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Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic diseases

Nature Clinical Practice Rheumatology volume 1, pages 93–101 (2005)Cite this article

Abstract

Rapid advances in the understanding of endothelin as a naturally occurring peptide with developmental and regulatory roles in normal physiology, along with a number of deleterious effects under pathologic conditions (including vasoconstriction, fibrosis, vascular hypertrophy, and inflammation) have led to the development of endothelin-receptor antagonists (ERAs). Bosentan, an antagonist with dual specificity for the endothelin-receptor subtypes A and B, has been shown to be efficacious and well tolerated in placebo-controlled clinical trials and is now approved in many countries, including the US, Canada, and Europe, for treatment of pulmonary arterial hypertension (PAH), including PAH associated with rheumatic diseases. ERAs with specificity for the endothelin-receptor subtype A, including sitaxsentan and ambrisentan, are currently undergoing investigation. This article reviews PAH associated with systemic rheumatic diseases and describes the role of ERAs in this setting.

Key Points

  • Pulmonary arterial hypertension (PAH) describes a group of diseases characterized by raised pulmonary arterial pressure and obstruction of small precapillary pulmonary arteries leading to right-heart failure

  • PAH can occur as a devastating complication in patients with systemic sclerosis

  • Various treatment approaches for PAH have been investigated, including endothelin-receptor antagonists

  • Data support the use of the oral dual endothelin-receptor antagonist bosentan in stabilizing or improving exercise capacity in patients with PAH associated with systemic sclerosis

  • More information on long-term therapy is needed in order to evaluate long-term outcome in this difficult-to-treat population

  • Oral bosentan at a dose of 125 mg twice daily is approved for treatment of PAH in many countries, including North America and Europe

  • Monthly monitoring of liver function tests is mandatory in bosentan-treated patients because of the possible elevation of hepatic aminotransferase levels

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Figure 1: The endothelin pathway is involved in abnormal proliferation and contraction of pulmonary artery smooth-muscle cells in patients with pulmonary arterial hypertension associated with systemic sclerosis.
Figure 2: Algorithm for the treatment of pulmonary arterial hypertension.

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Authors and Affiliations

  1. Professors of Respiratory Medicine at the Center for Pulmonary Vascular Diseases, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Assistance-Publique Hôpitaux de Paris, Université Paris-Sud, France

    Marc Humbert & Gérald Simonneau

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  1. Marc Humbert
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Correspondence to Marc Humbert.

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Competing interests

The authors have relationships with drug companies including Actelion, Encysive, GlaxoSmithKline, Myogen, Schering, Pfizer and United Therapeutics. In addition to being investigators in trials involving these companies, relationships include consultancy services and memberships of scientific advisory boards.

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Humbert, M., Simonneau, G. Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic diseases. Nat Rev Rheumatol 1, 93–101 (2005). https://doi.org/10.1038/ncprheum0048

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