Pulmonary Arterial Hypertension Incidence in Patients With Systemic Sclerosis Treated With Bosentan for Digital Ulcers: Evidence From the SPRING-SIR Registry
Authors: Cacciapaglia Fabio , De Angelis Rossella , Ferri Clodoveo , Bajocchi Gianluigi , Bellando-Randone Silvia , Bruni Cosimo , Orlandi Martina , Fornaro Marco , Cipolletta Edoardo , Zanframundo Giovanni , Foti Roberta , Cuomo Giovanna , Ariani Alarico , Rosato Edoardo , Lepri Gemma , Girelli Francesco , Zanatta Elisabetta , Bosello Silvia L. , Cavazzana Ilaria , Ingegnoli Francesca , De Santis Maria , Murdaca Giuseppe , Abignano Giuseppina , Giorgio Pettiti , Della Rossa Alessandra , Caminiti Maurizio , Iuliano Annamaria , Ciano Giovanni , Beretta Lorenzo , Bagnato Gianluca , Lubrano Ennio , De Andres Ilenia , Giollo Alessandro , Saracco Marta , Agnes Cecilia , Campochiaro Corrado , Lumetti Federica , Spinella Amelia , Magnani Luca , De Luca Giacomo , Codullo Veronica , Visalli Elisa , Iandoli Carlo , Gigante Antonietta , Pellegrino Greta , Cozzi Franco , Lazzaroni Maria G. , Generali Elena , Mennillo Gianna , Barsotti Simone , Pagano-Mariano Giuseppa , Furini Federica , Vultaggio Licia , Parisi Simone , Peroni Clara Lisa , Bianchi Gerolamo , Fusaro Enrico , Sebastiani Gian D. , Govoni Marcello , D'Angelo Salvatore , Pigatto Erika , Franceschini Franco , Guiducci Serena , Dagna Lorenzo , Doria Andrea , Giuggioli Dilia , Riccieri Valeria , Salvarani Carlo , Matucci-Cerinic Marco , Iannone Florenzo 
Published: January 2025

Objective

Bosentan (BOS) is approved for treating pulmonary arterial hypertension (PAH) and preventing digital ulcers (DU) in systemic sclerosis (SSc). Our study aimed to evaluate whether BOS prescribed for DU could reduce the incidence of PAH in a large SSc cohort from the Systemic Sclerosis Progression Investigation (SPRING) registry.

Methods

Patients with SSc from the SPRING registry, meeting 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria with data on PAH onset, DU status, BOS exposure, and at least 1 year of follow-up between 2015 and 2020, and having no known PAH at baseline, were included. PAH was diagnosed with right heart catheterization during the follow-up, and its incidence rate (IR) was calculated. Kaplan-Meier curves were determined, and multivariate regression identified PAH risk factors.

Results

Among 727 eligible patients with SSc, followed for a median of 2.0 years, 54 (7.4%) developed PAH (IR 3.71 per 100 patient-years [PYs]). Patients with DU who were never exposed to BOS had a higher incidence of PAH (IR 4.90 per 100 PYs) compared to those exposed to BOS, whose rates matched those without DU and who were never exposed to BOS. Risk factors independently associated with PAH development included DU (hazard ratio [HR] 1.86), age (HR 1.05), modified Rodnan skin score > 4 (HR 2.07), interstitial lung disease (HR 2.29), and acetylsalicylic acid treatment (HR 1.78).

Conclusion

In our cohort, the presence of DU was confirmed as a leading risk factor for PAH development, and BOS use for DU prevention may reduce this risk. Only patients with DU who were not using BOS had an increased PAH incidence.