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

项目摘要 风湿性关节炎（RA）是一种全身性自身免疫性疾病，影响近1%的成年人， 破坏性炎症性关节炎，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过高。RA患者易发生间质性 肺疾病（ILD），一种具有高发病率和死亡率的毁灭性并发症。流变因子（RF）和 抗环瓜氨酸肽（ant-CCP）自身抗体在三分之二的患者血清中升高， RA.血清阳性RA患者更容易发生RA-ILD。先前的研究表明， 在吸烟或暴露于其他吸入剂后，肺表面可能是RA的起始部位，其中RF， 抗CCP和其他自身抗体可能在关节症状出现前数年形成。异常后- 对蛋白质的翻译修饰（PTM）可作为形成肺中局部炎症的新抗原 以及与PTM相关的自身抗体的产生。该部位的肺损伤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。因此，我们认为， RA相关自身抗体、关节炎和RA-ILD可能在RA的整个病程中存在联系， RA. 这些研究将研究RA相关的自身抗体和关节炎症是否预示亚临床 和临床上明显的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和合作伙伴生物库是用于研究的患者登记处。我们还发现了RA-ILD病例 在这些研究登记研究中作为RA但无ILD的对照，并建议测量临床和PTM RA- 相关的自身抗体在第二个目标中，我们将进行一项多中心前瞻性观察研究， 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，以评估早期RA患者的关节炎症负担是否 反映了亚临床RA-ILD的风险。在第三个目标中，我们将分析吸烟者在COPD基因中是否具有 RA相关自身抗体升高而无关节性RA的患者更可能患有亚临床ILD。COPD基因 是一项大型的美国全国性观察性研究， 胸部计算机断层扫描成像。 博士杰弗里·斯帕克斯（PI）是布里格姆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，此前由NIAMS通过K23和R 03资助。 研究肺在类风湿关节炎病因和预后中的作用。这些拟议的研究将询问 RA自身免疫、关节炎症和ILD之间存在内在联系的总体假设 RA的病程（RA前期、早期、确诊）。这些研究具有很高的潜力， 这些结果将阐明RA和RA-ILD的发病机制，并可能最终提供证据， RA-ILD筛查和预防策略的基础。

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.