Cytokine signatures differentiate systemic sclerosis patients at high versus low risk for pulmonary arterial hypertension

Background: Pulmonary arterial hypertension (PAH) affects approximately 10% of patients with systemic sclerosis (SSc) and is a leading cause of death. We sought to identify serum cytokine signatures that risk stratify SSc patients for this potentially fatal complication.

Methods: Subjects at high risk for PAH and with incident PAH based on right heart catheterization (RHC) were enrolled in the multi-center prospective registry, Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS). Low-risk SSc patients were enrolled at Stanford and had normal pulmonary function test and echocardiogram parameters. Serum was available from 71 high-risk patients, 81 incident PAH patients, 10 low-risk patients, and 20 healthy controls (HC). Custom 14- and 65-plex arrays were used for cytokine analysis. Cytokine expression was compared between patient groups by principal component analysis and Tukey's test result. A multiple hypotheses corrected p value <0.05 was considered significant.

Results: Exploratory analysis using principal components showed unique clustering for each patient group. There was a significant difference in cytokine expression in at least one group comparison for every cytokine. Overall, there was very little difference in cytokine expression comparing high-risk and PAH patient groups; however, these groups had substantially different cytokine profiles compared to low-risk patients and HC.

Conclusion: These data suggest that cytokine profiles can distinguish SSc patients who are at high-risk for or have PAH from SSc patients who may be at lower risk for PAH and HC. However, high-risk and PAH patients had very similar cytokine profiles, suggesting that these patients are on a disease continuum.