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Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis

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


Leflunomide (LEF) is an isoxazole derivative used for the treatment of rheumatoid arthritis (RA). LEF, which inhibits pyrimidine synthesis, is structurally unrelated to other immunomodulatory disease-modifying antirheumatic drugs (DMARDs), exhibiting a distinct mechanism of action compared with other DMARDs used to treat RA.

The mechanism of action, pharmacology, dosing, and adverse effects of LEF, particularly in the context of its use in RA, will be reviewed here. The general approach to the management of RA and the use of LEF in the treatment of active disease are presented separately. (See "General principles of management of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

The use of LEF in other conditions, including psoriatic arthritis, juvenile idiopathic arthritis, dermatomyositis, and systemic lupus erythematosus, and the use of teriflunomide, its active metabolite, in multiple sclerosis are discussed separately. (See "Treatment of psoriatic arthritis", section on 'Leflunomide' and "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Leflunomide' and "Musculoskeletal manifestations of systemic lupus erythematosus", section on 'Treatment' and "Management of refractory discoid lupus and subacute cutaneous lupus", section on 'Leflunomide' and "Management of refractory cutaneous dermatomyositis in adults", section on 'Other systemic medications' and "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Teriflunomide'.)


Leflunomide (LEF) is an oral drug that is rapidly absorbed from the gastrointestinal tract; it acts as an immunomodulatory and immunosuppressive agent largely through inhibition of pyrimidine synthesis [1,2].

Inhibition of DHODH and rUMP synthesis — Once absorbed, LEF is converted to its active form, a malononitrilamide known as teriflunomide (figure 1) [3]. 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).

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Literature review current through: Nov 2017. | This topic last updated: Nov 01, 2017.
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