Pulmonary arterial hypertension in four patients treated by leflunomide

Pulmonary arterial hypertension (PAH) is a rare disorder that can be drug-induced, mostly following treatment by appetite-suppressant drugs. We report four cases of patients who developed PAH following a treatment by leflunomide for rheumatoid arthritis, psoriatic arthritis or undetermined connective tissue disease. All patients described a progressive dyspnea from grade II to IV of NYHA classification; clinical examination found signs of heart failure. PAH was finally diagnosed and confirmed by right heart catheterisation. Haemodynamic explorations found pre-capillary pulmonary hypertension with mean pulmonary arterial pressure above 25 mmHg, and pulmonary capillary wedge pressure under 15 mmHg. Explorations of this pre-capillary pulmonary hypertension were conducted according to international guidelines: pulmonary or chronic thromboembolic aetiologies were excluded after ventilation/perfusion lung scan and high-resolution computed tomography. All other etiologic explorations were negative. Imputability of leflunomide was finally retained. Leflunomide was stopped for all patients; three of them received specific PAH treatments. A favourable clinical and/or haemodynamic evolution was observed for all patients. The conclusions of the investigations conducted by our pharmacovigilance centre were communicated to the European Medicines Agency, leading to the addition of “pulmonary hypertension” in the paragraph “special warning and precautions of use” of the package leaflet of leflunomide.