Leflunomide in the treatment of rheumatoid arthritis

Clin Ther. 2004 Apr;26(4):447-59. doi: 10.1016/s0149-2918(04)90048-3.


Background: Current drug therapies for rheumatoid arthritis (RA), including nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs, help control inflammation but can cause significant toxicity. Drugs are needed that are able to suppress inflammation and modify the underlying immune response with improved tolerability. Leflunomide is an agent that affects the inflammatory process, particularly in RA.

Objective: This paper reviews the pharmacology of leflunomide, its approved use in RA, and the results of major clinical trials, including adverse events.

Methods: Relevant trials were identified through a search of the English-language literature indexed on EMBASE, MEDLINE, Current Contents, and the Cochrane Controlled Trials Register from January 1980 to November 2003. Search terms were limited to leflunomide.

Results: In 3 large Phase III clinical trials (US301, MN301, and MN302), leflunomide had equivalent clinical efficacy and tolerability to methotrexate and sulfasalazine and superior efficacy and tolerability compared with placebo. In US301 (N = 482), the ACR (American College of Rheumatology) 20 response rate (proportion of patients with > or =20% improvement from baseline in tender and swollen joint counts, patient's assessment of pain, patient's and physician's global assessment of disease activity, physical function, and acute-phase reactant value) at 1 year was similar with leflunomide and methotrexate and significantly greater with both active treatments than with placebo (52%, 46%, and 26%, respectively; both, P < 0.001). The efficacy of leflunomide was seen early (after 4 weeks of treatment) and was sustained throughout the study. There was less radiographic damage in both active-treatment groups compared with placebo (leflunomide, P < or = 0.001; methotrexate, P = 0.02). In MN301 (N = 358), the ACR20 response rate at 6 months was similar with leflunomide and sulfasalazine and significantly greater with both active treatments compared with placebo (55%, 56%, and 29%, respectively; both, P < 0.001). Radiographic progression was also similar with leflunomide and sulfasalazine, both of which were significantly superior to placebo (Larsen score, 0.42, 0.41, and 1.4; both, P < 0.001). An extension of this study revealed maintenance of efficacy at 12 and 24 months. In MN302 (intent-to-treat population, N = 999), 50.5% of patients in the leflunomide group were ACR20 responders at the end of 1 year, compared with 64.8% in the methotrexate group (P < 0.001 vs leflunomide). After 2 years, ACR20 response rates were similar with leflunomide and methotrexate (64.3% and 71.7%). The overall safety profile of leflunomide appears promising, although monitoring for elevations in liver enzymes and bone marrow suppression is recommended. The most common drug-related adverse events associated with leflunomide in these clinical trials were diarrhea, abnormalities in liver enzymes, rash, and hypertension.

Publication types

  • Review

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy*
  • Clinical Trials, Phase III as Topic
  • Dihydroorotate Dehydrogenase
  • Drug Therapy, Combination
  • Humans
  • Isoxazoles / adverse effects
  • Isoxazoles / pharmacokinetics
  • Isoxazoles / therapeutic use*
  • Leflunomide
  • Methotrexate / adverse effects
  • Methotrexate / therapeutic use
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antirheumatic Agents
  • Dihydroorotate Dehydrogenase
  • Isoxazoles
  • Oxidoreductases Acting on CH-CH Group Donors
  • Protein-Tyrosine Kinases
  • Leflunomide
  • Methotrexate