Limited Systemic Sclerosis Patients with Pulmonary Arterial Hypertension Show Biomarkers of Inflammation and Vascular Injury

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a common complication for individuals with limited systemic sclerosis (lSSc). The identification and characterization of biomarkers for lSSc-PAH should lead to less invasive screening, a better understanding of pathogenesis, and improved treatment.Methods and FindingsForty-nine PBMC samples were obtained from 21 lSSc subjects without PAH (lSSc-noPAH), 15 lSSc subjects with PAH (lSSc-PAH), and 10 healthy controls; three subjects provided PBMCs one year later. Genome-wide gene expression was measured for each sample. The levels of 89 cytokines were measured in serum from a subset of subjects by Multi-Analyte Profiling (MAP) immunoassays. Gene expression clearly distinguished lSSc samples from healthy controls, and separated lSSc-PAH from lSSc-NoPAH patients. Real-time quantitative PCR confirmed increased expression of 9 genes (ICAM1, IFNGR1, IL1B, IL13Ra1, JAK2, AIF1, CCR1, ALAS2, TIMP2) in lSSc-PAH patients. Increased circulating cytokine levels of inflammatory mediators such as TNF-alpha, IL1-beta, ICAM-1, and IL-6, and markers of vascular injury such as VCAM-1, VEGF, and von Willebrand Factor were found in lSSc-PAH subjects.Conclusions and SignificanceThe gene expression and cytokine profiles of lSSc-PAH patients suggest the presence of activated monocytes, and show markers of vascular injury and inflammation. These genes and factors could serve as biomarkers of PAH involvement in lSSc.

Association of C‐reactive protein with high disease activity in systemic sclerosis: Results from the Canadian Scleroderma Research Group

“…The database does not record the results of RHC and markers of vascular endothelial injury have not been collected (such as vascular cell adhesion molecule 1, vascular endothelial growth factor, and von Willebrand factor). The latter has been reported as being associated with SSc PAH in lcSSc (39).…”

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

“…In one study of PAH lung tissue, of ϳ14,000 genes with measurable expression, 13,889 were altered (57). Among studies of PAH patient-derived samples, there have been three studies of lung tissue specimens (28,39,57), four studies of freshly isolated circulating cells (11,30,56,63), and three studies of cells cultured from PAH patients (5,24,65). While the overall results have been recently reviewed (48), we reexamined these data to determine whether they also identified alterations in expression of Wnt signaling molecules as a disease-associated signaling pathway (Table 2).…”

Monitoring and Diagnostic Approaches for Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis

“…52 Furthermore, vWF has been associated with PAP greater than 40 mm Hg and to predict the future development of PAH. 73,74 In addition, one study showed that patients from the PHAROS registry with incident SSc-PAH expressed higher levels of hepatocyte grown factor than patients with SSc without definite PAH. These levels also correlated with increased RVSP on echocardiogram.…”