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: 9308669
• 负责人: Joan Marie Bathon
• 金额: $ 264.65万
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308669
• 关键词: Achievement; Aftercare; Algorithms; Aorta; Arthritis; Atherosclerosis; Basic Science; Biological Markers; Cardiovascular Diseases; Carotid Arteries; Cessation of life; Chronic; Clinical; Comorbidity; Data; Data Science; 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; Patient risk; Patients; Positron-Emission Tomography; Prevention trial; Proteins; Provider; Published Comment; Randomized; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Regimen; 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; secondary analysis; tool; treatment response; tumor necrosis factor-alpha inhibitor; 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（由申请人提供）：风湿性关节炎（RA）是一种慢性炎症性疾病，可导致关节损伤和残疾。虽然过去二十年来RA治疗的显著进展改善了许多结局，但RA的死亡率仍然是非RA对照的1.5-3倍。心血管疾病（CVD）是RA过度死亡的主要原因，大多数专家认为，血管炎症增强是加速动脉粥样硬化和CV事件的基础。然而，这一假设并没有直接的证据。如果是真的，那么减少关节炎症的RA治疗也可能降低CV风险。缺乏RA特异性CV风险工具阻碍了循证指南，因为一般人群工具在RA中表现不佳。这些知识上的差距给患者和医疗服务提供者管理类风湿关节炎及其合并症带来了不确定性。 虽然以CV事件作为结局的RCT是研究RA治疗对CVD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要求（约10，000），要求患者保持随机化的长期试验持续时间（约3年）以及相关成本（约6000万美元）。此外，许多DMARD会升高LDL，这在CVD预防试验中提出了伦理挑战，其中需要招募高风险患者。因此，使用直接反映血管炎症的替代CV指标并已证明对治疗有反应的替代结局（例如，与他汀类药物）将作为一个科学上重要的和可行的概念验证试验。我们建议使用18氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描（FDG PET/CT）作为一种新的成像方式来检测基线，DMARD相关的变化，血管炎症RA。 我们将在甲氨蝶呤（MTX）疗效不佳的RCT中比较2种治疗方案对FDG PET/CT的影响，这代表了风湿病学家和患者的关键和常见决策点：在背景MTX中添加TNFi vs柳氮磺胺吡啶+羟氯喹（目标1）。最近的随机对照试验显示，关节疾病活动度的降低几乎相当，但这些方案对CV风险的相对影响尚不清楚。大量基础科学数据以及流行病学证据支持TNFi在CV炎症方面优于非生物DMARD，但这从未在RCT中进行过研究。 使用RCT的数据，我们还将比较达到低疾病活动度或缓解与保持中-高疾病活动度对血管炎症的影响。这些预先规定的次要分析将汇总治疗组，以检查疾病活动目标的实现是否与血管炎症的更大减少相关。目标2a将使用DAS-28评分对治疗反应进行分类，并将其与血管炎症相关联。目标2b将使用RA疾病活动的多生物标志物对治疗反应进行分类，并将其与血管炎症相关联。目标2c将使用FDG PET/CT测量的关节炎症对治疗反应进行分类，并与血管炎症相关。