CYTOKINES AS PREDICTORS OF DISEASE PROGRESSION IN SCLERODERMA LUNG DISEASE

描述（由申请人提供）：肺纤维化是系统性硬化症（SSc）的主要死亡原因。NIH/ nhlbi赞助的硬皮病肺研究（SLS）是一项13中心，双盲，随机对照试验，旨在评估口服环磷酰胺（CYC；小于或等于2mg /kg/d）与安慰剂相比，作为活动性症状性硬皮病相关间质性肺疾病（SSc-ILD）患者1年治疗的有效性和安全性。这项超加速奖励申请的目标是评估储存在SLS中的生物样本，以确定SSc-ILD的病理生理机制，预测SSc-ILD的存在和活性，预测从细胞毒性治疗中获益最多的患者亚群，并帮助设计未来的临床研究，在这些研究中，其他生物制剂具有其他作用机制，可以评估其改善临床反应的能力，而不是单独使用CYC。将对BAL液、细胞颗粒mRNA和血浆样本进行分析，重点关注代表SSc-ILD炎症、增殖和闭塞性血管以及纤维化/组织基质成分的候选生物标志物。该方案的独特优势在于其生物样本近乎完整，其中包括来自血浆和主要靶器官（肺）的材料；来自SLS的丰富数据集，其中既有确定疾病存在和程度的广泛基线特征，也有对治疗的多种积极结果；鉴定不同的致病成分，集中我们的生物学分析。通过这项研究的完成，我们希望能够获得关于SSc-ILD生物学的重要新见解，能够使用血浆和/或BAL样本来识别潜在反应性肺部和皮肤疾病的患者，并为SLS研究者计划未来的治疗性临床试验提供重要见解。此外，我们将获得关于SSc-ILD的生物学和发病机制的新信息。与公共卫生的相关性：本研究的成功完成将进一步加深我们对硬皮病肺病的了解。它还将使我们能够开发疾病进展的生物标志物和预测因子，并确定哪些患者将从细胞毒性治疗中获益最多。

DESCRIPTION (provided by applicant): 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.