Heart Disease in Rheumatoid Arthritis

描述（由申请人提供）：类风湿性关节炎（RA）是一种慢性炎症和自身免疫性疾病，其特征是高发病率和死亡率以及严重残疾。在该奖项的前几个周期中，我们发现RA患者更容易发生心血管（CV）疾病（即，心肌梗死和心力衰竭），并且与一般人群相比，CV疾病后的结局显著更差。此外，RA患者的心血管疾病显示出明显不同的风险特征，传统的心血管风险因素发挥相对不那么重要（有时是矛盾的）的作用，炎症/免疫功能障碍的标志物发挥更大的作用。事实上，我们证明了为普通人群开发的CV风险预测工具（例如，由于校准不良（即，预测绝对风险的能力），以及差的辨别力（即，区分低风险和高风险的能力）。因此，我们在当前的资助周期中引入了一种新的表型生物标志物，免疫反应特征，它（在横断面研究中）显著提高了对无症状心肌功能障碍的RA受试者的识别。本次更新申请的目的是改善RA患者的CV风险预测。我们建议：1）建立（在纵向研究中）免疫应答特征的效用，结合我们丰富的流行病学数据，用于预测RA的心肌功能，检查疾病活动和生物治疗的影响; 2）创建并验证新的RA特异性CV风险评估工具。在目标1中，我们将重复评估心肌功能，并检验以下假设：在调整人口统计学、疾病特征和CV特征后，11种细胞因子免疫应答特征（在当前资助周期中开发）是未来心肌功能障碍的重要预测因子。我们将比较在2个时间点测量的免疫应答特征，并检验特征改善与心肌功能障碍风险降低相关的假设，以及研究生物疗法的影响。在目标2中，我们将设计一种新的RA特异性CV风险评分，方法是重新校准RA和其他可用的CV风险评分，以更准确地预测RA的CV风险;并系统评价RA疾病特征、实验室指标和免疫应答特征，以纳入新的CV风险评分，以最大限度地提高区分度。为了确保新评分的普遍性，将使用大型（n= 25，977）和完善的风湿病国家数据库进行外部验证。有效的心血管风险预测工具和生物标志物的创建将使筛查和预防策略的目标对准那些可能受益最大的人，从而降低心血管疾病的发病率，死亡率和RA患者的医疗费用。

DESCRIPTION (provided by applicant): Rheumatoid Arthritis (RA) is a chronic inflammatory and autoimmune disorder characterized by high morbidity and mortality, and profound disability. During the prior cycles of this award, we discovered that RA patients are significantly more likely to develop cardiovascular (CV) disease (i.e., myocardial infarction and heart failure) and have significantly worse outcomes after CV disease, compared to the general population. Moreover, CV disease in persons with RA showed a markedly different risk profile, with traditional CV risk factors playing a relatively less important (and sometimes paradoxical) role, and markers of inflammation/immune dysfunction playing a much greater role. Indeed, we demonstrated that CV risk prediction tools developed for the general population (e.g., Framingham) were of little value in RA, due to poor calibration (i.e., ability to predict absolute risk), and poor discrimination (i.e., ability to distinguish low from high risk). Thus, we introduced, in the current grant cycle, a novel phenotypic biomarker, immune response signatures, which (in cross sectional studies) significantly improved identification of RA subjects with silent myocardial dysfunction. The objective of this renewal application is to improve CV risk prediction for persons with RA. We propose to: 1) establish (in longitudinal studies) the utility of immune response signatures, when combined with our rich epidemiological data, for predicting myocardial function in RA, examining the impact of disease activity and biological treatment; and 2) create and validate a new, RA-specific, CV risk assessment tool. In Aim 1 we will repeat assessment of myocardial function and test the hypothesis that the 11 cytokine immune response signature (developed in the current grant cycle) is a significant predictor of future myocardial dysfunction after adjusting for demographic, disease features and CV characteristics. We will compare immune response signatures measured at 2 time points and test the hypotheses that improvement in signature is associated with lower risk for myocardial dysfunction, as well as investigating the impact of biological therapies. In Aim 2 we will devise a new, RA-specific, CV risk score by re-calibrating the Framingham, and other available CV risk scores to more accurately predict CV risk for RA; and by systematically evaluating RA disease characteristics, laboratory measures and immune response signatures for inclusion into the new CV risk score, in order to maximize discrimination. To ensure generalizability of the new score, external validation will be conducted using the large (n=25,977) and well established National Databank for Rheumatic Diseases. The creation of effective CV risk prediction tools and biomarkers will enable targeting of screening and prevention strategies towards those who could benefit the most, thereby reducing CV morbidity, mortality, and healthcare costs in persons with RA.