Vasculitis and Translational Medicine

血管炎和转化医学

• 批准号: 10271328
• 负责人: Peter Grayson
• 金额: $ 152.27万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271328
• 关键词: 2019-nCoV; Adult; Affect; Angiography; Antineutrophil Cytoplasmic Antibodies; Aortitis; Area; Arteries; Arteritis; Autoimmune Diseases; Biological Markers; Blood Vessels; Bone Marrow Transplantation; COVID-19; Characteristics; Chronic Disease; Classification; Clinical; Clinical Research; Clinical Trials; Clinical Trials Database; Clinical assessments; Collaborations; Communities; Complex; Data; Data Collection; Development; Diagnosis; Diagnostic radiologic examination; Diagnostic tests; Disease; Disease Management; Ear; Ethics; Etiology; Evaluation; Exposure to; Extramural Activities; Eye; Foundations; Future; Genetic; Germ-Line Mutation; Goals; Health; Hearing Tests; Hematology; Hematopoiesis; Image; Immune response; Immunologics; Inflammation; International; Intramural Research; Joints; Kinetics; Laboratories; Laryngoscopy; Lesion; Life; Light; Magnetic Resonance Imaging; Methods; Monitor; Morbidity - disease rate; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural History; Neck; North America; Nose; Organ; Oscillometry; Outcome; Outcome Measure; Paper; Pathogenesis; Patient Recruitments; Patients; Pattern; Performance; Physical Examination; Physicians; Positron-Emission Tomography; Prediction of Response to Therapy; Protocols documentation; Publishing; Pulmonary function tests; Radiology Specialty; Randomized Clinical Trials; Recording of previous events; Relapse; Relapsing polychondritis; Reporting; Research; Research Design; Research Personnel; Role; Sampling; Shapes; Skin; Somatic Mutation; Source; Standardization; Steroids; Structure; Surveys; System; Systemic disease; Takayasu' s Arteritis; Temporal Arteritis; Time; Tissues; Tracheostomy procedure; Translational Research; Treatment Efficacy; United States National Institutes of Health; Vasculitis; Waiting Lists; Work; aged; base; behavioral outcome; biobank; biomarker development; biomarker discovery; cartilaginous; chest computed tomography; clinical care; clinical center; clinical heterogeneity; clinical remission; cohort; data standards; deep sequencing; design; disability; disease natural history; fluorodeoxyglucose positron emission tomography; genetic variant; imaging approach; imaging biomarker; imaging study; indexing; inflammatory marker; molecular imaging; mortality; novel; novel marker; novel therapeutic intervention; pandemic disease; patient advocacy group; patient oriented; patient subsets; personalized medicine; predict clinical outcome; programs; prospective; recruit; research clinical testing; standard of care; stem cells; systemic autoimmunity; therapeutic evaluation; translational medicine; translational research program; trial design; uptake; vascular inflammation

Recruitment to date remains strong within the Vasculitis Natural History Study. All patients seen at the NIH Clinical Center receive comprehensive clinical evaluation and contribute samples to a growing biobank. Over the last year, we have focused on two forms of vasculitis: large vessel vasculitis (LVV) and relapsing polychondritis (RP). We have currently evaluated >600 patients with vasculitis under an observational protocol (14-AR-0200) and continue to see approximately 100 new patients each year in addition to following selected patients over time. Since the last report, we continue to publish articles on the role of vascular imaging as a biomarker of disease activity in large-vessel vasculitis. Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are the two major forms of large-vessel vasculitis (LVV), defined by inflammation of the aorta and primary branches. Clinical assessment of disease activity in LVV can be challenging, thus posing a barrier to effective monitoring and treatment. Patients with LVV can develop new vascular lesions during periods of apparent sustained clinical remission with normal inflammatory markers. While several studies have examined the potential of molecular imaging in LVV, the role of FDG-PET to detect vascular inflammation, monitor disease activity over time, and predict clinical outcomes remains unclear. In the past year, we have reported on the complicated relationship between clinical