Treatments Against RA and Effect on FDG PET CT: The TARGET TRIAL

RA 治疗方法及 FDG PET CT 的影响：目标试验

• 批准号: 9026031
• 负责人: Joan Marie Bathon
• 金额: $ 96.36万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-28 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026031
• 关键词: Achievement; Aftercare; Algorithms; Aorta; Arthritis; Atherosclerosis; Basic Science; Biological Markers; Cardiovascular Diseases; Carotid Arteries; Cessation of life; Chronic; Clinical; Comorbidity; Data; Decision Making; Deoxyglucose; Disease; Disease remission; Disease-Modifying Second-Line Drugs; Enrollment; Epidemiology; Ethics; Event; General Population; Hydroxychloroquine; Inflammation; Inflammatory; Knowledge; Low-Density Lipoproteins; Measures; Methotrexate; Outcome; PET/CT scan; Patients; Positron-Emission Tomography; Prevention trial; Proteins; Provider; Published Comment; Randomized; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Regimen; Relative (related person); Rheumatoid Arthritis; Risk; Sample Size; Signal Transduction; Specific qualifier value; Sulfasalazine; TNF gene; Time; Treatment Protocols; Uncertainty; X-Ray Computed Tomography; arm; arthritis therapy; base; cardiovascular disorder prevention; cost; disability; evidence based guidelines; fluorodeoxyglucose positron emission tomography; high risk; imaging modality; improved; inhibitor/antagonist; joint injury; liquid crystal polymer; mortality; novel; public health relevance; rheumatologist; tool; treatment response; uptake; vascular inflammation

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease causing joint damage and disability. While, remarkable progress in the treatment of RA over the past two decades has improved many outcomes, mortality rates in RA remain 1.5-3-fold above non-RA controls. Cardiovascular disease (CVD) is the leading cause of excess deaths in RA, and most experts believe that enhanced vascular inflammation underpins accelerated atherosclerosis and CV events. Yet, there has been no direct proof for this hypothesis. If true, then RA therapies that reduce joint inflammation might also reduce CV risk. The lack of an RA-specific CV risk tool hampers evidence-based guidelines, as general population tools perform poorly in RA. These gaps in knowledge create uncertainty for patients and providers in managing RA and its comorbidities. While an RCT with CV events as the outcome would be an ideal study approach to investigate the effect of RA treatments on CVD, there are notable barriers, including very large sample size requirement (~10,000), long trial duration (~3 years) requiring patients to maintain randomization, and the associated costs (~$60M). Moreover, many DMARDs raise LDL presenting ethical challenges in a CVD prevention trial, where enrolling high-risk patients would be desired. Therefore, an alternative outcome utilizing a surrogate CV measure that directly reflects vascular inflammation and has been demonstrated to be responsive to treatment (e.g., with statins) would serve as a scientifically important and feasible proof-of-concept trial. We propose here to use 18fluoro-deoxyglucose by positron emission tomography/computed tomography (FDG PET/CT) as a novel imaging modality to detect baseline, and DMARD-associated changes in, vascular inflammation in RA. We will compare the effects on FDG PET/CT of 2 treatment regimens in an RCT among methotrexate (MTX) inadequate responders, representing a critical and common decision point for rheumatologists and patients: addition of a TNFi vs sulfasalazine + hydroxychloroquine to background MTX (Aim 1). Recent RCTs show near equivalent reduction in articular disease activity, but the relative effects of these regimens on CV risk is unknown. Substantial basic science data as well as epidemiologic evidence support the superiority of TNFi on CV inflammation over non-biologic DMARDs, but this has never been studied in an RCT. Using data from the RCT, we will also compare the effects on vascular inflammation of achieving low disease activity or remission vs remaining in moderate-high disease activity. These pre-specified secondary analyses will pool the treatment arms to examine whether achievement of a disease activity target associates with greater reduction in vascular inflammation. Aim 2a will use DAS-28 scores to categorize treatment response and correlate it with vascular inflammation. Aim 2b will use a multi-biomarker of RA disease activity to categorize treatment response and correlate it with vascular inflammation. Aim 2c will use joint inflammation as measured by FDG PET/CT to categorize treatment response and correlate with vascular inflammation.

 描述（由适用提供）：类风湿关节炎（RA）是一种慢性炎症性疾病，导致关节损伤和残疾。尽管在过去的二十年中，在RA治疗中取得了显着进展有所提高，但RA的死亡率仍然比非RA对照组高1.5-3倍。心血管疾病（CVD）是RA过多死亡的主要原因，大多数专家认为，增强的血管感染构成了加速动脉粥样硬化和CV事件的基础。但是，没有直接证明这一假设。如果是真的，那么减少关节感染的RA疗法也可能会降低简历风险。由于一般人口工具在RA中的表现较差，因此缺乏RA特异性简历风险工具阻碍了基于证据的指南。知识中的这些差距会给患者和提供者管理RA及其合并症而产生不确定性。虽然具有CV事件作为结果的RCT将是研究RA治疗对CVD的影响的理想研究方法，但存在明显的障碍，包括非常大的样本量需求（〜10,000），长期试验持续时间（〜3年），要求患者保持随机性和相关成本（约6000万美元）。此外，许多DMARD在CVD预防试验中提出了LDL，提出了道德挑战，在该试验中，需要招募高危患者。因此，利用替代CV测量的替代结果直接反映了血管感染，并已证明对治疗有反应（例如，他汀类药物）将是一项科学重要且可行的概念证明试验。我们在这里建议通过正电子发射断层扫描/计算机断层扫描（FDG PET/CT）作为一种新型成像模态来检测基线，以及与DMARD相关的RA中的血管注射。我们将比较方法转移酸盐（MTX）不足的反应者中对2种治疗方案的FDG PET/CT的影响，这代表了风湿病学家和患者的关键和共同决策点：添加TNFI与Sulfasalazine + sulfasalazine + Hydroxychoroquine + Hydroxychoroquine对背景MTX（AIM 1）。最近的RCT显示关节疾病活动的同等减少，但是这些方案对简历风险的相对影响尚不清楚。大量的基础科学数据以及流行病学证据支持TNFI对CV感染的优越性，而不是非生物DMARDS，但这从未在RCT中进行研究。使用来自RCT的数据，我们还将比较对低疾病活动或缓解疾病活性中疾病活性低的血管炎症的影响。这些预先指定的二次分析将汇集治疗臂，以检查疾病活性靶向促进血管感染降低的目标的实现。 AIM 2A将使用DAS-28分数对治疗反应进行分类并将其与血管感染相关。 AIM 2B将使用RA疾病活性的多生物标志物分类治疗反应并将其与血管感染相关。 AIM 2C将使用FDG PET/CT测量的关节炎症对治疗反应进行分类并与血管感染相关。