Pulmonary hypertension (PH) occurs in 10-50% of scleroderma (SSc) patients depending on the study and mode of diagnosis. PH increases with disease duration, with later age of disease onset, and is greater in males and in patients with limited SSc. PH is a leading cause of mortality in SSc patients;incidence may be increasing due to longer life span of SSc patients. Unlike PH resulting from hypoxemia due to interstitial lung disease (ILD), PH associated predominantly with limited SSc (IsSSc) is histologically identical to other forms of pulmonary arterial hypertension (PAH). Whether SSc-PAH has similar predispositions to other forms of PAH and/or whether the molecular basis is similar is not known. In contrast to other forms of PAH, with possible exception of HIV-associated PAH, SSc-PAH is characterized by autoimmunity. We have developed data demonstrating that a molecular profile reflecting immune processes exists in patients with SSC-PAH. TO investigate further the hypotheses that: 1) vascular changes in SSc-PAH result from EC dysfunction, initiated by interaction of autoimmunity and injury leading to subsequent excessive angiogenesis;and 2) specific markers of autoimmunity and EC injury and/or angiogenesis can define phenotypes in the SSc population and predict development and progression of PAH, we propose to: 1) Identify markers of inflammation/injury and angiogenesis in SSc patients with PAH (SSc-PAH phenotype) in patients with established SSc-PAH and in SSc patients who develop PAH during the tenure of this proposal. 2) Compare markers identified in patients with SSc-PAH with those markers identified in patients with SSc-ILD. Overlap Aim with Dr. Lafyatis. We will compare and contrast candidate molecules of the "SSc-PAH phenotype" with those of the "SSc-ILD phenotype", the two phenotypes most associated with morbidity and mortality in SSc. 3) Determine the relationship between outcomes in patients with SSc-PAH and vascular endothelial endoplasmic reticulum (ER) stress. Overlap Aim with Dr. Trojanowska. The proposed studies will determine a predictive phenotype important in development and outcome of PAH in SSc patients. This may allow better screening, identify atrisk patients and, potentially, contribute to prevention strategies.

Public Health Relevance

PAH is a life-threatening complication of IsSSc;its incidence seems to be increasing due to longer life span of SSc patients. Together, PAH and ILD are eading causes of morbidity and mortality in SSc patients. Little is known about molecules that identify SSc-PAH or contribute to its development in these patients. We will develop and compare predictive phenotypes (the SSc-PAH penotype and the SSc-ILD phenotype) to permit better screenina. more pointed-care. and better determinants of clinical outcome in SSc patients.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center (P50)
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Special Emphasis Panel (ZAR1-MLB)
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Boston University
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