Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease

描述（由申请人提供）： 风湿性关节炎（RA）是美国最常见的全身性自身免疫性疾病，影响1-2%的成年人口。虽然关节和滑膜是这种疾病的主要靶点，但涉及眼睛、皮肤、心脏、脉管系统和肺的关节外表现可导致显著的发病率以及过高的死亡率。在RA中发生的各种肺部并发症中，间质性肺病（ILD）是最具破坏性的，其影响范围从亚临床炎症/瘢痕形成到终末期肺纤维化。由于类风湿性关节炎相关间质性肺病（RA-ILD）的早期亚临床形式可能代表了更可治疗的肺纤维化前体，因此需要非侵入性外周生物标志物在临床失代偿之前识别这种肺部并发症。基于CXCR 3结合趋化因子和各种基质金属蛋白酶在RA-ILD中驱动炎症以及组织损伤中起重要作用的假设，特异性目的1在有/无各种形式ILD的RA患者中采用多重ELISA，以将这些信号传导分子和降解酶的外周血/血清水平与肺部疾病的分期相关联。扩展了特异性目的1的分析，特异性目的2定义了具有不同ILD阶段的VA源性RA患者的平行队列中血清蛋白表达模式的复合生物标志物谱，验证了血清多重ELISA的使用并阐明了重要次要因素（如吸烟）的贡献。最后，Specific Aim 3补充了这种分子表型分析方法，利用免疫沉淀和ELISA技术描绘与ILD存在或不存在相关的血清抗瓜氨酸化蛋白自身抗体谱。通过开发与RA-ILD相关的外周血生物标志物特征，这些集体方法将提供关于RA-ILD和其他形式的免疫介导的肺部疾病的发病机制的见解。更重要的是，定义ILD的分子表型将确定治疗靶点，促进对这种潜在破坏性RA关节外并发症的早期治疗干预。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is the most common systemic autoimmune disease in the United States, affecting 1-2% of the adult population. Although joints and synovium are the primary targets in this disorder, extra-articular manifestations involving the eyes, skin, heart, vasculature, and lungs can lead to significant morbidity as well as excess mortality. Among the various pulmonary complications that occur in RA, interstitial lung disease (ILD) is the most damaging, with effects that range from subclinical inflammation/scarring to end stage pulmonary fibrosis. Because earlier, subclinical forms of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) may represent more treatable precursors of pulmonary fibrosis, non-invasive peripheral biomarkers are needed to identify this pulmonary complication in advance of clinical decompensation. Based on the hypothesis that CXCR3-binding chemokines and various matrix metalloproteinases play a significant role in driving inflammation as well as tissue damage in RA-ILD, Specific Aim 1 employs multiplex ELISA in RA patients with/without various forms of ILD to correlate the peripheral blood/serum levels of these signaling molecules and degradative enzymes with stage of lung disease. Extending the analysis of Specific Aim 1, Specific Aim 2 defines composite biomarker profiles of serum protein expression patterns in a parallel cohort of VA-derived RA patients with varying stages of ILD, validating the use of serum multiplex ELISA and elucidating the contribution of important secondary factors such as smoking. Finally, Specific Aim 3 complements this molecular phenotyping approach, utilizing immunoprecipitation and ELISA-based techniques to delineate serum anti-citrullinated protein autoantibody profiles that correlate with the presence or absence of ILD. Through the development of peripheral blood biomarker signatures associated with RA-ILD, these collective approaches will provide insight regarding the pathogenesis of RA-ILD and other forms of immunologically mediated lung disease. More importantly, defining the molecular phenotype of ILD will identify therapeutic targets facilitating early treatment intervention in this potentially devastating extra-articular complication of RA.