Rheumatoid Arthritis-Related Autoantibodies, Articular Inflammation, and RA-Associated Interstitial Lung Disease

类风湿关节炎相关自身抗体、关节炎症和 RA 相关间质性肺病

• 批准号: 10491725
• 负责人: Jeffrey Andrew Sparks
• 金额: $ 72.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-27 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491725
• 关键词: Acetaldehyde; Adult; Affect; Ants; Autoantibodies; Autoimmunity; Award; Chest; Clinical; Colorado; Complication; Cyprinus carpio; Data; Data Set; Derivation procedure; Development; Disease; Enrollment; Etiology; Excess Mortality; Exposure to; Fibrosis; Foundations; Funding; General Hospitals; Genetic; Genotype; Goals; High Resolution Computed Tomography; Hospitals; Image; Inflammation; Inflammatory Arthritis; Inhalant dose form; Interstitial Lung Diseases; Investigation; Joints; Lead; Life Style; Link; Lung; MUC5B gene; Malondialdehyde; Massachusetts; Measures; Medicine; Michigan; Mission; Morbidity - disease rate; Mucous Membrane; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nested Case-Control Study; Observational Study; Outcome; Pain; Pathogenesis; Patient Recruitments; Patients; Performance; Phenotype; Post-Translational Protein Processing; Predisposition; Prevention strategy; Process; Production; Prospective cohort; Protein-arginine deiminase; Proteins; Pulmonary Inflammation; Registries; Research; Research Personnel; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Risk Factors; Role; Scanning; Serum; Site; Smoker; Smoking; Smoking History; Surface; Sushi Domain; Symptoms; Testing; United States National Institutes of Health; Universities; Variant; Woman; X-Ray Computed Tomography; biobank; chest computed tomography; chronic autoimmune disease; chronic pain; clinical risk; cohort; cyclic citrullinated peptide; disability; disease phenotype; disorder risk; high risk; improved; insight; lung injury; medical schools; mortality; neoantigens; patient registry; patient stratification; predictive modeling; prevent; professor; promoter; prospective; screening; seropositive; systemic autoimmune disease; systemic inflammatory response

PROJECT SUMMARY Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting nearly 1% of adults causing a painful, destructive inflammatory arthritis with serious long-term consequences including chronic pain, disability, accumulation of morbidities, and excess mortality. Patients with RA are susceptible to developing interstitial lung disease (ILD), a devastating complication with high morbidity and mortality. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (ant-CCP) autoantibodies are elevated in the serum of two-thirds of patients with RA. Seropositive RA patients are more likely to develop RA-ILD. Previous studies suggest that mucosal surfaces of the lung may be an initiating site for RA, after smoking or exposure to other inhalants, where RF, anti-CCP, and other autoantibodies may be formed years before joint symptoms develop. Aberrant post- translational modifications (PTM) to proteins may serve as neoantigens forming local inflammation in the lungs and production of autoantibodies related to PTM. This site of lung injury may later manifest clinically as RA-ILD and articular inflammation may impact risk for subclinical RA-ILD through systemic inflammation. Therefore, RA-related autoantibodies, articular inflammation, and RA-ILD may be linked throughout the disease course of RA. These investigations will study whether RA-related autoantibodies and articular inflammation predict subclinical and clinically-apparent RA-ILD. In the first aim, we will perform a nested case-control study using a derivation dataset in the Brigham RA Sequential Study (BRASS) and a replication dataset in the Partners Biobank. BRASS and the Partners Biobank are patient registries for research. We have identified RA-ILD cases as well as controls with RA but no ILD in these research registries and propose to measure clinical and PTM RA- related autoantibodies. In the second aim, we will perform a multi-site prospective observational study of patients with new-onset RA who will undergo serial measures of articular inflammation and chest high- resolution computed tomography imaging to evaluate whether the burden of articular inflammation in early RA reflects risk for subclinical RA-ILD. In the third aim, we will analyze whether smokers in COPDGene with elevation of RA-related autoantibodies without articular RA are more likely to have subclinical ILD. COPDGene is a large US nationwide observational study that has already been phenotyped for presence or absence of ILA on chest computed tomography imaging. Dr. Jeffrey Sparks (the PI) is an Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School. He is an early-stage investigator previously funded by NIAMS through K23 and R03 awards to investigate the role of the lung in RA etiology and outcomes. These proposed studies will interrogate the overarching hypothesis that RA autoimmunity, articular inflammation, and ILD are intrinsically linked across the disease course of RA (pre-RA, early RA, established RA). These studies have high potential for impactful results that will elucidate the pathogenesis of both RA and RA-ILD and may ultimately provide the evidence basis for RA-ILD screening and prevention strategies for this devastating complication.

项目摘要 类风湿关节炎（RA）是一种全身性自身免疫性疾病，几乎影响1％的成年人，导致痛苦， 破坏性炎症性关节炎，长期后果，包括慢性疼痛，残疾， 病毒的积累和过多的死亡率。 RA患者容易发育 肺部疾病（ILD），这是一种具有高发病率和死亡率的毁灭性并发症。类风湿因子（RF）和 三分之二三分之二的患者的血清中，抗偶然柠檬硫化肽（ANT-CCP​​）自身抗体升高 RA。血清反应RA患者更有可能发展RA-ILD。先前的研究表明粘膜 肺的表面可能是吸烟或暴露于其他继承后的RA的发起位置 抗CCP和其他自身抗体可能是在产生联合症状之前数年形成的。异常后 转化修饰（PTM）对蛋白质可能充当新抗原，形成肺部局部炎症 和与PTM相关的自身抗体的产生。该肺损伤部位后来可能在临床上表现为RA-ild 关节炎症可能会通过全身性炎症影响亚临床RA-ILD的风险。所以， 与RA相关的自身抗体，关节炎症和RA-ELD可能在整个疾病过程中联系起来 RA。 这些研究将研究与RA相关的自身抗体和关节感染是否预测亚临床 和临床上的RA-ild。在第一个目标中，我们将使用推导进行嵌套的病例对照研究 Brigham RA顺序研究（黄铜）和合作伙伴生物库中的复制数据集中的数据集。 黄铜和合作伙伴生物库是研究的患者注册。我们也确定了RA-ILD案件 作为RA的控制，但在这些研究注册表中没有ILD，并提出了衡量临床和PTM RA-的建议 相关的自身抗体。在第二个目标中，我们将对 具有新发RA的患者将接受关节炎症的系列措施和胸部高 - 分辨率计算机断层扫描成像，以评估RA早期关节炎症的燃烧是否燃烧 反映了亚临床RA-ild的风险。在第三个目的中，我们将分析Copdgene吸烟者是否与 没有关节RA的RA相关自身抗体的升高更可能具有亚临床ILD。科德吉尼 是一项大型美国国家观察研究，已经被表型用于ILA的存在或不存在 在胸部计算机断层扫描成像上。 Jeffrey Sparks博士（PI）是Brigham and妇女医院医学助理教授， 哈佛医学院。他是一名先前由NIAMS通过K23和R03资助的早期调查员 奖励研究肺在RA病因和结果中的作用。这些提出的研究将审问 RA自身免疫性，关节炎症和ILD的总体假设与本质上联系在一起 RA的疾病疗程（RA前，早期RA，已建立RA）。这些研究具有很高的影响力 将阐明RA和RA-ILD的发病机理的结果，并可能最终提供证据 RA-ILD筛查和预防策略的基础。