Association between Leflunomide and Pulmonary Hypertension

Lacoste-Palasset, Thomas; Chaumais, Marie-Camille; Weatherald, Jason; Savale, Laurent; Jaïs, Xavier; Price, Laura; Khouri, Charles; Bulifon, Sophie; Seferian, Andrei; Jevnikar, Mitja; Boucly, Athénaïs; Manaud, Grégoire; Pancic, Stefana; Chabanne, Céline; Kazemi, Ahmad; Volpato, Mathilde; Favrolt, Nicolas; Guillaumot, Anne; Horeau-Langlard, Delphine; Prévôt, Grégoire; Fesler, Pierre; Bertoletti, Laurent; Reynaud‐Gaubert, Martine; Lamblin, Nicolas; Launay, David; Simonneau, Gérald; Sitbon, Olivier; Perros, Frédèric; Humbert, Marc; Montani, David

doi:10.1513/annalsats.202008-913oc

Cited by 12 publications

(8 citation statements)

References 52 publications

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“…For example, several experiments failed to reproduce PAH with well identified drugs such as aminorex or fenfluramine 28,29 . Nevertheless, these experiments, sometimes complemented by the use of human tissue samples from PAH patients and human primary cells, are indispensable to understand the mechanisms of drug provoked PAH and have proven their importance in the exploration of recent signals of PAH, such as with dasatinib or leflunomide 24,30,31 …”

Section: Discussionmentioning

confidence: 99%

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis

Hlavaty

Roustit

Montani

et al. 2022

Brit J Clinical Pharma

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Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine‐like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH. Methods We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories. Results We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin). Conclusion Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH.

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Section: Discussionmentioning

confidence: 99%

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis

Hlavaty

Roustit

Montani

et al. 2022

Brit J Clinical Pharma

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“…However, similar to dasatinib-induced PAH, there were patients with persistent PAH despite permanent discontinuation of the offending medication. On the other hand, leflunomide is an immune modulator commonly used in multiple myeloma treatment regimens [11]. There have been reports of leflunomide being associated with PAH, but a recent series found pulmonary hypertension associated with leflunomide was rare and more common in patients with other PH risk factors.…”

Section: Medication-induced Pahmentioning

confidence: 99%

“…There have been reports of leflunomide being associated with PAH, but a recent series found pulmonary hypertension associated with leflunomide was rare and more common in patients with other PH risk factors. 11 Recently published European Society of Cardiology guidelines on cardio-oncology recommend baseline echocardiography before starting therapy with proteasome inhibitors (carfilzomib) or dasatinib [13].…”

Section: Medication-induced Pahmentioning

confidence: 99%

Etiology of pulmonary hypertension in multiple myeloma: A case series and literature review

Desmarais

Yang

Narezkina

et al. 2023

Respiratory Medicine

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“…We also confirmed that high dose of mdivi-1 induced cellular senescence in VSMC treated with ox-LDL ( 151 ). In addition, mitochondrial fusion activator leflunomide used for the treatment rheumatoid arthritis has an adverse effect on humans, resulting in development of pulmonary hypertension ( 178 ).…”

Section: Perspectivementioning

confidence: 99%

Current Understanding of the Pivotal Role of Mitochondrial Dynamics in Cardiovascular Diseases and Senescence

Uchikado

Ikeda

Ohishi

2022

Front. Cardiovasc. Med.

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The heart is dependent on ATP production in mitochondria, which is closely associated with cardiovascular disease because of the oxidative stress produced by mitochondria. Mitochondria are highly dynamic organelles that constantly change their morphology to elongated (fusion) or small and spherical (fission). These mitochondrial dynamics are regulated by various small GTPases, Drp1, Fis1, Mitofusin, and Opa1. Mitochondrial fission and fusion are essential to maintain a balance between mitochondrial biogenesis and mitochondrial turnover. Recent studies have demonstrated that mitochondrial dynamics play a crucial role in the development of cardiovascular diseases and senescence. Disruptions in mitochondrial dynamics affect mitochondrial dysfunction and cardiomyocyte survival leading to cardiac ischemia/reperfusion injury, cardiomyopathy, and heart failure. Mitochondrial dynamics and reactive oxygen species production have been associated with endothelial dysfunction, which in turn causes the development of atherosclerosis, hypertension, and even pulmonary hypertension, including pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Here, we review the association between cardiovascular diseases and mitochondrial dynamics, which may represent a potential therapeutic target.

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Association between Leflunomide and Pulmonary Hypertension

Cited by 12 publications

References 52 publications

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis

Etiology of pulmonary hypertension in multiple myeloma: A case series and literature review

Current Understanding of the Pivotal Role of Mitochondrial Dynamics in Cardiovascular Diseases and Senescence

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