Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis
- Robert Fox, MD, PhD
Robert Fox, MD, PhD
- Section Editor — Sjögren's syndrome
- Member, Rheumatology Clinic
- Scripps Memorial Hospital and Ximed Medical Group
- Simon M Helfgott, MD
Simon M Helfgott, MD
- Section Editor — General Rheumatology and Related Topics
- Associate Professor of Medicine
- Harvard Medical School
- Section Editor
- Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
- Section Editor — Rheumatoid Arthritis
- Emeritus Professor of Rheumatology, Imperial College London
- Visiting Professor, Oxford University
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'.)
MODE OF ACTION
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) . 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).To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
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- MODE OF ACTION
- Inhibition of DHODH and rUMP synthesis
- Effects on immune cells and inflammation
- Genetic factors influencing effects of leflunomide
- PHARMACOKINETICS AND DRUG ELIMINATION
- Drug metabolism and drug interactions
- Treatment to accelerate drug elimination
- Role of loading dose
- Ongoing daily dose
- ADVERSE EFFECTS
- Routine laboratory monitoring
- Warnings and monitoring for liver disease
- Patients receiving vitamin K antagonists
- PREGNANCY AND LACTATION
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS