Association between Leflunomide and Pulmonary Hypertension.

Abstract

Rationale: Pulmonary hypertension (PH) has been described in patients treated with leflunomide. Objectives: To assess the association between leflunomide and PH. Methods: We identified incident cases of PH in patients treated with leflunomide from the French PH Registry and through the pharmacoVIGIlAnce in Pulmonary ArTerial Hypertension (VIGIAPATH) program between September 1999 to December 2019. PH etiology, clinical, functional, radiologic, and hemodynamic characteristics were reviewed at baseline and follow-up. A pharmacovigilance disproportionality analysis using the World Health Organization's global database was conducted. We then investigated the effect of leflunomide on human pulmonary endothelial cells. Data are expressed as median (min-max). Results: Twenty-eight patients treated with leflunomide before PH diagnosis was identified. A total of 21 (75%) had another risk factor for PH and 2 had two risk factors. The median time between leflunomide initiation and PH diagnosis was 32 months (1-120). Right heart catheterization confirmed precapillary PH with a cardiac index of 2.37 L⋅min-1 ⋅m-2 (1.19-3.1) and elevated pulmonary vascular resistance at 9.63 Wood Units (3.6-22.1) without nitric oxide reversibility. Five patients (17.9%) had no other risk factor for PH besides exposure to leflunomide. No significant hemodynamic improvement was observed after leflunomide withdrawal. The pharmacovigilance disproportionality analysis using the World Health Organization's database revealed a significant overrepresentation of leflunomide among reported pulmonary arterial hypertension-adverse drug reactions. In vitro studies showed the dose-dependent toxicity of leflunomide on human pulmonary endothelial cells. Conclusions: PH associated with leflunomide is rare and usually associated with other risk factors. The pharmacovigilance analysis suggests an association reinforced by experimental data.

• Authors: Thomas Lacoste-Palasset, Marie-Camille Chaumais, Jason Weatherald, Laurent Savale, Xavier Jaïs, Laura C Price, Charles Khouri, Sophie Bulifon, Andrei Seferian, Mitja Jevnikar, Athénaïs Boucly, Grégoire Manaud, Stefana Pancic, Celine Chabanne, Kaïs Ahmad, Mathilde Volpato, Nicolas Favrolt, Anne Guillaumot, Delphine Horeau-Langlard, Grégoire Prévot, Pierre Fesler, Laurent Bertoletti, Martine Reynaud-Gaubert, Nicolas Lamblin, David Launay, Gérald Simonneau, Olivier Sitbon, Frédéric Perros, Marc Humbert, David Montani
• Journal: Annals of the American Thoracic Society (Ann Am Thorac Soc) Vol. 18 Issue 8 Pg. 1306-1315 (Aug 2021) ISSN: 2325-6621 [Electronic] United States
• PMID: 33502958 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Leflunomide

Topics

• Cardiac Catheterization
• Endothelial Cells
• Humans
• Hypertension, Pulmonary (chemically induced, drug therapy, epidemiology)
• Leflunomide
• Lung
• Pharmacovigilance