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.

迄今为止，在血管炎自然史研究中招募仍然很强。在NIH临床中心看到的所有患者均接受全面的临床评估，并为不断增长的生物库贡献样本。在过去的一年中，我们专注于两种形式的血管炎：大血管血管炎（LVV）和复发性多发性炎（RP）。 我们目前已经根据观察方案（14-AR-0200）评估了> 600例血管炎患者，并且除了随着时间的推移选择以下患者外，每年仍将看到大约100名新患者。 自上次报告以来，我们将继续发表有关血管成像作为大周围血管炎的疾病活性生物标志物的作用的文章。巨细胞动脉炎（GCA）和高山动脉炎（TAK）是大型血管炎（LVV）的两种主要形式，是由主动脉和原发性分支的炎症定义的。 LVV中疾病活动的临床评估可能具有挑战性，从而为有效的监测和治疗带来了障碍。 LVV患者可以在正常的炎症标志物和正常的临床临床缓解期间出现新的血管病变。 尽管几项研究检查了LVV中分子成像的潜力，但FDG-PET在检测血管炎症，随着时间的推移监测疾病活动以及预测临床结果的作用尚不清楚。在过去的一年中，我们报道了LVV患者随着时间的流逝，临床评估，实验室评估和血管成像研究之间的复杂关系。这项工作已告知Omeract社区中正在进行的努力，以开发LVV中疾病活动的标准化定义，以用于临床试验。我们继续完善FDG-PET血管炎症的定性和定量指标。我们开发和验证的一种标准，即宠物血管活性评分（PETVA），目前正在正在进行的血管炎的国际临床试验中使用，作为一种新的结果指标。我们还完善了PET成像协议，以优化PET的性能特征以检测和监测血管活性。我们发表了有关FDG动脉摄取的动力学的发表，证明了LVV中延迟的成像方法是可取的。我们还继续使用由血管造影或FDG-PET定义的血管参与模式，作为鉴定LVV患者临床意义的子集的一种方法。我们小组的工作继续塑造LVV中临床疾病活动评估的护理标准，影响新的试验设计以测试治疗功效，并将其告知研究人员有关疾病的自然史。 我们还牢固地建立了一项新的研究计划，以复发多层炎。复发性多发性炎是一种多系统的风湿病疾病，其特征是软骨结构的炎症，包括耳朵，鼻子，关节和气道。 目前尚无针对RP的诊断测试，器官受累是可变的，并且诊断取决于识别临床特征模式的识别，这些模式有时可能很微妙。 RP对死亡率和发病率具有很大的影响，并具有高器官损伤和导致的残疾。 气道参与可以使RP患者无法交流，呼吸困难，并依赖于气管造口术以生存。 我们于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名患者，并确认了RP的确认诊断，目前有80多名患者在等待名单上。 所有患者都接受了全面的疾病特异性临床评估，包括详细的病史和体格检查，听力测定法，直接喉镜检查，具有振荡的肺功能测试以及颈部的磁共振成像。 此外，我们开发了一种新颖的方法来执行胸部的动态计算机断层扫描（CT）作为一种非侵入性方法来检测对大型航空公司的结构损害。 我们预计，随着我们开始将这种复杂的，异质性疾病的特征来看，这一队列将是未来几年的丰富临床信息来源。 除了临床分析RP外，我们还收集和银行生物测量供以后的机械研究中使用。 今年，我们使用潜在类别分析发表了一篇论文，以识别RP患者的三个临床子集。我们预计这些发现将创建一个框架来了解RP中临床异质性的因果因素。最近，我们的小组参与了血液学祖细胞中的体细胞突变，该突变是NIH同伴8％的RP患者的疾病因果关系。这一发现增加了体细胞突变在成人发作的风湿病条件中的作用的激动人心的可能性，并在这些疾病中提高了新型治疗方法（包括骨髓移植）的潜力。我们已经开始开发深层测序方案，以鉴定RP患者和其他形式的血管炎患者的克隆造血。 最后，鉴于正在进行的大流行，我们正在参加研究，旨在评估Covid-19对包括血管炎在内的自身免疫性疾病患者的影响。 这些工作包括旨在评估大流行对血管炎患者健康相关行为和结果的影响的基于患者的调查，以及确定暴露于SARS-COV-2患者的血管炎患者的免疫反应。调查工作正在与患者动力研究网络（VPPRN）合作进行。 机械工作将根据玛丽安娜·卡普兰（Mariana Kaplan）博士领导的壁内NIH计划的合作计划进行。