assessment, laboratory assessment, and vascular imaging studies over time in patients with LVV. This work has informed ongoing efforts within the OMERACT community to develop standardized definitions of disease activity in LVV for use in clinical trials. We continue to refine qualitative and quantitative metrics of vascular inflammation by FDG-PET. One such metric that we developed and validated, PET Vascular Activity Score (PETVAS), is currently being used in ongoing international clinical trials in vasculitis as a novel outcome measure. We also have refined PET imaging protocols to optimize performance characteristics of PET to detect and monitor vascular activity. We published on the kinetics of FDG arterial uptake, demonstrating that delayed imaging approaches are preferable in LVV. We have also continued to use pattern of vascular involvement, as defined by angiography or FDG-PET, as a method to identify clinically meaningful subsets of patients with LVV. Work from our group continues to shape standard of care for clinical disease activity assessment in LVV, to influence novel trial designs to test therapeutic efficacy, and to inform researchers about the natural history of the disease. We have also firmly established a new research initiative in relapsing polychondritis. Relapsing polychondritis is a multisystem, rheumatologic disease characterized by inflammation of cartilaginous structures including the ear, nose, joints and airways. There are currently no diagnostic tests for RP, organ involvement is variable, and diagnosis is dependent on the identification of a pattern of clinical features that can be, at times, quite subtle. RP has a large impact on mortality and morbidity with a high rate of organ damage and resultant disability. Airway involvement can render patients with RP unable to communicate, struggling to breath, and dependent on a tracheostomy for survival. We started recruiting patients with RP to the NIH Clinical Center in August 2016. Since that time, we have evaluated >100 patients with a confirmed diagnosis of RP, with over 80 patients currently on the waiting list to be seen. All patients undergo comprehensive disease-specific clinical assessment including a detailed history and physical examination, audiometry, direct laryngoscopy, pulmonary function tests with oscillometry, and magnetic resonance imaging of the neck. In addition, we developed a novel method to perform dynamic computed tomography (CT) of the chest as a non-invasive way to detect structural damage to large airways. We anticipate that this cohort will be a rich source of clinical information for years to come as we begin to prospectively characterize this complex, heterogeneous disease. In addition to clinically profiling RP, we collect and bank biospecimens for use in future mechanistic studies. This year we have published a paper using latent class analysis to identify three clinical subsets of patients with RP. We anticipate these findings will create a framework to understand causal factors that underlie clinical heterogeneity in RP. Recently, our group participated in the discovery of a somatic mutation in hematologic progenitor cells that is causal for disease in 8% of patients with RP in the NIH cohort. This discovery raises exciting possibilities of the role of somatic mutations in adult-onset rheumatologic conditions and raises potential for novel therapeutic approaches, including bone marrow transplantation, in these diseases. We have begun to develop deep sequencing protocols to identify clonal hematopoiesis in patients with RP and other forms of vasculitis. Finally, in light of the ongoing pandemic, we are participating in research designed to assess the impact of COVID-19 on patients with autoimmune diseases, including vasculitis. These efforts have included both patient-based surveys designed to assess the impact of the pandemic on health related behavior and outcomes in patients with vasculitis as well as mechanistic studies to determine immune responses in patients with vasculitis who are exposed to SARS-COV-2. Survey work is being conducted in collaboration with the Vasculitis Patient Powered Research Network (VPPRN). Mechanistic work will be conducted under a collaborative initiative at the Intramural NIH Program led by Dr. Mariana Kaplan.

到目前为止，在脉管炎自然史研究中招募人数仍然很多。所有在NIH临床中心就诊的患者都会接受全面的临床评估，并将样本贡献给不断增长的生物库。在过去的一年里，我们重点研究了两种形式的血管炎：大血管血管炎(LVV)和复发性多软骨炎(RP)。我们目前已经在观察性方案(14-AR-0200)下评估了&GT；600名脉管炎患者，除了随着时间的推移跟踪选定的患者外，每年还会继续看到大约100名新患者。 自上次报告以来，我们继续发表关于血管成像作为大血管血管炎疾病活动性的生物标记物的作用的文章。巨细胞动脉炎(GCA)和大动脉炎(TAK)是大血管血管炎(LVV)的两种主要形式，定义为主动脉和初级分支的炎症。对LVV疾病活动性的临床评估可能具有挑战性，因此对有效监测和治疗构成了障碍。在炎症标志物正常的临床持续缓解期，LVV患者可出现新的血管病变。虽然有几项研究已经检验了分子成像在左心室的潜力，但FDG-PET在检测血管炎症、监测一段时间内的疾病活动和预测临床结果方面的作用仍不清楚。在过去的一年里，我们报道了随着时间的推移，临床评估、实验室评估和血管成像研究之间的复杂关系。这项工作为OMERACT社区内正在进行的努力提供了信息，以开发用于临床试验的LVV疾病活动的标准化定义。我们继续通过FDG-PET改进血管炎症的定性和定量指标。我们开发和验证的一种这样的指标，PET血管活动评分(PETVAS)，目前正被用于正在进行的血管炎国际临床试验，作为一种新的结果衡量标准。我们还改进了PET成像协议，以优化PET的性能特征，以检测和监控血管活动。我们发表了关于FDG动脉摄取动力学的文章，表明延迟成像方法在LVV中更可取。我们还继续使用血管受累模式，如血管造影术或FDG-PET所定义的，作为识别有临床意义的LVV患者亚群的一种方法。我们团队的工作继续形成LVV临床疾病活动评估的护理标准，影响测试治疗效果的新试验设计，并向研究人员通报疾病的自然历史。 我们还在复发性多软骨炎方面确立了一项新的研究计划。复发性多软骨炎是一种多系统的风湿性疾病，以耳、鼻、关节和呼吸道等软骨结构的炎症为特征。目前还没有RP的诊断测试，器官受累情况多种多样，诊断依赖于对临床特征模式的识别，而临床特征有时可能非常微妙。RP对死亡率和发病率有很大的影响，器官损害和由此导致的残疾的比率很高。呼吸道受累可使RP患者无法交流，呼吸困难，并依赖气管切开术生存。我们从2016年8月开始招募RP患者到NIH临床中心。从那时起，我们评估了100名确诊为RP的患者，目前有80多名患者在等待接受治疗。所有患者都要接受全面的疾病特异性临床评估，包括详细的病史和体检、听力测量、直接喉镜检查、肺功能振荡器测试和颈部磁共振成像。此外，我们开发了一种新的方法来对胸部进行动态计算机断层扫描(CT)，作为一种非侵入性的方法来检测大气道的结构性损伤。我们预计，随着我们开始前瞻性地描述这种复杂的、不同种类的疾病，该队列将在未来几年成为丰富的临床信息来源。除了临床分析RP外，我们还收集和储存生物标本，以用于未来的机制研究。 今年，我们发表了一篇使用潜在分类分析的论文，以确定RP患者的三个临床亚群。我们期望这些发现将建立一个框架，以了解导致RP临床异质性的原因。最近，我们小组参与了在血液学前体细胞中发现的一种体细胞突变，该突变是NIH队列中8%的RP患者的致病原因。这一发现增加了体细胞突变在成人发病的风湿病中作用的令人兴奋的可能性，并增加了包括骨髓移植在内的治疗这些疾病的新方法的可能性。我们已经开始开发深度测序方案来鉴定RP和其他形式的血管炎患者的克隆性造血。 最后，鉴于持续的大流行，我们正在参与旨在评估新冠肺炎对包括脉管炎在内的自身免疫性疾病患者的影响的研究。这些努力既包括以患者为基础的调查，旨在评估大流行对脉管炎患者的健康相关行为和结果的影响，也包括机制研究，以确定接触SARS-COV-2的脉管炎患者的免疫反应。调查工作正在与脉管炎患者支持的研究网络(VPPRN)合作进行。机械工作将在玛丽安娜·卡普兰博士领导的NIH内部计划的合作倡议下进行。