Towards Evidence-Based Monitoring of Low Dose Methotrexate: CIRT Ancillary Study

描述（由申请人提供）：心血管炎症减轻试验（CIRT）是一项由NHLBI资助的试验（U 01 HL 101422），旨在检查低剂量甲氨蝶呤（LDM）对无全身性风湿性疾病的高风险MI后人群心血管（CV）事件二级预防的影响。本试验的假设与CV疾病的炎症基础以及LDM抑制炎症是否可减少复发性CV事件有关。LDM已被广泛用于风湿性疾病几十年，但大多数毒性警告和监测指南是基于相对较小的试验和观察数据集的数据，而不是设计用于研究药物安全性。我们建议在CIRT中随机分配至LDM或安慰剂组的7，000名MI后受试者中研究不良事件（AE），包括肝损伤、肺炎、血液学缺陷、感染、恶心、口腔炎和皮疹。我们的团队拥有丰富的药物流行病学、遗传学和预测建模专业知识。具体目的是：1）估计LDM AE（包括肝脏、肺部、血液学、感染性和皮肤粘膜AE）的发生率和相对风险; 2）研究社会人口统计学、生活方式、人体测量学、合并症、合并用药、遗传和甲氨蝶呤代谢物作为LDM AE的预测因子; 3）开发和测试LDM AE的各种风险预测规则。我们将利用我们的流行病学专业知识建立综合模型，包括临床变量，药物代谢物，遗传预测因子和药物暴露，可用于个性化靶向治疗。如果CIRT试验显示LDM导致的心血管事件减少，则发现和临床使用与LDM导致AE的可能性更大相关的标志物将为风湿性疾病患者提供重要的公共卫生获益，并可能为普通人群中的大量人群提供公共卫生获益。

DESCRIPTION (provided by applicant): The Cardiovascular Inflammation Reduction Trial (CIRT) is an NHLBI funded trial (U01 HL 101422) that will examine the effects of low dose methotrexate (LDM) on secondary prevention of cardiovascular (CV) events in a high-risk post-MI population without systemic rheumatic disease. The hypothesis underlying this trial relates to the inflammatory underpinnings of CV disease and whether suppression of inflammation with LDM can reduce recurrent CV events. LDM has been in widespread use for several decades for rheumatic diseases, but most of the toxicity warnings and monitoring guidelines are based on data from relatively small trials and observational datasets not designed to study drug safety. We propose to study adverse events (AE) including hepatic injury, pneumonitis, hematologic deficiencies, infection, nausea, stomatitis and rash among 7,000 post- MI subjects randomized to LDM or placebo in CIRT. Our team has substantial expertise pharmacoepidemiology, genetics and predictive modeling. Specific Aims are 1) To estimate the incidence rate and relative risk of LDM AEs, including hepatic, pulmonary, hematologic, infectious, and mucocutaneous; 2) To study sociodemographic, lifestyle, anthropometric, co-morbidities, co-medications, genetic, and methotrexate metabolites as predictors of LDM AEs; and 3) To develop and test various risk prediction rules for LDM AEs. We will use our epidemiologic expertise to build comprehensive models that include clinical variables, drug metabolites, genetic predictors and drug exposure that can be used to personalized targeted therapy. The discovery and clinical use of markers associated with a greater likelihood of AE from LDM would provide an important public health benefit to rheumatic disease patients and potentially to a large population from the general population if the CIRT trial shows reduction on cardiovascular events with LDM.