Vasculitis and Translational Medicine

尽管持续的大流行带来了挑战，但到目前为止，脉管炎自然史研究中的招募工作仍然很强劲。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。在过去的几年里，我们主要关注两种类型的血管炎：大血管血管炎(LVV)和复发性多软骨炎(RP)。我们目前已经根据观察方案(14-AR-0200)评估了800多名脉管炎患者，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(LVV)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，我们报道了队列中的纵向数据，以显示血管炎症随时间的变化趋势，并调查FDG-PET检测到的血管炎症是否具有预后价值。我们提供了一些世界上仅有的关于PET扫描结果与未来疾病进展关系的数据。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。 我们还继续在前瞻性观察队列研究中调查复发性多软骨炎。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。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。 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，自体炎症，躯体)综合征。VEXAS是由威胁生命的多系统疾病成人患者骨髓中UBA1的体细胞突变引起的。我们最近确定了影响生存的预后因素和这些关联的潜在机制基础。我们正在努力确定这种经常致命的疾病的治疗方案，包括在NIH与我们的血液学同事合作实施骨髓移植方案。我们正在帮助领导世界范围内在临床表现、诊断算法、治疗和流行病学研究方面定义这种新疾病的努力。 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健康相关行为和结果的影响，也包括机制研究，以确定暴露于SARS-COV-2的脉管炎患者的免疫反应。机械工作是在玛丽安娜·卡普兰博士领导的NIH内部计划的合作倡议下进行的。

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.