Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD

J Rheumatol. 2004 Oct;31(10):1906-11.


Objective: To determine and compare the incidence of serious adverse events (AE) during treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARD), focusing on leflunomide (LEF).

Methods: A retrospective cohort study of a large US insurance claims database was performed. Study groups were patients with RA classified by DMARD exposure as either no-DMARD therapy, single-agent DMARD (monotherapy), or combination-DMARD therapy. Specific DMARD examined were leflunomide (LEF) and methotrexate (MTX), compared to other DMARD (penicillamine, hydroxychloroquine, sulfasalazine, gold, etanercept, infliximab) and no DMARD (nonsteroidal antiinflammatory drugs, COX-2 inhibitors). All AE reported were considered endpoints; primary endpoints included hepatic, dermatologic, hematologic, infectious, respiratory, hypertension, and pancreatitis AE.

Results: The 40,594 RA patients of the study period (September 1998 to December 2000) accumulated 83,143 person-years (PY) of followup. Followup for each of the groups was: DMARD-monotherapy, 46,054 PY (55% of total); combination-DMARD, 25,830 PY (14%); and no-DMARD, 11,259 PY (14%). The incidence rate of all AE combined was significantly lower for LEF monotherapy (94 events/1000 PY) than MTX (145 events/1000 PY), other DMARD (143 events/1000 PY), or no DMARD (383 events/1000 PY) (p < 0.001 for all comparisons). The "all-AE" rates during combination therapy with LEF + MTX (43/1000 PY) and LEF + other DMARD (59/1000 PY) were lower than the "all-AE" rate for DMARD + MTX (70/1000 PY; p = 0.002). LEF monotherapy had the lowest rate of hepatic events in the DMARD monotherapy groups.

Conclusion: The rates of AE in the LEF group, alone and combined with MTX, were generally lower than or comparable to the AE rates seen with MTX and other agents.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anti-Inflammatory Agents, Non-Steroidal* / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal* / therapeutic use
  • Antirheumatic Agents* / adverse effects
  • Antirheumatic Agents* / therapeutic use
  • Arthritis, Rheumatoid / diagnosis
  • Arthritis, Rheumatoid / drug therapy*
  • Cohort Studies
  • Female
  • Humans
  • Isoxazoles* / adverse effects
  • Isoxazoles* / therapeutic use
  • Leflunomide
  • Male
  • Middle Aged
  • Retrospective Studies


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antirheumatic Agents
  • Isoxazoles
  • Leflunomide