LAUSR

Background Pulmonary arterial hypertension (PAH) continues to be a major complication in systemic sclerosis (SSc); indicating an unmet need for rational therapeutic targets. Recently, we found that chemokine CCL21 was upregulated in SSc and associated with PAH. CCL21 appears to be a key regulator of the expression and secretion of vascular endothelial growth factor-C (VEGF-C); a critical growth factor for lymphatic vessels. This is interesting as SSc is marked by lymphatic vessel abnormalities; and high blood levels of Angiopoietin-2, which is a known regulator of VEGF-C. Moreover, it was recently shown that VEGFR3, the cognate receptor for VEGF-C, is down-regulated in pulmonary arterial endothelial cells from human idiopathic PAH subjects with BMPR2 gene defects. Based on these observations, we reasoned that the observed upregulation of CCL21 in SSc-PAH could be linked to VEGF-C and Ang-2 dysregulation. Objectives Assess serum concentrations of CCL21, the VEGF family and Ang-2 in right heart catheterization (RHC) verified SSc-PAH patients and compare these to patients with borderline PAH, no PH and to healthy controls. Methods Sera from the prospective Oslo University Hospital SSc cohort (n=372) and healthy controls (n=100) were analysed for VEGF-A,C,D, CCL21 and Ang2 using Luminex kits from Millipore. Patients with an incident RHC (n=167) were included in the present study. PAH was defined as precapillary PH (mean pulmonary arterial pressure, mPAP ≥25 mmHg) in the absence of significant interstitial lung disease (ILD), based on high resolution computed tomography and lung function tests. Borderline PAH was defined as mPAP of 20–24 mmHg in in the absence of significant ILD. Patients with pulmonary hypertension (PH) due to other causes were excluded. Descriptive statistics and logistic regression analyses were performed and tested by the goodness-of-fit test with area under the curve (AUC). Results Mean age at onset was 54±14.1, at RHC 61±10.9 years. The time from sera to RHC was 0.9±3.1 years. In total, 73.7% (123) patients had limited cutaneous SSc, 46.7%48 were positive for anti-centromere antibody and 80.2% (134) were females. Of these, 123 (73.7%) patients were included in the study, 28 patients with PAH, 45 borderline PAH and 50 patients with no PH. Mean VEGF-A,C,D, CCL21 and Ang2 levels are shown in figure 1A. VEGF-A was significantly higher in SSc patients compared to healthy controls (p=0.001), no significant differences between PAH and no PH patients were found. VEGF-D was decreased in SSc-PAH but not significantly. CCL21 and Ang2 levels were increased in patients with PAH, whereas in VEGF-C was significantly decreased in patients with PAH (figure 1 B-D). In univariable logistic regression analyses, VEGF-C (OR 0.99, 95% CI 0.997–0.998,p=0.001, AUC=0.79), CCL21 (OR 1, 95% CI 1–1.003,p=0.050, AUC=0.69) and Ang2 (OR 1, 95% CI 1–1.0001,p=0.49, AUC=0.67) were associated with PAH compared to no PH patients. Due to few event numbers, no multivariable analyses were performed.Abstract FRI0431 – Figure 1 Serum levels of A) all; B) CCL21; C) VEGF-C and D) Ang2 Conclusions The present study is the first to demonstrate dysregulation of lymphangiogenetic factor expression of multiple targets in sera of SSc-PAH patients. Disclosure of Interest None declared