undergoes rapid conversion to its active form in vivo, A77-1726. A77-1726 inhibits the mitochondrial enzyme DHODH, which plays a key role in the de novo synthesis of pyrimidine ribonucleotide uridine monophosphate (rUMP). Leflunomide prevents clonal expansion of activated 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 non-lymphoid 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. Several phase II clinical trials of patients with RA revealed that leflunomide was effective and well tolerated. Large-scale phase III clinical trials have shown that leflunomide (20mg/day) provided a statistically significant clinical benefit and prevention of radiographic progression in comparison to placebo. The clinical benefits of leflunomide were similar to or greater than methotrexate and sulfasalazine. Now, many multi-national studies are in progress and planning, including combination therapy with other DMARD. In future, those studies will provide us more information about the effectiveness and potential adverse effect of leflunomide.