Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports

Background: Pneumonitis has very rarely been observed in patients taking leflunomide in clinical trials. Evidence is emerging that it is more frequent in clinical practice. Aim: The aim of this study was to investigate voluntary reports of suspected respiratory reactions to leflunomide held by the New Zealand Pharmacovigilance Centre (NZPhvC) and the Australian Adverse Drug Reactions Unit (ADRU) to ascertain if they fulfilled the criteria for pneumonitis and to define characteristics of this reaction. Method: Reports of respiratory adverse reactions attributed to leflunomide and received by the NZPhvC and the ADRU were analysed to identify those that were likely to be pneumonitis based on the criteria of Searles and McKendry. Features of these reports were examined to provide further information about this adverse reaction. Results: The NZPhvC and the ADRU received 14 reports considered to be pneumonitis occurring in patients taking leflunomide. Two case reports fulfilled the Searles and McKendry criteria for definite or probable hypersensitivity pneumonitis. The patients in the remaining reports had radiological evidence of pulmonary infiltrates, an acute respiratory illness and no evidence of precipitating infection. In two cases the patients were taking leflunomide alone; one improved when it was withdrawn. In the other 12 cases, patients were taking leflunomide in combination with methotrexate. In nine of these 12 patients pneumonitis occurred after leflunomide was added to methotrexate, usually within 12-20 weeks. One of the two patients who died had possible previous methotrexate pneumonitis. Leflunomide washout with cholestyramine was used to treat three patients, one with life-threatening illness, with good results. Conclusion: This case series supports observations that leflunomide can cause pneumonitis either as monotherapy or in combination with methotrexate. The case histories indicate that prompt recognition is important to avoid life-threatening disease and support the use of cholestyramine to remove leflunomide.