Pulmonary Arterial Hypertension Incidence in Patients With Systemic Sclerosis Treated With Bosentan for Digital Ulcers: Evidence From the SPRING-SIR Registry

Fabio Cacciapaglia¹, Rossella De Angelis², Clodoveo Ferri³, Gianluigi Bajocchi⁴, Silvia Bellando-Randone⁵, Cosimo Bruni⁶, Martina Orlandi⁷, Marco Fornaro⁸, Edoardo Cipolletta⁹, Giovanni Zanframundo¹⁰, Roberta Foti¹¹, Giovanna Cuomo¹², Alarico Ariani¹³, Edoardo Rosato¹⁴, Gemma Lepri⁵, Francesco Girelli¹⁵, Elisabetta Zanatta¹⁶, Silvia L Bosello¹⁷, Ilaria Cavazzana¹⁸, Francesca Ingegnoli¹⁹, Maria De Santis²⁰, Giuseppe Murdaca²¹, Giuseppina Abignano²², Pettiti Giorgio²³, Alessandra Della Rossa²⁴, Maurizio Caminiti²⁵, Annamaria Iuliano²⁶, Giovanni Ciano²⁷, Lorenzo Beretta²⁸, Gianluca Bagnato²⁹, Ennio Lubrano³⁰, Ilenia De Andres³¹, Alessandro Giollo³², Marta Saracco³³, Cecilia Agnes³⁴, Corrado Campochiaro³⁵, Federica Lumetti⁷, Amelia Spinella⁷, Luca Magnani⁴, Giacomo De Luca³⁵, Veronica Codullo¹⁰, Elisa Visalli¹¹, Carlo Iandoli¹², Antonietta Gigante¹⁴, Greta Pellegrino³⁶, Franco Cozzi³⁷, Maria G Lazzaroni¹⁸, Elena Generali²⁰, Gianna Mennillo²², Simone Barsotti²⁴, Giuseppa Pagano-Mariano²⁵, Federica Furini³⁸, Licia Vultaggio³⁸, Simone Parisi³⁹, Clara Lisa Peroni³⁹, Gerolamo Bianchi⁴⁰, Enrico Fusaro³⁹, Gian D Sebastiani²⁶, Marcello Govoni³⁸, Salvatore D'Angelo⁴¹, Erika Pigatto⁴², Franco Franceschini¹⁸, Serena Guiducci⁵, Lorenzo Dagna³⁵, Andrea Doria¹⁶, Dilia Giuggioli⁷, Valeria Riccieri³⁶, Carlo Salvarani⁷, Marco Matucci-Cerinic³⁵, Florenzo Iannone; Systemic Sclerosis Progression Investigation Group of the Italian Society for Rheumatology (SPRING-SIR)

