Leflunomide-induced interstitial pneumonitis might be a representative of disease-modifying antirheumatic drug-induced lung injury

Expert Opin Drug Saf. 2011 Jul;10(4):603-11. doi: 10.1517/14740338.2011.560835. Epub 2011 Mar 17.


Introduction: Although disease-modifying antirheumatic drugs (DMARDs) are crucial for rheumatoid arthritis (RA) therapy, they have severe adverse events including interstitial pneumonitis (IP). DMARD-induced IP attracts attention because of its relatively high prevalence, occasionally fatal outcome and clinical features which are common to the IP caused by different DMARDs.

Areas covered: Immediately after the introduction of leflunomide (LEF) in Japan in 2003, IP frequently developed under its use and cases with a fatal outcome were reported. The data obtained by a registration system for all patients who were prescribed LEF are examined, and the features are compared to those of other DMARD-induced IP. The features included acute respiratory distress with severe inflammatory reaction; ground-glass opacities and/or consolidations in the upper, anterior and central lung fields on XP/CT; peripheral blood lymphopenia; and diffuse alveolar damage confirmed in autopsied cases. The most outstanding risk for LEF-induced lung injury was pre-existing IP with an odds ratio of 8.17. A good response to LEF in terms of arthritis remission was suggested. Similar cases have been reported in countries other than Japan, although fewer cases were in Western countries.

Expert opinion: LEF use should be avoided at least for Japanese RA patients with pre-existing IP. The pathogenesis of DMARD-induced lung injury may have common features that need to be clarified in the future.

Publication types

  • Review

MeSH terms

  • Animals
  • Antirheumatic Agents / adverse effects*
  • Humans
  • Isoxazoles / adverse effects*
  • Japan / epidemiology
  • Leflunomide
  • Lung Diseases, Interstitial / chemically induced*
  • Lung Diseases, Interstitial / diagnostic imaging*
  • Lung Diseases, Interstitial / epidemiology
  • Lung Injury / chemically induced*
  • Lung Injury / diagnostic imaging*
  • Lung Injury / epidemiology
  • Radiography


  • Antirheumatic Agents
  • Isoxazoles
  • Leflunomide