Thomas Lacoste Palasset1,2,3, Marie-Camille Chaumais3,4,5, Jason Weatherald6, Laurent Savale1,2,3, Xavier Jaïs1,2,3, Laura C Price7, Charles Khouri8, Sophie Bulifon1,2,3, Andrei Seferian1,2,3, Mitja Jevnikar1,2,3, Athénaïs Boucly1,2,3, Grégoire Manaud3, Stefana Pancic9, Celine Chabanne10, Kaïs Ahmad11, Mathilde Volpato12, Nicolas Favrolt13, Anne Guillaumot14, Delphine Horeau-Langlard15, Grégoire Prévot16, Pierre Fesler17, Laurent Bertoletti18, Martine Reynaud-Gaubert19, Nicolas Lamblin20, David Launay21, Gérald Simonneau1,2,3, Olivier Sitbon1,2,3, Frédéric Perros2,3, Marc Humbert1,2,3, David Montani1,2,3. 1. Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, and. 2. Université Paris-Saclay, Le Kremlin-Bicêtre, France. 3. Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France. 4. Service de Pharmacie, Centre Hospitalier Universitaire de Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France. 5. Faculté de Pharmacie, Université Paris-Saclay, Chatenay-Malabry, France. 6. Division of Respirology, Department of Medicine, and. 7. National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, London, United Kingdom. 8. Centre Régional de Pharmacovigilance, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. 9. Department of Medicine, University of Calgary, Calgary, Alberta, Canada. 10. Service de Cardiologie et Maladies Vasculaires, Institut National de la Santé et de la Recherche Médicale Unité 1099, Centre Hospitalier Universitaire de Rennes, Rennes, France. 11. Groupe Hospitalier Est, Service de Pneumologie-Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Lyon, France. 12. Service de Pneumologie, and. 13. Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalier Universitaire de Dijon, Dijon, France. 14. Département de Pneumologie, Hôpital de Brabois, Centre Hospitalier Régional Universitaire de Nancy, Vandoeuvre-lès-Nancy, France. 15. Service de pneumologie, Hôpital Laënnec, Centre Hospitalier Universitaire de Nantes, Nantes, France. 16. Service de Pneumologie, Hôpital Larrey, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. 17. CNRS, Institut National de la Santé et de la Recherche Médicale et Départment de Médecine Interne Lapeyronie, Centre Hospitalier Universitaire de Montpellier, Montpellier, France. 18. Service de Médecine Vasculaire et Thérapeutique, Institut National de la Santé et de la Recherche Médicale Unité 1059 et Centre d'Investigation Clinique 1408, Centre Hospitalier Universitaire de Saint-Etienne, Université Jean-Monnet, Saint-Etienne, France. 19. Service de Pneumologie Centre Hospitalier Universitaire Nord, Assistance Publique Hôpitaux de Marseille, Marseille, France; and. 20. Centre Hospitalier Régional Universitaire de Lille, Service de Cardiologie, Institut Pasteur, and. 21. Département de Médecine Interne et Immunologie Clinique, Centre Hospitalier Régional Universitaire de Lille, Université de Lille, Lille, France.
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.
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.
Entities:
Keywords:
antirheumatic agents; pharmacovigilance; pulmonary hypertension; translational medical research