Leflunomide Use and Risk of Lung Disease in Rheumatoid Arthritis: A Systematic Literature Review and Metaanalysis of Randomized Controlled Trials

J Rheumatol. 2016 May;43(5):855-60. doi: 10.3899/jrheum.150674. Epub 2016 Mar 15.


Objective: To evaluate the relative risk (RR) of pulmonary disease among patients with rheumatoid arthritis (RA) treated with leflunomide (LEF).

Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to April 15, 2014. We included double-blind randomized controlled trials (RCT) of LEF versus placebo or active comparator agents in adults with RA. Studies with fewer than 50 subjects or shorter than 12 weeks were excluded. Two investigators independently searched both databases. All authors reviewed selected studies. We compared RR differences using the Mantel-Haenszel random-effects method to assess total respiratory adverse events, infectious respiratory adverse events, noninfectious respiratory adverse events, interstitial lung disease, and death.

Results: Our literature search returned 5673 results. A total of 8 studies, 4 with placebo comparators, met our inclusion criteria. There were 708 respiratory adverse events documented in 4579 participants. Six cases of pneumonitis occurred, all in the comparator group. Four pulmonary deaths were reported, none in the LEF group. LEF was not associated with an increased risk of total adverse respiratory events (RR 0.99, 95% CI 0.56-1.78) or infectious respiratory adverse events (RR 1.02, 95% CI 0.58-1.82). LEF was associated with a decreased risk of noninfectious respiratory adverse events (RR 0.64, 95% CI 0.41-0.97).

Conclusion: Our study found no evidence of increased respiratory adverse events in RCT of LEF treatment.


Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Arthritis, Rheumatoid / drug therapy*
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / therapeutic use
  • Isoxazoles / adverse effects*
  • Isoxazoles / therapeutic use
  • Leflunomide
  • Lung Diseases / chemically induced*
  • Randomized Controlled Trials as Topic
  • Risk


  • Immunosuppressive Agents
  • Isoxazoles
  • Leflunomide