Vasculitis and Translational Medicine

迄今为止，血管炎自然史研究中的招募仍然很强。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。在过去的一年里，我们重点关注了两种形式的血管炎：大血管炎（LVV）和复发性多囊炎（RP）。 我们目前已经根据观察方案（14-AR-0200）评估了超过600例血管炎患者，除了随时间推移随访选定患者外，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，我们报道了LVV患者的临床评估、实验室评估和血管影像学检查之间的复杂关系。这项工作为OMERACT社区正在进行的努力提供了信息，以制定用于临床试验的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个这样的指标，PET血管活动评分（PETVAS），目前正在进行的国际血管炎临床试验中作为一种新的结局指标。我们还改进了PET成像协议，以优化PET的性能特征，从而检测和监测血管活动。我们发表了FDG动脉摄取的动力学，证明延迟成像方法在LVV中是优选的。我们还继续使用血管造影或FDG-PET定义的血管受累模式作为识别LVV患者临床有意义亚组的方法。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。 我们还坚定地建立了一个新的研究计划，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。 我们于2016年8月开始招募RP患者到NIH临床中心。 从那时起，我们已经评估了超过100例确诊为RP的患者，目前有超过80例患者在等待就诊。 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。 今年，我们发表了一篇论文，使用潜在类分析来确定RP患者的三个临床子集。我们预期这些发现将建立一个框架，以了解RP临床异质性的因果因素。最近，我们的小组参与了在血液祖细胞中发现的体细胞突变，该突变是NIH队列中8% RP患者的病因。这一发现提出了令人兴奋的可能性的作用，体细胞突变在成人发病的风湿性疾病，并提高了潜在的新的治疗方法，包括骨髓移植，在这些疾病。我们已经开始开发深度测序方案，以确定RP和其他形式血管炎患者的克隆造血。 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。调查工作正在与血管炎患者动力研究网络（VPPRN）合作进行。 机械工作将在由Mariana Kaplan博士领导的NIH校内项目的合作倡议下进行。

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.