Redefining systemic sclerosis-associated pulmonary hypertension as an immune-mediated vasculopathy across the...

Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is a heterogeneous, difficult-to-treat condition in which multiple pulmonary hypertension groups frequently overlap. Recent evidence suggests that vascular involvement may contribute to multiple SSc-PH phenotypes. This review highlights recent advances in understanding vascular features and emerging therapeutic strategies beyond vasodilation.

Pathological and imaging studies demonstrate that vascular remodeling in SSc-PH extends beyond pulmonary arteries to pulmonary veins, capillaries, and coronary microcirculation, consistent with widespread immune-mediated vascular dysfunction. These features are increasingly recognized across various SSc-PH phenotypes: pulmonary arterial hypertension and pulmonary veno-occlusive disease; pulmonary hypertension associated with left heart disease, most commonly heart failure with preserved ejection fraction (PH-HFpEF); and pulmonary hypertension-associated with interstitial lung disease (PH-ILD); each of which is often accompanied by intrinsic right ventricular (RV) dysfunction. Emerging therapies targeting activin signaling, macrophage-vascular crosstalk, B-cell immunity, and endothelial-to-mesenchymal transition require further study but may be essential to identifying disease-modifying approaches across SSc-PH phenotypes.

There is increasing recognition that vascular remodeling across the cardiopulmonary circulation may underlie multiple SSc-PH phenotypes, providing novel insight into SSc-PH disease mechanisms and rationale for the development of therapies targeting vascular remodeling, fibrosis, inflammation, and intrinsic RV dysfunction beyond conventional vasodilator treatment.