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(U01 HL 101422)，该试验将在没有系统性风湿病的高危心肌梗死后人群中检验低剂量甲氨蝶呤对心血管事件的二级预防作用。这项试验的假设与心血管疾病的炎症基础有关，以及LDM抑制炎症是否可以减少复发的心血管事件。几十年来，LDM一直被广泛用于风湿病，但大多数毒性警告和监测指南都是基于相对较小的试验和观察性数据集的数据，而不是为了研究药物安全性而设计的。我们建议研究7000名心肌梗塞后患者随机接受LDM或安慰剂治疗的不良事件(AE)，包括肝脏损伤、肺炎、血液系统缺陷、感染、恶心、口炎和皮疹。我们的团队在药物流行病学、遗传学和预测建模方面拥有丰富的专业知识。具体目标是：1)评估LDMAEs的发病率和相对风险，包括肝、肺、血液、感染性和皮肤粘膜；2)研究社会人口学、生活方式、人体测量、共病、联合用药、遗传和甲氨蝶呤代谢产物作为LDMAEs的预测因子；以及3)开发和测试LDMAEs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全面的模型，其中包括可用于个性化靶向治疗的临床变量、药物代谢物、遗传预测因素和药物暴露。如果CIRT试验显示LDM患者的心血管事件减少，那么发现和临床使用与LDM中较大可能性的AE相关的标记物将为风湿病患者提供重要的公共健康益处，并可能使普通人群中的大量人群受益。

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.