Leflunomide: mode of action in the treatment of rheumatoid arthritis

Abstract

Leflunomide is a selective inhibitor of de novo pyrimidine synthesis. In phase II and III clinical trials of active rheumatoid arthritis, leflunomide was shown to improve primary and secondary outcome measures with a satisfactory safety profile. The active metabolite of leflunomide, A77 1726, at low, therapeutically applicable doses, reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate limiting step in the de novo synthesis of pyrimidines. Unlike other cells, activated lymphocytes expand their pyrimidine pool by approximately eightfold during proliferation; purine pools are increased only twofold. To meet this demand, lymphocytes must use both salvage and de novo synthesis pathways. Thus the inhibition of DHODH by A77 1726 prevents lymphocytes from accumulating suYcient pyrimidines to support DNA synthesis. At higher doses, A77 1726 inhibits tyrosine kinases responsible for early T cell and B cell signalling in the G 0 /G 1 phase of the cell cycle. Because the immunoregulatory eVects of A77 1726 occur at doses that inhibit DHODH but not tyrosine kinases, the interruption of de novo pyrimidine synthesis may be the primary mode of action. Recent evidence suggests that the observed anti-inflammatory eVects of A77 1726 may relate to its ability to suppress interleukin 1 and tumour necrosis factor selectively over their inhibitors in T lymphocyte/monocyte contact activation. A77 1726 has also been shown to suppress the activation of nuclear factor B, a potent mediator of inflammation when stimulated by inflammatory agents. Continuing research indicates that A77 1726 may downregulate the glycosylation of adhesion molecules, eVectively reducing cell-cell contact activation during inflammation.

Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: A multinational, double‐blind, randomized, placebo‐controlled clinical trial

“…The increased incidence of diarrhea observed in leflunomide-treated patients may be caused by the inhibition of dihydroorotate dehydrogenase in intestinal epithelial cells, resulting in a high rate of cellular turnover in the gastrointestinal tract (20). Patients with transaminase elevations Ն3 times the ULN were followed up, and transaminase elevations were reversible in all cases.…”

“…Because activated lymphocytes require a large pyrimidine pool, leflunomide preferentially inhibits T cell activation and proliferation (20) and thus has the potential to address underlying pathophysiologic events in RA, PsA, and psoriasis. Leflunomide has been approved for the treatment of RA in the US, countries of the European Union, and numerous other countries for several years.…”

Leflunomide in active rheumatoid arthritis: a prospective study in daily practice

“…Responder categories according to DAS 28 -criteria at the Good responders ( ), moderate responders ( ), non-responders ( ). 1 Due to missing DAS 28 scores the number of patients that can be evaluated is lower than the number at risk 124 99 72 Evaluable patients n 60 36 25 % 48 36 35 2, 6 and 12 month follow-up visits are shown in Figure 1. During follow-up in 89 patients (65%) at least one adverse drug reaction was registered.…”

“…Leflunomide represents a novel class of disease modifying antirheumatic drugs (DMARD), the isoxazole derivatives. The active metabolite, A77 1726, reversibly inhibits the enzyme dihydro-orotate dehydrogenase, the rate limiting step in the de novo synthesis of pyrimidines [1]. Hypotheses on the pathogenesis of RA suggest an important role of activated T lymphocytes [2].…”

The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: A five‐year followup study

“…Activated CD4ϩ T cells proliferate rapidly during the progression of RA, a process involving de novo pyrimidine synthesis (5). Leflunomide acts to inhibit T cell proliferation by preventing pyrimidine generation and subsequent DNA synthesis (6)(7)(8).…”