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

项目总结 类风湿性关节炎(RA)是一种全身性自身免疫性疾病，影响近1%的成年人，导致疼痛， 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、 疾病的累积和过高的死亡率。类风湿关节炎患者易发生间质病变 肺部疾病(ILD)是一种发病率和死亡率都很高的破坏性并发症。类风湿因子(RF)和 抗环瓜氨酸肽(ANT-CCP)自身抗体在三分之二的慢性阻塞性肺疾病患者血清中升高 拉。血清阳性的RA患者更容易发生RA-ILD。先前的研究表明，粘膜 在吸烟或接触其他吸入剂后，肺表面可能是类风湿性关节炎的起始点，其中RF， 抗CCP和其他自身抗体可能在关节症状发展前数年形成。异常后遗症- 蛋白质的翻译修饰(PTM)可以作为新的抗原在肺部形成局部炎症 和产生与PTM相关的自身抗体。此肺损伤部位可能稍后在临床上表现为RA-ILD 关节炎症可能通过全身炎症影响亚临床RA-ILD的发病风险。因此， RA相关自身抗体、关节炎症和RA-ILD可能在整个病程中联系在一起 拉。 这些研究将研究RA相关自身抗体和关节炎症是否预示亚临床 临床表现为RA-ILD。在第一个目标中，我们将使用派生进行嵌套病例对照研究 Brigham RA序贯研究(BRASS)中的数据集和合作伙伴生物库中的复制数据集。 Brass和合作伙伴生物库是研究的患者登记处。我们也发现了RA-ILD病例 作为RA的对照，但在这些研究登记中没有ILD，并建议测量临床和PTM RA- 相关自身抗体。在第二个目标中，我们将进行一项多点前瞻性观测研究 新发的类风湿关节炎患者将接受一系列的关节炎症和胸高测量。 分辨率CT成像评价早期类风湿关节炎关节炎症负担 反映了亚临床RA-ILD的风险。在第三个目标中，我们将分析COPD基因中的吸烟者是否患有 无关节类风湿性关节炎的类风湿性关节炎相关自身抗体升高更有可能发生亚临床ILD。COPD基因 是一项大型的美国全国性观察性研究，已经根据ILA的存在与否进行了表型分析 胸部计算机断层扫描成像。 杰弗里·斯帕克斯博士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，之前由NIAMS通过K23和R03资助 获奖调查肺在类风湿性关节炎病因和预后中的作用。这些拟议的研究将审问 认为RA自身免疫、关节炎症和ILD之间存在内在联系的重要假设 类风湿关节炎的病程(类风湿性关节炎前期、早期类风湿关节炎、确诊类风湿关节炎)。这些研究具有很高的影响力 结果将阐明RA和RA-ILD的发病机制，并可能最终提供证据 为RA-ILD筛查和预防这种破坏性并发症的策略奠定了基础。

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.