Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). The NIH/NHLBI-sponsored Scleroderma Lung Study (SLS) was a 13-center, double-blind, randomized controlled trial designed to evaluate the effectiveness and safety of oral cyclophosphamide (CYC;less than or equal to 2 mg/kg/d) versus placebo as a 1- year treatment for patients with active, symptomatic scleroderma-related interstitial lung disease (SSc-ILD). The goal of this hyper-accelerated award application is to evaluate stored biologic samples from the SLS in order to define the pathophysiologic mechanisms that underlie SSc-ILD, to predict the presence and activity of SSc-ILD, to predict patient subsets that will benefit the most from cytotoxic therapy, and to aid in the design of future clinical studies in which other biologic agents, with other mechanisms of action, can be evaluated for their ability to improve clinical responses beyond those observed with CYC alone. Analysis of the BAL fluid, cell pellet mRNA, and plasma samples will be carried out with a focus on candidate biomarkers representative of the inflammatory, proliferative and obliterative vascular, and fibrotic/tissue matrix components of SSc-ILD. The unique strengths of this proposal are the near complete set of biologic samples which include material from the plasma as well as the primary target organ (lung);the rich data set from the SLS in which there are both extensive baseline features that define the presence and extent of disease and multiple positive outcomes in response to treatment;the identification of distinct pathogenic components upon which to focus our biologic analysis. By the completion of this study, we hope to have gained important new insight into the biology of SSc-ILD, to be able to use plasma and/or BAL samples to identify patients with potentially responsive lung and skin disease, and to provide important insight to the SLS Investigators as they plan future therapeutic clinical trials. Furthermore, we will garner new information as to the biology and pathogenesis of SSc-ILD. Relevance to Public Health: Successful completion of this study will further our understanding of scleroderma lung disease. It will also allow us to develop biologic markers and predictors of disease progression and to determine which patients would benefit most from treatment with cytotoxic therapy.
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