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Leflunomide in the treatment of rheumatoid arthritis

Authors
Robert Fox, MD, PhD
Simon M Helfgott, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD

INTRODUCTION

Leflunomide (LEF) is an isoxazole derivative used for the treatment of rheumatoid arthritis (RA). LEF is structurally unrelated to other immunomodulatory disease-modifying antirheumatic drugs (DMARDs) and offers a unique mechanism for the therapy of RA.

LEF has also been effective in patients with psoriatic arthritis [1,2], juvenile polyarthritis [3], refractory dermatomyositis [4], and systemic lupus erythematosus [5], but it has not been effective in ankylosing spondylitis [6]. Teriflunomide, the active metabolite of LEF, was found effective in patients with multiple sclerosis and is available for use in that condition [7]. The use of leflunomide in these other conditions is discussed separately. (See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Leflunomide' and "Management of refractory cutaneous dermatomyositis", section on 'Other systemic medications' and "Musculoskeletal manifestations of systemic lupus erythematosus", section on 'Treatment' and "Management of refractory discoid lupus and subacute cutaneous lupus", section on 'Leflunomide' and "Treatment of psoriatic arthritis", section on 'Leflunomide'.)

The pharmacology of LEF, its immunologic effects, and its use in RA will be reviewed here. The general approach to the management of RA and the treatment of active disease are presented separately, as is the use of teriflunomide in patients with multiple sclerosis. (See "General principles of management of rheumatoid arthritis in adults" and "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Teriflunomide'.)

MODE OF ACTION

Leflunomide (LEF) is an oral drug that is rapidly absorbed from the gastrointestinal tract. Once absorbed, LEF is converted to its active form, a malononitrilamide known as teriflunomide (figure 1) [8]. The major action of teriflunomide at the doses given for rheumatoid arthritis (RA) is inhibition of the synthesis of a pyrimidine known as ribonucleotide uridine monophosphate pyrimidine (rUMP).

LEF decreases the synthesis of rUMP through inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Inhibition of DHODH leads to inability of activated cells to move from G1 to the S phase by activating the p52 pathways of apoptotic selection. Additional mechanisms of action are listed below, but the inhibition of rUMP is thought to be the primary mechanism involved at the levels of drug reached in most patients [9,10].

                        

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Literature review current through: Nov 2016. | This topic last updated: Tue Apr 21 00:00:00 GMT 2015.
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