University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
University of Miami Miller School of Medicine, Miami, Florida.
Arthritis Rheumatol. 2020 Mar;72(3):409-419. doi: 10.1002/art.41123. Epub 2020 Feb 5.
Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA), occurring in up to 40% of patients during the course of their disease. Early diagnosis is critical, particularly given the shared clinicoepidemiologic features between advanced rheumatoid arthritis-associated ILD (RA-ILD) and idiopathic pulmonary fibrosis (IPF). This study was undertaken to define the molecular basis of this overlap through comparative profiling of serum proteins in RA-ILD and IPF.
Multiplex enzyme-linked immunosorbent assays (ELISAs) were used to profile 45 protein biomarkers encompassing cytokines/chemokines, growth factors, and matrix metalloproteinases (MMPs) in sera obtained from RA patients with ILD and those without, individuals with IPF, and healthy controls. Levels of selected serum proteins were compared between patient subgroups using adjusted linear regression, principal component analysis (PCA), and least absolute shrinkage and selection operator (LASSO) modeling.
Multiplex ELISA-based assessment of sera from 2 independent cohorts (Veterans Affairs [VA] and Non-VA) revealed a number of non-overlapping biomarkers distinguishing RA-ILD from RA without ILD (RA-no ILD) in adjusted regression models. Parallel analysis of sera from IPF patients also yielded a discriminatory panel of protein markers in models adjusted for age/sex/smoking, which showed differential overlap with profiles linked to RA-ILD in the VA cohort versus the Non-VA cohort. PCA revealed several distinct functional groups of RA-ILD-associated markers that, in the VA cohort, encompassed proinflammatory cytokines/chemokines as well as 2 different subsets of MMPs. Finally, LASSO regression modeling in the Non-VA and VA cohorts revealed distinct biomarker combinations capable of discriminating RA-ILD from RA-no ILD.
Comparative serum protein biomarker profiling represents a viable method for distinguishing RA-ILD from RA-no ILD and identifying population-specific mediators shared with IPF.
间质性肺病（ILD）是类风湿关节炎（RA）的常见并发症，在疾病过程中多达 40%的患者会发生。早期诊断至关重要，特别是鉴于晚期类风湿关节炎相关间质性肺病（RA-ILD）和特发性肺纤维化（IPF）之间具有共同的临床流行病学特征。本研究旨在通过比较 RA-ILD 和 IPF 患者的血清蛋白谱来定义这种重叠的分子基础。
使用多重酶联免疫吸附测定（ELISA）分析方法，对来自患有ILD 的 RA 患者和无ILD 的 RA 患者、IPF 患者以及健康对照者的血清中的 45 种蛋白生物标志物（细胞因子/趋化因子、生长因子和基质金属蛋白酶（MMPs））进行蛋白谱分析。使用调整后的线性回归、主成分分析（PCA）和最小绝对值收缩和选择算子（LASSO）模型比较患者亚组之间的选定血清蛋白水平。
基于多重 ELISA 的对来自 2 个独立队列（退伍军人事务部 [VA] 和非-VA）的血清评估结果显示，在调整后的回归模型中，有许多非重叠的生物标志物可将 RA-ILD 与无ILD 的 RA（RA-no ILD）区分开来。对 IPF 患者的血清进行平行分析，在调整年龄/性别/吸烟因素的模型中也产生了一组具有鉴别力的蛋白标记物，这些标记物与 VA 队列中 RA-ILD 相关的特征重叠，但与非-VA 队列中的特征重叠程度不同。PCA 揭示了 RA-ILD 相关标志物的几个不同的功能组，在 VA 队列中，这些标志物包括促炎细胞因子/趋化因子以及 2 种不同的 MMP 亚群。最后，非-VA 和 VA 队列中的 LASSO 回归模型揭示了能够将 RA-ILD 与 RA-no ILD 区分开的不同的生物标志物组合。
比较血清蛋白生物标志物分析代表了一种可行的方法，可以将 RA-ILD 与 RA-no ILD 区分开来，并确定与 IPF 共享的人群特异性介质。