Affiliations

¹ F. Cacciapaglia, MD, PhD, Rheumatology Unit, Department of Precision and Regenerative Medicine of Jonian Area University of Bari, and Rheumatology Service, "F. Miulli" Hospital and Department of Medicine and Surgery, LUM University, Casamassima, Bari, Italy; cacciapaglia@lum.it.
² R. De Angelis, MD, PhD, Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, and IRCSS INRCA, Ancona, Italy.
³ C. Ferri, MD, Rheumatology Clinic "Madonna dello Scoglio" Cotronei, Crotone, and University Hospital of Modena and Reggio Emilia School of Medicine, Department of Medical and Surgical Sciences for Children and Adults, Modena, Italy.
⁴ G. Bajocchi, MD, L. Magnani, MD, Rheumatology Clinic "Madonna dello Scoglio" Cotronei, Crotone, Italy.
⁵ S. Bellando-Randone, MD, G. Lepri, MD, S. Guiducci, MD, Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.
⁶ C. Bruni, MD, PhD, Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy, and Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland.
⁷ M. Orlandi, MD, F. Lumetti, MD, A. Spinella, MD, D. Giuggioli, MD, C. Salvarani, MD, University Hospital of Modena and Reggio Emilia School of Medicine, Department of Medical and Surgical Sciences for Children and Adults, Modena, Italy.
⁸ M. Fornaro, MD, F. Iannone, MD, PhD, Rheumatology Unit, Department of Precision and Regenerative Medicine of Jonian Area University of Bari, Bari, Italy.
⁹ E. Cipolletta, MD, Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
¹⁰ G. Zanframundo, MD, V. Codullo, MD, PhD, Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy.
¹¹ R. Foti, MD, E. Visalli, MD, Rheumatology Unit, AOU Policlinico San Marco, Catania, Italy.
¹² G. Cuomo, MD, C. Iandoli, MD, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
¹³ A. Ariani, MD, Department of Medicine, Internal Medicine and Rheumatology, Azienda Ospedaliero Universitaria di Parma, Parma, Italy.
¹⁴ E. Rosato, MD, A. Gigante, MD, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
¹⁵ F. Girelli, MD, Department of Medicine, Rheumatology Unit, Ospedale GB Morgagni-L Pierantoni, Forlì, Italy.
¹⁶ E. Zanatta, MD, A. Doria, MD, Department of Rheumatology, University of Padua, Padova, Italy.
¹⁷ S.L. Bosello, MD, Rheumatology Division, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
¹⁸ I. Cavazzana, MD, M.G. Lazzaroni, MD, F. Franceschini, MD, Rheumatology and Clinical Immunology, ASST Spedali Civili of Brescia, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹⁹ F. Ingegnoli, MD, Division of Clinical Rheumatology, ASST Pini, Dept. of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Research Center for Environmental Health, Università degli Studi di Milano, Milan, Italy.
²⁰ M. De Santis, MD, E. Generali, MD, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan and IRCCS-Humanitas Research Hospital, Rozzano-Milan, Italy.
²¹ G. Murdaca, MD, Department of Internal Medicine, University of Genoa, and IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
²² G. Abignano, MD, G. Mennillo, MD, Rheumatology Institute of Lucania (IReL) and Rheumatology Department of Lucania, San Carlo Hospital, Potenza, Italy.
²³ P. Giorgio, MD, Rheumatology Unit, S. Croce e Carle Hospital, Cuneo, Italy.
²⁴ A. Della Rossa, MD, S. Barsotti, MD, Department of Rheumatology, University of Pisa, Pisa, Italy.
²⁵ M. Caminiti, MD, G. Pagano-Mariano, MD, Departmental Rheumatology Unit, Grande Ospedale Metropolitano, Reggio Calabria, Italy.
²⁶ A. Iuliano, MD, G.D. Sebastiani, MD, Rheumatology Unit, San Camillo-Forlanini Hospital, Rome, Italy.
²⁷ G. Ciano, MD, Local Health Department, Ariano Irpino Hospital, Avellino, Italy.
²⁸ L. Beretta, MD, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico di Milano, Milan, Italy.
²⁹ G. Bagnato, MD, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
³⁰ E. Lubrano, MD, PhD, Department of Rheumatology, University of Molise, Campobasso, Italy.
³¹ I. De Andres, MD, Rheumatology Unit, Azienda Ospedaliera di Rilievo Nazionale ed Alta Specializzazione Garibaldi, Catania, Italy.
³² A. Giollo, MD, PhD, Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy.
³³ M. Saracco, MD, Rheumatology Unit, Mauriziano-Umberto I Hospital, Turin, Italy.
³⁴ C. Agnes, MD, Department of Medicine, Division of Rehabilitation, Turin, Carmagnola, Italy.
³⁵ C. Campochiaro, MD, G. De Luca, MD, L. Dagna, MD, M. Matucci-Cerinic, MD, PhD, Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy.
³⁶ G. Pellegrino, MD, V. Riccieri, MD, Rheumatology Unit, Department of Clinical Internal, Anesthesiological Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
³⁷ F. Cozzi, MD, Department of Medicine, Villa Salus Hospital, Mestre, Italy.
³⁸ F. Furini, MD, L. Vultaggio, MD, M. Govoni, MD, Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera-Universitaria S. Anna di Ferrara, Ferrara, Italy.
³⁹ S. Parisi, MD, C.L. Peroni, MD, E. Fusaro, MD, Rheumatology Unit, Città della Salute e della Scienza, Turin, Italy.
⁴⁰ G. Bianchi, MD, Rheumatology Unit, Department of Medical Specialities, Local Health Trust 3, Genoa, Italy.
⁴¹ S. D'Angelo, MD, PhD, Rheumatology Institute of Lucania (IReL), and Rheumatology Department of Lucania, San Carlo Hospital, and University of Basilicata, Department of Health Science, Potenza, Italy.
⁴² E. Pigatto, MD, Internal Medicine Unit, San Bassiano Hospital, Bassano del Grappa, Italy.

