Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases

Abstract

Leflunomide (Arava™) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). The drug, due to its protective effects on structural joint damage, has been classified as a disease modifying anti-rheumatic drug (DMARD). Leflunomide is structurally dissimilar from other drugs currently used to treat RA and exhibits a different mechanism of action. It has shown to be protective in a variety of animal models of arthritis and autoimmunity based on its immunomodulatory activity. Leflunomide is rapidly converted in vivo to its pharmacologically active metabolite A77 1726. This metabolite is a potent non-cytotoxic inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo synthesis of uridine monophosphate (UMP). Activated lymphocytes depend on the pyrimidine de novo syntheses to fulfill their metabolic needs for clonal expansion and terminal differentiation into effector cells. De novo synthesis of pyrimidines is not only essential to provide precursors for new RNA and DNA synthesis, but also for phospholipid synthesis and the pyrimidine sugars necessary for protein glycosylation, which support the massive expansion in membrane biosynthesis to form daughter cells. This mechanism likely contributes to leflunomide's action as a DMARD in RA and other autoimmune diseases. This review is a summary of current in vivo and in vitro data, focussing primarily on the mechanism of action of leflunomide in RA.

Introduction

Rheumatoid arthritis (RA), an autoimmune disorder of unknown etiology, is characterized by chronic inflammation of synovial tissues and infiltration of the affected joints by blood-derived cells. This includes memory T cells, dendritic cells, macrophages and plasma cells, all of which show signs of activation. In most cases, this leads to progressive erosion of adjacent cartilage and underlying bone. Joint destruction is believed to be mediated mainly by cytokine-induced destructive enzymes, particularly members of the matrix metalloproteinase family. The consequences of this progressive disease are chronic/acute morbidity, reduced ability to perform activities of daily living, permanent disability and increased mortality Janossy et al., 1981, Cush and Lipsky, 1988, Muller-Ladner, 1996, Dudler and So, 1998.

The underlying cause of RA is not known and there is currently no consensus as to which principal regulatory cell represents an optimal therapeutic target. However, in light of the postulated autoimmune basis for RA, a number of reports have implicated a role for T lymphocytes in either the initiation or the persistence of the disease Goronzy and Weyand, 1995, Panayi, 1997, Moots, 1998. Recent observations in animal models support the key role of T cells in RA. Depletion of synovial T cells from SCID mice that have been transplanted with inflamed synovial tissue led to an immediate reduction of proinflammatory cytokines, monokines and tissue destructive metalloproteinases (Klimiuk et al., 1999). Other studies have shown that perturbations in T cell homeostasis and clonal outgrowth of CD4⁺ cells can lead to chronic, persistent synovitis in RA patients Rittner et al., 1997, Striebich et al., 1998, Wagner et al., 1998. Anti-T cell directed therapies have demonstrated to be partially efficacious (Matteson, 1997) and the resolution of pre-existing RA in patients developing AIDS also indicated an involvement of T cells (Calabrese et al., 1989). Most recently, B lymphocytes, in their role as secretors of arthrogenic immunoglobulins in T cell-initiated autoimmunity, have been shown to play a more important role in the pathogenesis of RA than had been previously suspected (Korganow et al., 1999). Despite the large number of activated lymphocytes in the synovial lesions, lymphokine production has been difficult to demonstrate. Conversely, macrophage-derived cytokines, such as IL-1β and TNFα, are readily detectable, indicating a possible role for macrophages in the pathogenesis of RA (Burmester et al., 1997). However, the activation of synovial macrophages may not require soluble mediators, since direct cell–cell contact between activated T cells and macrophages or fibroblasts is sufficient for activation and itself may be important in the progression of rheumatoid synovitis Lacraz et al., 1994, Chizzolini et al., 1997 It is therefore not clear whether macrophages or synovial fibroblasts themselves orchestrate this pathway, or whether they are merely acting as lymphocyte-directed mediators in RA.

Leflunomide (Arava™) is a novel immunoregulatory and disease-modifying anti-rheumatic drug, structurally unrelated to other immunosuppressive agents. It is an isoxazole derivative and originated from an anti-arthritis drug development program at Hoechst (Heubach, 1977). Leflunomide, a non-cytotoxic inhibitor of the proliferation of mitogen-stimulated T- and B-lymphocytes in vitro, is effective in several rodent autoimmune disease models and prolongs tissue graft survival in animals (Graul and Castaner, 1998). More recently, leflunomide has shown clinical efficacy in multiple phase III studies in Europe and the US Dunn and Small, 1999, Smolen et al., 1999, Strand et al., 1999.

This article will review recent work on both the pharmacological effects as well as the mechanism of action of leflunomide, with the intention of providing a basis for understanding leflunomide's immunomodulatory activity, toxicity, drug interactions and the rationale for its use in single- and combination disease modifying anti-rheumatic drug (DMARD) therapy. Several mechanisms of action for leflunomide that have been proposed will be discussed in this review. The main focus, however, will be on the inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo synthesis of UMP. This biochemical reaction is a critical step in the progression of the cell cycle from G₁ to S phase in activated lymphocytes. Potential models for molecular and cellular mechanisms underlying leflunomide-induced immunomodulatory effects, which explain the selective nature of the drug to affect primarily activated, autoimmune lymphocytes, will be discussed.