Leflunomide: A Review of its Use in Active Rheumatoid Arthritis

Prakash, Amitabh; Jarvis, Blair

doi:10.2165/00003495-199958060-00010

Cited by 136Rheumatoid Arthritis Research and TherapiesNatural Compounds in Disease TreatmentAutoimmune and Inflammatory Disorders Research

Leflunomide: A Review of its Use in Active Rheumatoid Arthritis

Prakash, Amitabh, Jarvis, Blair·1999·Drugs

DOI 10.2165/00003495-199958060-00010

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Abstract

Unlabelled A77 1726, the active metabolite of leflunomide, is an immunomodulator which inhibits cell proliferation in activated lymphocytes in patients with active rheumatoid arthritis. Because A77 1726 has a long half-life (approximately 2 weeks), treatment with oral leflunomide is initiated with a loading dose of 100mg once daily for 3 days and continued with 20mg once daily. Results of large randomised, double-blind, multicentre trials of up to 24 months' duration have shown that leflunomide is significantly superior to placebo and at least as effective as sulfasalazine in improving primary outcome measures, such as tender joint counts, swollen joint counts and physicians' and patients' global assessment, in adult patients with active rheumatoid arthritis. Whereas improvement in all primary outcome measures with leflunomide was similar to or significantly less than that with methotrexate after 12 months, the efficacy of both agents was similar after 24 months. The therapeutic effect of leflunomide appears earlier (at 4 weeks) than that of sulfasalazine or methotrexate, and reduction from baseline values in functional disability was significantly greater with leflunomide than with sulfasalazine, methotrexate or placebo at end-point. Leflunomide was at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease. The most common adverse events reported in patients receiving leflunomide in randomised double-blind, placebo-controlled trials were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic aminotransferases (10%), dyspepsia (10%) and alopecia (9%). Leflunomide was as well tolerated as sulfasalazine or methotrexate in clinical trials. Monitoring of serum hepatic enzyme levels is recommended in patients receiving leflunomide. The drug is not recommended in female patients who are or may become pregnant. Drug treatment should be discontinued, and hastened drug elimination procedure should be considered, in male patients wishing to father a child. 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of leflunomide in 76,000 patients to date. Conclusions Leflunomide is a disease-modifying antirheumatic drug which reduces the signs and symptoms of inflammatory arthritis and delays the radiological progression of disease in adult patients with active rheumatoid arthritis. The drug appears to be as effective and as well tolerated as sulfasalazine or methotrexate, and represents a suitable alternative to these agents in adult patients with active rheumatoid arthritis. Benefits with leflunomide are evident within 4 weeks and efficacy is maintained for durations of up to 24 months.

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Leflunomide's metabolic effects stem from its active metabolite, A77 1726, which inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).
“Mechanistically, the metabolic effects of leflunomide stem from its active metabolite, A77 1726, which inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).”
From Drug repurposing for cancer therapy (2024) · cites this paper as [102]

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Authors: Prakash, A., & Jarvis, B.
Corresponding author: Prakash, Amitabh
Venue: Drugs
Publisher: Springer Science and Business Media LLC
Published: 1999
Volume: 58
Issue: 6
Pages: 1137-1164
ISSN: 0012-6667 (ISSN-L)
DOI: 10.2165/00003495-199958060-00010
OpenAlex: W2020790398
Cited by: 135
References: 67
Citations by year: 2026: 5 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 1 · 2014: 4 · 2013: 5 · 2012: 6
FWCI: 2.49
Type: journal article
Language: en
Open access: closed
Locations: Drugs (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
Keywords: leflunomide, rheumatoid arthritis, immunomodulation, sulfasalazine, methotrexate, disease-modifying antirheumatic drugs, drug safety, adverse events, hepatotoxicity, drug interactions, pregnancy contraindication, pancytopenia, skin reactions, radiographic progression, functional disability
MeSH terms: Leflunomide, Adult, Animals, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Rheumatoid, Female, Humans, Isoxazoles, Male, Pregnancy

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Leflunomide: A Review of its Use in Active Rheumatoid Arthritis

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