PMID: 39814435
DOI: 10.3899/jrheum.2024-0750

Pulmonary Arterial Hypertension Incidence in Patients With Systemic Sclerosis Treated With Bosentan for Digital Ulcers: Evidence From the SPRING-SIR Registry

Fabio Cacciapaglia et al. J Rheumatol. 2025.

. 2025 Apr 1;52(4):375-382.

doi: 10.3899/jrheum.2024-0750.

Authors

Affiliations

¹ F. Cacciapaglia, MD, PhD, Rheumatology Unit, Department of Precision and Regenerative Medicine of Jonian Area University of Bari, and Rheumatology Service, "F. Miulli" Hospital and Department of Medicine and Surgery, LUM University, Casamassima, Bari, Italy; cacciapaglia@lum.it.
² R. De Angelis, MD, PhD, Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, and IRCSS INRCA, Ancona, Italy.
³ C. Ferri, MD, Rheumatology Clinic "Madonna dello Scoglio" Cotronei, Crotone, and University Hospital of Modena and Reggio Emilia School of Medicine, Department of Medical and Surgical Sciences for Children and Adults, Modena, Italy.
⁴ G. Bajocchi, MD, L. Magnani, MD, Rheumatology Clinic "Madonna dello Scoglio" Cotronei, Crotone, Italy.
⁵ S. Bellando-Randone, MD, G. Lepri, MD, S. Guiducci, MD, Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.
⁶ C. Bruni, MD, PhD, Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy, and Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland.
⁷ M. Orlandi, MD, F. Lumetti, MD, A. Spinella, MD, D. Giuggioli, MD, C. Salvarani, MD, University Hospital of Modena and Reggio Emilia School of Medicine, Department of Medical and Surgical Sciences for Children and Adults, Modena, Italy.
⁸ M. Fornaro, MD, F. Iannone, MD, PhD, Rheumatology Unit, Department of Precision and Regenerative Medicine of Jonian Area University of Bari, Bari, Italy.
⁹ E. Cipolletta, MD, Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
¹⁰ G. Zanframundo, MD, V. Codullo, MD, PhD, Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy.
¹¹ R. Foti, MD, E. Visalli, MD, Rheumatology Unit, AOU Policlinico San Marco, Catania, Italy.
¹² G. Cuomo, MD, C. Iandoli, MD, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
¹³ A. Ariani, MD, Department of Medicine, Internal Medicine and Rheumatology, Azienda Ospedaliero Universitaria di Parma, Parma, Italy.
¹⁴ E. Rosato, MD, A. Gigante, MD, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
¹⁵ F. Girelli, MD, Department of Medicine, Rheumatology Unit, Ospedale GB Morgagni-L Pierantoni, Forlì, Italy.
¹⁶ E. Zanatta, MD, A. Doria, MD, Department of Rheumatology, University of Padua, Padova, Italy.
¹⁷ S.L. Bosello, MD, Rheumatology Division, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
¹⁸ I. Cavazzana, MD, M.G. Lazzaroni, MD, F. Franceschini, MD, Rheumatology and Clinical Immunology, ASST Spedali Civili of Brescia, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹⁹ F. Ingegnoli, MD, Division of Clinical Rheumatology, ASST Pini, Dept. of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Research Center for Environmental Health, Università degli Studi di Milano, Milan, Italy.
²⁰ M. De Santis, MD, E. Generali, MD, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan and IRCCS-Humanitas Research Hospital, Rozzano-Milan, Italy.
