Pulmonary hypertension (PH) and ischemic digital lesions (DL) are two scleroderma vascular outcomes that in cross-sectional studies are associated with abnormalities in biomarkers of angiogenesis. The clinical usefulness of these biomarkers is unknown in part due to lack of data on longitudinal measurement.
We conducted a prospective cohort study of 300 patients with systemic sclerosis (SSc) who were followed for at least a five-year period, who at enrollment lacked evidence of PH and/or active DL. Levels of hepatocyte growth factor (HGF), soluble Flt-1, soluble endoglin, endostatin, and platelet-derived growth factor (PlGF) were obtained at multiple time points and assessed for their ability to predict the development of PH/DL.
46 patients (15%) developed PH and 69 (23%) developed a DL. In time-to-event analyses, three biomarkers measured at cohort entry were found to significantly associate with the development of PH: HGF (HR 1.99, 95%CI 1.24-3.17, p=0.004), sFlt1 (HR 3.04, 95%CI 1.29-7.14, p=0.011), and PlGF (HR 2.74, 95%CI 1.32-5.69, p=0.007). As time approaching PH diagnosis decreased, there was no corresponding increase in any biomarker level. Upon converting each continuous vascular biomarker into a binary variable, a dose-response relationship was observed for the number of elevated biomarkers at cohort entry and risk of developing PH: With each additional elevated biomarker at cohort entry, there was a 78% increase in hazard of developing PH (HR 1.78, 95% CI 1.2-2.6, p=0.004).
These data suggest that molecules involved in angiogenesis reflect vascular perturbation and elevations at first encounter can risk-stratify patients.

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