Plasma GDF-15 and PSP-D Predict the Development of Pulmonary Arterial Hypertension in Systemic Sclerosis

Patients with pulmonary arterial hypertension (PAH) experience long diagnostic delays, high functional class at diagnosis and poor prognosis. We aimed to study the differentiative and predictive value of 90 inflammatory and immunomodulatory related proteins in idiopathic and hereditary PAH (IPAH/HPAH) and systemic sclerosis-associated PAH (SSc-APAH). Cohort 1 comprised patients with SSc-APAH (n = 36), IPAH/HPAH (n = 54) and healthy controls (n = 55). Cohort 2 comprised SSc patients without PAH (n = 15) and SSc-APAH (n = 15), with blood samples both ~6 years before, and at PAH diagnosis. This cohort was used for internal validation and to predict future development of PAH in SSc. Cohort 3 comprised connective tissue disease (CTD) APAH (n = 19) and IPAH (n = 20), and was used for external validation. Plasma protein levels were measured with proximity extension assay. In cohort 1, we found that higher IL-27 differentiated PAH patients from controls (odds ratio (OR) = 1.24; area under the curve (AUC) = 0.94), whereas higher TNFRSF4 differentiated SSc-APAH from IPAH/HPAH (OR = 1.14; AUC = 0.82), and controls (OR = 1.30; AUC = 0.99). In cohort 2, GDF-15 and PSP-D were higher in female SSc patients that would develop vs those that wouldn't develop PAH, and predicted PAH-development ~6 years before diagnosis (OR = 1.24; AUC = 0.78 and 1.22; 0.73, respectively). Using equivalence testing, levels of IL-27, GDF-15 and PSP-D were equivalent (p = 0.0072, p = 0.0048 and p = 0.00076) in cohort 3 and 1. In conclusion, GDF-15 and PSP-D emerged as promising potential biomarkers in early screening and prediction of future PAH development in SSc, whereas IL-27 and TNFRSF4 appeared promising in diagnosis and subtype differentiation of PAH and SSc-APAH.