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Observational Study
. 2025 Sep:160:107529.
doi: 10.1016/j.vph.2025.107529. Epub 2025 Aug 19.

Evaluation of non-invasive low-risk criteria in patients with connective tissue disease-associated pulmonary arterial hypertension: A 12-months analysis from the INSPECTIO study

Livio Giuliani  1 , Michele D'Alto  2 , Emma Di Poi  3 , Lorenzo Dagna  4 , Federico Guerra  5 , Marco Corda  6 , Gian Piero Perna  7 , Andrea Doria  8 , Roberto Badagliacca  9 , Marco Vicenzi  10 , Edoardo Airò  11 , Matteo Toma  12 , Laura Scelsi  13 , Cristina Piccinino  14 , Natale Daniele Brunetti  15 , Carlo Mario Lombardi  16 , Fabiana Baldi  17 , Matteo Biancospino  18 , Alessia Uglietti  18 , Stefano De Santis  19
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Free article
Observational Study

Evaluation of non-invasive low-risk criteria in patients with connective tissue disease-associated pulmonary arterial hypertension: A 12-months analysis from the INSPECTIO study

Livio Giuliani et al. Vascul Pharmacol. 2025 Sep.
Free article

Abstract

Background: Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a progressive, high-risk subtype of PAH characterized by immune-mediated vascular remodeling, poor treatment response, and reduced survival. Real-world data on therapeutic response and risk evolution in this population remain limited.

Methods: This post hoc analysis of the multicenter, prospective INSPECTIO study evaluated the CTD-PAH subpopulation treated with macitentan and/or selexipag. The primary endpoint was the change in the number of non-invasive low-risk criteria (World Health Organization functional class I-II, 6-min walk distance >440 m, BNP <50 ng/L or NT-proBNP <300 ng/L) from baseline to 12 months. Secondary endpoints included changes in risk stratification, 6MWD, BNP/NT-proBNP levels, echocardiographic and hemodynamic parameters, a comparison with the non-CTD PAH population of the study was also conducted.

Results: Among a total of 176 patients enrolled in the INSPECTIO study, 64 (36.4 %) had CTD-PAH. The CTD group, with a larger prevalence of systemic sclerosis (SSc) patients, was predominantly female (93.8 %) and older than the non-CTD group (66.4 vs. 59.6 years, p = 0.0005). The mean number of non-invasive low-risk criteria increased significantly from baseline to Month 12 (+0.20; p = 0.0389), with 10.9 % of CTD patients achieving three low-risk criteria at Month 12. Secondary endpoints (Investigator's risk assessment, 6MWD, BNP, NT-proBNP, echocardiographic and hemodynamic parameters, baseline therapeutic strategy, vital signs) remained collectively stable.

Conclusions: CTD-PAH patients showed improvement in non-invasive risk criteria and stabilization of functional, echocardiographic, and hemodynamic parameters under macitentan and/or selexipag therapy. Despite the observational nature and small sample size, this real-world analysis supports the use of risk-based treatment strategies and close monitoring in this patient population.

Keywords: Connective tissue disease; Macitentan; Pulmonary arterial hypertension; Real-world evidence; Risk stratification; Selexipag.

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Conflict of interest statement

Declaration of competing interest M.D. reported speaker bureau fees from AOP Health, Janssen and MSD; support for attending meetings and/or travel from AOP Health, Dompé and Janssen; participation on a Data Safety Monitoring Board or Advisory Board for MSD. E.D.P. reported participation on an Advisory Board for Johnson & Johnson. L.D. reported consultancy fees from Abbvie, Alfasigma, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, GlaxoSmithKline, Johnson & Johnson, Kiniksa Pharmaceuticals, Merk Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI, and Vifor; speakers bureaus fees from Abbvie, Alfasigma, Biogen, Eli Lilly, Galapagos, GlaxoSmithKline, Johnson & Johnson, Novartis and Vifor; support for attending meetings and/or travel from Abbvie, Alfasigma, AstraZeneca, Johnson & Johnson, Novartis. F.G. reported speaker bureau fees and support for attending meetings and/or travel from Amgen, Bayer, Boehringer-Ingelheim, Bristol-Meyer-Squibb, Daiichi-Sankyo, Janssen, Novartis, Novo Nordisk, Pfizer and Sanofi. A.D. reported consultancy fees from Biogen and Bristol Myers Squibb; speaker bureau fees from Abbvie, AstraZeneca, GlaxoSmithKline, Johnson & Johnson, Lilly and Otsuka. R.B. reported consultancy fees from AOP Health, Gossamer Bio, Janssen, MSD and UT; speaker bureau fees from AOP Health, Gossamer Bio, Janssen, MSD, and UT. M.V. reported consultancy fees from Johnson & Johnson and Roche. E.A. reported speaker bureau fees and support for attending meetings and/or travel from Johnson & Johnson. C.M.L. reported speaker bureau fees from AstraZeneca, Bayern, Boehringer-Ingelheim, Novartis, Novo Nordisk, and Pfizer. F.B. reported support for attending meetings and/or travel from Dompé, Janssen, MSD; participation on a Data Safety Monitoring Board or Advisory Board for MSD. M.B., A.U. and S.D.·S are full-time employees of Johnson & Johnson.

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