目的：本研究通过建立全国多中心类风湿关节炎合并肺间质病变（RA-ILD）研究队列，对我国RA-ILD患者的临床基本特征，包括人口学特征、RA病情评估、ILD病情评估、基线治疗情况进行᧿述，并探讨RA患者合并ILD危险因素。同时通过质谱分析手段开展代谢组学研究，筛选与RA-ILD诊断及预后相关生物标志物。方法：本研究主要分为临床研究和基础研究两个部分。临床研究部分，通过回顾性和前瞻性收集全国多中心结缔组织病相关肺间质病变（CTD-ILD）诊治中心基于胸部高分辨率CT（HRCT）确诊RA-ILD患者的基线资料。首先进行横断面基线特征᧿述，进一步纳入同期入组中国类风湿关节炎直报项目（CREDIT）数据库的未合并ILD的RA患者（RA-nonILD）进行巢式病例对照研究，通过Logistic回归分析寻找RA-ILD患病的独立危险因素。基础研究方面，通过质谱分析手段进行代谢组学研究，筛选在RA-ILD和RA-nonILD患者血清中差异性表达的小分子代谢物。结果：临床研究部分：全国多中心RA-ILD研究队列共纳入2119例患者。1、基线特征：RA-ILD中女性所占比例为67.9%，基线年龄为62.5±10.7岁，吸烟患者占25.6%，平均吸烟量17.4±10.7支/天。25.9%的患者以ILD为疾病的首发表现。最常见的影像学分型为非特异性间质性肺炎（NSIP），占比50.1%。用力肺活量占预测值百分比（FVC%）为74.9 ± 29.0%，一氧化碳弥散量占预测值百分比（DLCO%）为59.4 ± 26.8%。基线糖皮质激素与甲氨蝶呤的使用率为52.7%和16.3%。有3.1%的患者在基线时接受了抗肺纤维化药物治疗。2、患病危险因素研究：高龄（OR 1.101, 95% CI 1.035 - 1.170, P = 0.002），吸烟史（OR 4.423, 95% CI 1.402 - 13.961, P = 0.011），抗MCV抗体阳性（OR 3.901, 95% CI 1.309 - 11.628, P = 0.015），SDAI中高度活动（OR 3.088, 95% CI 1.051 - 9.074, P = 0.040）为RA患者合并ILD的独立危险因素。基础研究部分：共纳入RA-ILD患者22例，RA-non-ILD患者22例。一级质谱筛选得到RA-ILD相对RA患者差异表达代谢物174种，二级质谱鉴定得到16种差异代谢物。结论：本研究建立了目前世界范围内最大的RA-ILD单病种队列研究，并且首次建立了全国多中心RA-ILD队列研究，得到中国RA-ILD患者合并ILD的危险因素，ᨀ示对临床上具有高危因素（高龄、吸烟史、抗MCV抗体阳性、SDAI中重度活动）的RA患者应进行ILD相关临床表现、肺功能和HRCT的筛查，以期实现ILD的早期诊断，改善患者临床预后。本研究通过质谱分析完成了RAILD 患者与RA-nonILD 患者差异代谢物的初步筛选，候选代谢物可以通过扩大样本量进行验证，并进一步探索其在纤维化发生过程中的作用。本研究为RAILD患者的早期诊断、预后预测和发现新型生物标志物提供了研究依据。

Objective: By establishing a nationwide multi-center cohort study of Chinese patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD), we aimed to describe cross-sectional characteristics of patients with RA-ILD, including demographics, disease assessment of RA and ILD, and baseline treamtent regimen. We also aimed to analyze risk factors of RA-ILD. We focused on screening diagnostic biomarkers of RA-ILD by metabolomics study through mass spectrum. Methods: This study is mainly consisted of two sections. For clinical study section, clinical data of patients with RA-ILD, who were diagnosed by nationwide medical centers in CTD-ILD through chest high-resolutional CT (HRCT), were retrospectively and prospectively collected. Cross-sectional characteristics of patients with RA-ILD were described. Nested case control study was conducted between patients with RAILD and patients with RA but not ILD (RA-nonILD) to identify risk factors. For biomarker study section, metabolomics study was carried out through mass spectrumto screen for potential metabolites used as diagnostic biomarkers.Result: A total of 2119 patients with RA-ILD were recruited in the study. In clinical study section, 1) Baseline characteristics: 67.9% patients were female, mean age at baseline was 62.5 ± 10.7. 25.6% patients had a history of smoking, average amount of cigarette was 17.4 ± 10.7 per day. In 25.9% patients, ILD was the initial manifestation. The most common radiographic type was nonspecific interstitial pneumonia (NSIP). Mean forced vital capacity (FVC%) was 74.9 ± 29.0% and mean diffusing capacity of the lungs for carbon monoxide (DLCO) was 59.4 ± 26.8%. Glucocorticoids and methotrexate were administrated in 52.7% and 16.3% of patients, respectively. 3.1% of patients were treated with anti-pulmonary fibrosis pharmaceuticals at baseline. 2) Risk factors: older age (OR 1.101, 95% CI 1.035 - 1.170, P = 0.002), a history of smoking (OR 4.423, 95% CI 1.402 - 13.961, P = 0.011), anti-MCV antibody positivity (OR 3.901, 95% CI 1.309 - 11.628, P = 0.015) and medium to high disease activity using SDAI index (OR 3.088, 95% CI 1.051 - 9.074, P = 0.040) were identified as independent risk factors for patients with RA to develop ILD. In biomarker study section, metabolomics of 22 RA-ILD and 22 RA-nonILD patients were sereened using liquid chromatography – mass spectrometry. 174 metabolites with significant difference between two groups were found. Among them, 16 metabolites were identified. Conclusion: This study established the world largest and is the first multi-center cohort study of patients with RA-ILD. Clinical characteristics and risk factors of Chinese patients with RA-ILD were described. Regular screening for ILD is recommended in patients with high risks, including older age, a history of smoking, anti-MCV antibody positivity and medium to high disease activity using SDAI index. Novel serum biomarkers for identifying ILD in patients with RA were identified, which will act as novel biomarkers for patients with RA-ILD after identified in larger cohort.