²¹ G. Murdaca, MD, Department of Internal Medicine, University of Genoa, and IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
²² G. Abignano, MD, G. Mennillo, MD, Rheumatology Institute of Lucania (IReL) and Rheumatology Department of Lucania, San Carlo Hospital, Potenza, Italy.
²³ P. Giorgio, MD, Rheumatology Unit, S. Croce e Carle Hospital, Cuneo, Italy.
²⁴ A. Della Rossa, MD, S. Barsotti, MD, Department of Rheumatology, University of Pisa, Pisa, Italy.
²⁵ M. Caminiti, MD, G. Pagano-Mariano, MD, Departmental Rheumatology Unit, Grande Ospedale Metropolitano, Reggio Calabria, Italy.
²⁶ A. Iuliano, MD, G.D. Sebastiani, MD, Rheumatology Unit, San Camillo-Forlanini Hospital, Rome, Italy.
²⁷ G. Ciano, MD, Local Health Department, Ariano Irpino Hospital, Avellino, Italy.
²⁸ L. Beretta, MD, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico di Milano, Milan, Italy.
²⁹ G. Bagnato, MD, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
³⁰ E. Lubrano, MD, PhD, Department of Rheumatology, University of Molise, Campobasso, Italy.
³¹ I. De Andres, MD, Rheumatology Unit, Azienda Ospedaliera di Rilievo Nazionale ed Alta Specializzazione Garibaldi, Catania, Italy.
³² A. Giollo, MD, PhD, Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy.
³³ M. Saracco, MD, Rheumatology Unit, Mauriziano-Umberto I Hospital, Turin, Italy.
³⁴ C. Agnes, MD, Department of Medicine, Division of Rehabilitation, Turin, Carmagnola, Italy.
³⁵ C. Campochiaro, MD, G. De Luca, MD, L. Dagna, MD, M. Matucci-Cerinic, MD, PhD, Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy.
³⁶ G. Pellegrino, MD, V. Riccieri, MD, Rheumatology Unit, Department of Clinical Internal, Anesthesiological Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
³⁷ F. Cozzi, MD, Department of Medicine, Villa Salus Hospital, Mestre, Italy.
³⁸ F. Furini, MD, L. Vultaggio, MD, M. Govoni, MD, Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera-Universitaria S. Anna di Ferrara, Ferrara, Italy.
³⁹ S. Parisi, MD, C.L. Peroni, MD, E. Fusaro, MD, Rheumatology Unit, Città della Salute e della Scienza, Turin, Italy.
⁴⁰ G. Bianchi, MD, Rheumatology Unit, Department of Medical Specialities, Local Health Trust 3, Genoa, Italy.
⁴¹ S. D'Angelo, MD, PhD, Rheumatology Institute of Lucania (IReL), and Rheumatology Department of Lucania, San Carlo Hospital, and University of Basilicata, Department of Health Science, Potenza, Italy.
⁴² E. Pigatto, MD, Internal Medicine Unit, San Bassiano Hospital, Bassano del Grappa, Italy.

PMID: 39814435
DOI: 10.3899/jrheum.2024-0750

Abstract

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.

Keywords: bosentan; digital ulcers; pulmonary arterial hypertension; systemic sclerosis.

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Pulmonary Arterial Hypertension Incidence in Patients With Systemic Sclerosis Treated With Bosentan for Digital Ulcers: Evidence From the SPRING-SIR Registry

Affiliations

Pulmonary Arterial Hypertension Incidence in Patients With Systemic Sclerosis Treated With Bosentan for Digital Ulcers: Evidence From the SPRING-SIR Registry

Authors

Affiliations

Abstract

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical