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: 10207955
• 负责人: Jeffrey Andrew Sparks
• 金额: $ 81.44万
• 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/10207955
• 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.

项目概要 类风湿性关节炎 (RA) 是一种系统性自身免疫性疾病，影响近 1% 的成年人，导致疼痛、 破坏性炎症关节炎，具有严重的长期后果，包括慢性疼痛、残疾、 发病率的累积和死亡率的过高。 RA 患者容易发生间质性病变 肺部疾病（ILD）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 三分之二的患者血清中抗环瓜氨酸肽（ant-CCP）自身抗体升高 RA。血清反应阳性的 RA 患者更有可能发展为 RA-ILD。先前的研究表明，粘膜 吸烟或接触其他吸入剂后，肺表面可能是 RA 的起始部位，其中 RF、 抗 CCP 抗体和其他自身抗体可能在关节症状出现前数年形成。异常的后 蛋白质的翻译修饰（PTM）可能作为形成肺部局部炎症的新抗原 以及与 PTM 相关的自身抗体的生产。该部位的肺损伤随后可能在临床上表现为 RA-ILD 关节炎症可能通过全身炎症影响亚临床 RA-ILD 的风险。所以， RA 相关自身抗体、关节炎症和 RA-ILD 可能在整个疾病过程中存在关联 RA。 这些研究将研究 RA 相关自身抗体和关节炎症是否预测亚临床 和临床明显的 RA-ILD。在第一个目标中，我们将使用推导进行嵌套病例对照研究 Brigham RA 序贯研究 (BRASS) 中的数据集和 Partners Biobank 中的复制数据集。 BRASS 和合作伙伴生物银行是用于研究的患者登记处。我们还发现了 RA-ILD 病例 作为在这些研究注册中患有 RA 但没有 ILD 的对照，并建议测量临床和 PTM RA- 相关自身抗体。在第二个目标中，我们将进行多地点前瞻性观察研究 新发 RA 患者将接受一系列关节炎症和胸高测量 分辨率计算机断层扫描成像评估早期 RA 关节炎症负担是否 反映亚临床 RA-ILD 的风险。在第三个目标中，我们将分析 COPDGene 中的吸烟者是否患有 RA 相关自身抗体升高而无关节 RA 的患者更有可能患有亚临床 ILD。慢阻肺基因 是一项大型美国全国性观察研究，已对 ILA 是否存在进行了表型分析 胸部计算机断层扫描成像。 Jeffrey Sparks 博士（PI）是布莱根妇女医院的医学助理教授， 哈佛医学院。他是一名早期研究员，之前由 NIAMS 通过 K23 和 R03 资助 奖项旨在调查肺部在 RA 病因和结果中的作用。这些拟议的研究将询问 总体假设是 RA 自身免疫、关节炎症和 ILD 之间存在内在联系 RA 的病程（RA 前期、RA 早期、RA 确诊）。这些研究具有产生影响力的巨大潜力 结果将阐明 RA 和 RA-ILD 的发病机制，并可能最终提供证据 RA-ILD 筛查和预防这一破坏性并发症的策略的基础。