Vasculitis and Translational Medicine

血管炎和转化医学

• 批准号: 10709760
• 负责人: Peter Grayson
• 金额: $ 161.45万
• 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/10709760
• 关键词: ANCA vasculitis; Adult; Affect; Aortitis; Area; Arteries; Autoimmune Diseases; Biological Markers; Biological Specimen Banks; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; COVID-19 impact; Chronic Disease; Classification; Clinical; Clinical Research; Clinical Trials; Clinical Trials Database; Clinical assessments; Cohort Studies; Collaborations; Complex; Data; Data Collection; Development; Diagnosis; Diagnostic tests; Disease; Disease Management; Disease Progression; Ear; Enzymes; Ethics; Etiology; Evaluation; Extramural Activities; Eye; Foundations; Future; Genetic; Germ-Line Mutation; Goals; Health behavior; Hearing Tests; Hematology; Image; Immune response; Immunologics; Inflammation; Intramural Research; Joints; Laboratories; Laryngoscopy; Lead; Lesion; Life; Light; Link; 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; Pathogenesis; Patients; Pattern; Physical Examination; Physicians; Positron-Emission Tomography; Prediction of Response to Therapy; Prognostic Factor; Protocols documentation; Publishing; Pulmonary function tests; Radiology Specialty; Randomized Clinical Trials; Recording of previous events; Relapse; Relapsing polychondritis; Reporting; Research; Research Design; Research Personnel; Rheumatism; Role; SARS-CoV-2 exposure; Sampling; Shapes; Skin; Somatic Mutation; Source; Steroids; Structure; Surveys; Syndrome; System; Systemic disease; Takayasu' s Arteritis; Temporal Arteritis; Time; Tissues; Tracheostomy procedure; Translational Research; Treatment Efficacy; United States National Institutes of Health; Vacuole; Vasculitis; Work; aged; autoinflammatory; base; behavioral outcome; biobank; biomarker development; biomarker discovery; cartilaginous; chest computed tomography; clinical care; clinical center; clinical heterogeneity; clinical outcome measures; clinical remission; cohort; data standards; design; diagnostic algorithm; disability; disease natural history; epidemiology study; fluorodeoxyglucose positron emission tomography; genetic variant; imaging biomarker; indexing; inflammatory marker; molecular imaging; mortality; novel; novel marker; pandemic disease; patient advocacy group; patient oriented; patient subsets; personalized medicine; predict clinical outcome; prognostic value; programs; prospective; radiological imaging; recruit; research clinical testing; standard of care; systemic autoimmunity; therapeutic evaluation; translational medicine; translational research program; trend; trial design; vascular inflammation

Recruitment to date remains strong within the Vasculitis Natural History Study despite challenges imposed by the ongoing pandemic. All patients seen at the NIH Clinical Center receive comprehensive clinical evaluation and contribute samples to a growing biobank. Over the last few years, we have mainly focused on two forms of vasculitis: large vessel vasculitis (LVV) and relapsing polychondritis (RP). We have currently evaluated more than 800 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 (LVV). 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 longitudinal data within the cohort to show trends in vascular inflammation over time and to investigate whether vascular inflammation detected by FDG-PET has prognostic value. We have provided some of the only data available in the world on the relationship of PET scan findings and future disease progression. 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 also continue to investigate relapsing polychondritis in a prospective observational cohort study. 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 have evaluated over 100 patients with RP at the NIH Clinical Center over the last five years. 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. Over the last year, we continue to define a new disease that was discovered in our cohort known as the VEXAS (vacuole, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. VEXAS is caused by somatic mutations in UBA1 in bone marrow in adult patients with life-threatening multisystem disease. We recently identified prognostic factors for survival and underlying the mechanistic basis for these associations. We are working to define treatment options for this frequently fatal disease, including implementation of a bone marrow transplantation protocol at the NIH in collaboration with our hematology colleagues. We are helping to lead worldwide efforts to define this new disease in terms of clinical manifestations, diagnostic algorithms, treatment, and epidemiologic studies. 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. Mechanistic work is being conducted under a collaborative initiative at the Intramural NIH Program led by Dr. Mariana Kaplan.

尽管目前的大流行带来了挑战，但迄今为止，血管炎自然史研究的招募工作仍然很强。所有在NIH临床中心就诊的患者都接受了全面的临床评估，并将样本贡献给不断增长的生物库。在过去的几年里，我们主要集中在两种形式的血管炎：大血管炎（LVV）和复发性多囊炎（RP）。 我们目前已经根据一项观察性方案（14-AR-0200）评估了800多例血管炎患者，除了随时间推移对选定患者进行随访外，每年还将继续观察约100例新患者。 自上次报告以来，我们继续发表关于血管成像作为大血管炎（LVV）疾病活动性生物标志物的文章。巨细胞动脉炎（GCA）和Takayasu动脉炎（TAK）是大血管炎（LVV）的两种主要形式，由主动脉和主要分支的炎症定义。 LVV中疾病活动的临床评估可能具有挑战性，因此对有效监测和治疗构成障碍。 LVV患者在炎症标志物正常的明显持续临床缓解期间可发生新的血管病变。 虽然一些研究已经检查了分子成像在LVV中的潜力，但FDG-PET在检测血管炎症、随时间监测疾病活动以及预测临床结果方面的作用仍不清楚。在过去的一年中，我们报告了队列中的纵向数据，以显示血管炎症随时间的变化趋势，并研究FDG-PET检测到的血管炎症是否具有预后价值。我们提供了世界上仅有的一些关于PET扫描结果与未来疾病进展关系的数据。我们小组的工作继续塑造LVV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效果，并告知研究人员疾病的自然史。 我们还继续在一项前瞻性观察性队列研究中调查复发性多囊炎。复发性多关节炎是一种多系统的风湿性疾病，其特征是软骨结构（包括耳、鼻、关节和气道）的炎症。 目前还没有RP的诊断测试，器官受累是可变的，诊断取决于对临床特征模式的识别，有时可能非常微妙。 RP对死亡率和发病率有很大的影响，器官损伤率高，导致残疾。 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。 在过去的五年里，我们在NIH临床中心评估了100多名RP患者。 所有患者均接受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、直接喉镜检查、肺功能测试和颈部磁共振成像。 此外，我们开发了一种新的方法来执行动态计算机断层扫描（CT）的胸部作为一种非侵入性的方式来检测大气道的结构损伤。 我们预计，随着我们开始前瞻性地描述这种复杂的异质性疾病，该队列将成为未来几年丰富的临床信息来源。 除了临床分析RP，我们收集和银行生物标本用于未来的机制研究。 在过去的一年里，我们继续定义一种在我们的队列中发现的新疾病，称为VEXAS（空泡，E1酶，X连锁，自身炎症，体细胞）综合征。VEXAS是由患有危及生命的多系统疾病的成人患者骨髓中UBA 1的体细胞突变引起的。我们最近确定了生存的预后因素和这些关联的潜在机制基础。 我们正在努力为这种经常致命的疾病确定治疗方案，包括与我们的血液学同事合作在NIH实施骨髓移植方案。 我们正在帮助引领全球努力，从临床表现、诊断算法、治疗和流行病学研究方面定义这种新疾病。 最后，鉴于疫情持续，我们正参与旨在评估COVID-19对自身免疫性疾病（包括血管炎）患者影响的研究。 这些努力包括以患者为基础的调查，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，以及确定暴露于SARS-COV-2的血管炎患者免疫反应的机制研究。机械工作正在由Mariana Kaplan博士领导的NIH校内项目的合作倡议下进行。