Rheumatoid Arthritis-associated Parenchymal Lung Disease: Clinical and Molecular Phenotypes

项目总结/摘要 风湿性关节炎（RA）是一种全身性炎症性疾病，在美国约有150万人受到影响。 美国的虽然实质性肺疾病，包括间质性肺疾病（ILD）和 肺气肿是RA常见的肺部并发症，患病率和死亡率不断增加， 目前存在用于进行性疾病的早期检测或风险分层的方法。这是一个未满足需求的领域， 可能导致改善干预机会，降低相当大的发病率， RA相关肺实质疾病的死亡率。 在这项建议中，我们的目标是充分表征早期实质性肺疾病的RA和建立风险 进行性疾病的因素。我们假设临床和分子危险因素可以预测 RA相关实质性肺病的发生和进展，包括临床前ILD（preILD） 和肺气肿，并且进行性RA-preILD的分子谱将与纤维化RA-ILD重叠。到 为了检验这一假设，我们将提出以下建议：在具体目标1中，我们将确定患病率， 使用目视和客观放射学方法评估RA相关preILD和肺气肿的进展， 将这些测量与功能能力、呼吸道症状和健康相关的生活质量相关联 评估。在具体目标2中，我们将定义预测癌症的临床和分子决定因素。 RA肺气肿的发展和进展，并比较肺气肿的分子特征与 preILD提供机制洞察到RA引起的实质性肺损伤的不同模式。在 具体目标3，我们将证明进行性RA-preILD和纤维化RA-ILD具有相似的分子水平， 签名，表明表型和机械重叠。为实现本建议的目标， 将对200例无ILD病史的RA患者的纵向队列进行长达6年的随访， 临床、功能、放射学和分子表型。 这项研究的成功完成将使我们更好地了解早期 RA相关ILD和肺气肿的特征和自然史，并建立新的非侵入性 识别疾病进展风险的方法。这将有助于更密切地监测和更早地 干预的机会，可能导致患病者的发病率和死亡率下降 RA相关的肺实质疾病

PROJECT SUMMARY / ABSTRACT Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.5 million people in the United States. Although parenchymal lung disease, which encompasses interstitial lung disease (ILD) and emphysema, is a common lung complication of RA with increasing prevalence and mortality, no strategies currently exist for early detection or risk stratification of progressive disease. This is an area of unmet need that could lead to improved opportunities for intervention and a decrease in the considerable morbidity and mortality of RA-associated parenchymal lung disease. In this proposal, we aim to fully characterize early parenchymal lung disease in RA and establish risk factors for progressive disease. We hypothesize that clinical and molecular risk factors can predict the development and progression of RA-associated parenchymal lung disease, including preclinical ILD (preILD) and emphysema, and that the molecular profile of progressive RA-preILD will overlap with fibrotic RA-ILD. To test this hypothesis, we will propose the following: In Specific Aim 1, we will determine the prevalence and progression of RA-associated preILD and emphysema using visual and objective radiologic approaches and correlate these measurements with functional capacity, respiratory symptoms, and health-related quality of life assessments. In Specific Aim 2, we will define clinical and molecular determinants that predict the development and progression of RA emphysema and compare the molecular profile of emphysema with preILD to provide mechanistic insight into the divergent patterns of parenchymal lung injury caused by RA. In Specific Aim 3, we will demonstrate that progressive RA-preILD and fibrotic RA-ILD have similar molecular signatures, suggesting phenotypic and mechanistic overlap. To achieve the aims of this proposal, a longitudinal cohort of 200 RA patients without a history of ILD will be followed for up to 6 years with detailed clinical, functional, radiologic, and molecular phenotyping. The successful completion of this research will provide us with a better understanding of the early characteristics and natural history of RA-associated ILD and emphysema and establish novel non-invasive ways to identify those at risk for progressive disease. This will enable closer monitoring and earlier opportunities for intervention, potentially leading to decreased morbidity and mortality in individuals afflicted with RA-associated parenchymal lung disease.