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（由申请人提供）：类风湿性关节炎（RA）是一种导致关节损伤和残疾的慢性炎症性疾病，尽管过去二十年在 RA 治疗方面取得了显着进展，改善了许多结果，但 RA 的死亡率仍然为 1.5-3。心血管疾病 (CVD) 是 RA 患者过度死亡的主要原因，大多数专家认为，血管炎症加剧会加速动脉粥样硬化和心血管事件。如果这一假设成立，那么减少关节炎症的 RA 疗法也可能降低 CV 风险，因为一般人群工具在 RA 中表现不佳，因此缺乏针对 RA 的 CV 风险工具。虽然以心血管事件为结果的随机对照试验将是研究 RA 治疗对 CVD 影响的理想研究方法，但存在一些障碍，包括管理大样本。尺寸要求（约 10,000 例）、试验持续时间较长（约 3 年），需要患者维持随机化，以及相关成本（约 6000 万美元）。此外，许多 DMARD 给 CVD 预防试验（招募高危患者）带来了伦理挑战。因此，需要使用替代CV测量来直接反映血管炎症并已被证明对治疗（例如使用他汀类药物）有反应的替代结果，这将是一种在科学上重要且可行的方法。我们在此建议使用 18 氟脱氧葡萄糖通过正电子发射断层扫描/计算机断层扫描 (FDG PET/CT) 作为一种新的成像方式来检测 RA 血管炎症的基线和 DMARD 相关变化。将比较甲氨蝶呤 (MTX) 反应不足者的随机对照试验中 2 种治疗方案对 FDG PET/CT 的影响，代表了关键且常见的决策点风湿病学家和患者：在背景 MTX 中添加 TNFi 与柳氮磺胺吡啶 + 羟氯喹（目标 1）相比，最近的随机对照试验显示关节疾病活动度几乎相同，但这些方案对心血管风险的相对影响尚不清楚。流行病学证据支持 TNFi 治疗 CV 炎症优于非生物 DMARD，但这从未在随机对照试验中使用来自 DMARD 的数据进行过研究。 RCT，我们还将比较实现低疾病活动度或缓解与保持中度高疾病活动度对血管炎症的影响。这些预先指定的二次分析将汇集治疗组，以检查实现疾病活动度目标是否与更高的疾病活动度相关。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。 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联。