The Anti-Cyclic Citrullinated Protein Antibody Repertoire and Lung Involvement in Rheumatoid Arthritis

项目总结/摘要 虽然肺纤维化（PF）是类风湿关节炎（RA）的常见和病态并发症， 了解RA患者的发展风险以及预测进行性和致命性PF的因素。 环瓜氨酸蛋白抗体（ACPA）在关节疾病发生前就存在于患者体内， 类风湿性关节炎和普通型间质性肺炎（UIP）患者亚组中也有发现，UIP是类风湿性关节炎最常见的形式， PF见于RA和预后不良的RA。越来越多的证据表明，肺在 在这些ACPA的形成中起关键作用，并可能密切参与疾病的发病机制， RA患者的子集。该项目的假设是，随着患者从RA前（即，血清或 痰自身免疫无疾病）RA关节疾病进行性RA-UIP，有扩大的cit- 包括肺和关节特异性蛋白质的rullinated蛋白质靶点，并且该库可以预测 临床表型我们将通过确定4个亚组的患者来检验我们的假设：（1）RA前，（2）UIP前， RA，（3）RA无UIP和（4）RA-UIP。我们将看看这些合作者之间在ACPA曲目中的差异， 队列，确定可预测RA中UIP发作的肺特异性ACPA靶点，并探索 这些ACPA目标和进行性肺病之间的联系。这一建议有助于进一步的使命的Na- 关节炎、肌肉骨骼和皮肤疾病研究所，提出与患者相关的临床建议， 对类风湿性关节炎主要合并症的病因学假设进行检验的检索。这项建议会 拓宽了我们对RA与肺部关系的理解，发现了有价值的临床相关信息， 生物标志物，并为护理人员提供预测疾病发作和行为的工具， 治疗决定。该提案的长期目标包括减少疾病负担，加强 我们有能力为即将到来的临床试验丰富队列，并为未来的研究突出合理的疾病途径。 research.

PROJECT SUMMARY/ABSTRACT Though pulmonary fibrosis (PF) is a common and morbid complication of rheumatoid arthritis (RA), little is known about who with RA is at risk for its development and what predicts progressive and lethal PF. Anti-cy- clic citrullinated protein antibodies (ACPA) are present in patients before the development of joint disease in RA and are also found in a subset of patients with usual interstitial pneumonia (UIP), the most common form of PF seen in RA and the one that carries a dismal prognosis. Mounting evidence suggests that the lungs play a key role in the formation of these ACPA and may be intimately involved in the pathogenesis of disease in a subset of patients with RA. The hypothesis of this project is that as patients evolve from pre-RA (i.e., serum or sputum autoimmunity without disease) to RA joint disease to progressive RA-UIP, there is an expansion of cit- rullinated protein targets that encompass both lung and joint specific proteins, and this repertoire can predict clinical phenotype. We will test our hypothesis by identifying 4 subgroups of patients: (1) Pre-RA, (2) UIP pre- RA, (3) RA no UIP and (4) RA-UIP. We will look at the differences in this ACPA repertoire between these co- horts, identify lung-specific ACPA targets that can predict the onset of UIP in RA and explore the relationship between these ACPA targets and progressive lung disease. This proposal helps further the mission of the Na- tional Institute of Arthritis and Musculoskeletal and Skin Diseases by proposing patient-relevant clinical re- search that tests a hypothesis on the etiology of a major co-morbidity of rheumatoid arthritis. This proposal will broaden our understanding of the relationship between RA and the lungs, uncover valuable clinically relevant biomarkers and provide caregivers with tools to predict disease onset and behavior in order to personalize treatment decisions. Long-term goals of this proposal include reducing the burden of disease, strengthening our ability to enrich cohorts for upcoming clinical trials and highlighting plausible disease pathways for future research.