Assessment of the Complement Cascade as a Novel Biomarker, Genetic Risk Factor, and Treatment Target for Scleroderma-Associated Pulmonary Arterial Hypertension (SSc-PAH)


Benjamin Korman, MD
University of Rochester

Project Overview

Scleroderma patients are frequently affected by vascular complications, which include Raynaud’s phenomenon, digital ulcers, cardiovascular disease, and pulmonary hypertension. Pulmonary arterial hypertension (PAH) is a type of high blood pressure that affects the arteries of the lungs and the right side of your heart. Scleroderma associated PAH (SSc-PAH) is a severe vascular manifestation of scleroderma which currently has poor outcomes, is under-diagnosed, has no established biomarkers, responds poorly to standard pulmonary hypertension medication.

We have recently shown that circulating levels of complement factor D are altered in patients with scleroderma and particularly in patients with pulmonary hypertension. Further characterization of patients with pulmonary hypertension and mouse models of pulmonary hypertension have shown additional abnormalities in certain parts of the complement cascade, an important part of the immune system that helps clear microbes and damaged cells. My lab is exploring the relevance of the complement cascade as a risk factor for developing pulmonary hypertension, a marker of disease onset and severity, and a potential treatment target. We will utilize large-scale genetic studies to evaluate variation in complement genes as a risk factor for SSc-PAH. We will perform serum and plasma studies to evaluate the utility of complement components and functional assays as SSc biomarkers.  To assess whether blocking complement may be an effective therapeutic strategy for treating SSc-PAH, we will use genetic and pharmacologic approaches to treat mice with pulmonary hypertension and abnormalities in lung complement.

How this work will impact patients

We hope to discover new biomarkers and genetic risk factors to identify, risk-stratify, and predict outcomes in patients with SSc-PAH. Moreover, in pre-clinical studies, this work will determine whether blocking parts of the complement cascade, an important part of the immune system, may serve as a novel treatment strategy for SSc-PAH. Our hope is that this work will lead to improved diagnosis, monitoring, and treatment of SSc-PAH.

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