Sjögren’s Team for Accelerating Medicines Partnership (STAMP)

摘要 Sjögren病(SJD，以前称为Sjögren综合征)是一种常见的全身自身免疫性疾病 风湿性疾病的患病率仅次于类风湿性关节炎。它主要影响唾液和泪液。 腺体通过淋巴细胞渗入和自身抗体介导的炎症，导致显著的 发病率。大约三分之一的SJD患者有腺外受累，并有显著的 罹患淋巴瘤的风险增加。不幸的是，在解决许多未得到满足的问题方面取得的进展有限 SJD的需求。确认性诊断本质上是多学科的，往往会导致重大延误。稀缺 治疗选择存在于症状管理之外，最近的临床试验结果 令人失望。因此，更好地了解疾病的致病机制是至关重要的，而且可以 通过拆解和重建的办法来实现。这一目标的核心是需要深入地 描述了SJD患者的特征。加速药物合作的多学科Sjögren团队 (STAMP)是整合这一资源的理想人选。该团队的专业知识包括专注于自身免疫的 分子生物学、遗传学和流行病学/临床研究，以及在建立 大量参与者拥有储存的生物标本和精细的表型特征。 除了招募新的参与者外，现有的团队将提供独特的机会来执行 对先前评估的SJD参与者进行10至15年的随访。我们建议的疾病团队(DT)是 战略性定位，应用尖端技术审问组织和系统 SJD的生物学，以确定治疗途径和目标，目标如下：1)规划阶段： 共同制定5年科研议程和标准操作规程，对SJD患者进行表型鉴定 与其他AMP DIT以及技术和分析核心(TAC)配合使用。设计标准化协议以 招募、招募、收集生物标本，并对SJD和SJD的观察队列进行深入的表型鉴定 控制。确定SJD的研究重点，以更好地了解分子和表型异质性 和组织和细胞水平的自然病史；2)试点阶段：校准临床评估和 对招聘现场的采购进行抽样，并评估SOP。我们将与其他DT密切合作 和TAC来a)最终确定SOP并在所有地点实施；b)利用我们的多学科专业知识来 通过对分子和临床数据的初步分析，启动SJD的解构重建；3) 扩大规模阶段：增加参与者招募并与TAC合作，从分子上解构和 重建SJD。跨站点实施的标准化协议将使STAMP能够询问 使用深度测序和其他尖端技术的SJD的组织和系统生物学，以更好地 了解SJD的发病机制，并确定治疗靶点和新的生物标志物；以及2)疾病 SJD从非SJD到SJD，从“早期SJD”到“进展期SJD”的内在机制。

ABSTRACT Sjögren’s Disease (SjD, formerly known as Sjögren’s syndrome) is a common systemic autoimmune rheumatic disorder second only to rheumatoid arthritis in prevalence. It primarily affects salivary and lacrimal glands through lymphocytic infiltration and autoantibody-mediated inflammation, resulting in significant morbidity. Approximately one third of SjD patients have extraglandular involvement and have a remarkably elevated risk for lymphoma. Unfortunately, limited progress has been made in addressing the many unmet needs in SjD. Confirmatory diagnosis is multidisciplinary in nature and often results in significant delay. Scant therapeutic options exist outside of symptom management, and results from recent clinical trials have been disappointing. Thus, a better understanding of the pathogenetic mechanisms of disease is critical, and can be achieved using a de- and re-construction approach. Central to this goal, is the need for deeply characterized patients with SjD. The multidisciplinary Sjögren’s Team for Accelerating Medicines Partnership (STAMP) is ideally poised to assemble this resource. The team’s expertise includes autoimmunity-focused molecular biology, genetic, and epidemiologic/clinical research, and a remarkable track-record in establishing large cohorts of participants with stored biospecimens and exquisitely detailed phenotypic characterization. In addition to recruiting new participants, the existing cohorts will provide the unique opportunity to perform 10 to 15-year follow-up of previously evaluated SjD participants. Our proposed Disease Team (DT) is strategically positioned to apply cutting-edge technologies to interrogate the tissue and systems biology of SjD to identify therapeutic pathways and targets, with the following aims: 1) Planning Phase: Develop a 5-year scientific research agenda and SOPs for phenotyping SjD patients in collaboration with other AMP DTs and Technology and Analytics Cores (TACs). Design standardized protocols to recruit, enroll, collect biospecimens and perform deep phenotyping of observational cohorts of SjD and controls. Identify research priorities for SjD to better understand the molecular and phenotypic heterogeneity and natural history at both tissue and cell levels; 2) Pilot Phase: Calibrate clinical assessments and sample procurement across recruitment sites and evaluate SOPs. We will work closely with other DTs and TACs to a) finalize SOPs and implement them at all sites; b) leverage our multidisciplinary expertise to initiate the deconstruction-reconstruction of SjD via preliminary analyses of molecular and clinical data; 3) Scale up Phase: Increase participant recruitment and work with TAC to molecularly deconstruct and reconstruct SjD. Standardized protocols implemented across sites will enable STAMP to interrogate the tissue and systems biology of SjD using deep sequencing and other cutting-edge technologies, to better understand 1) the pathogenesis of SjD and identify therapeutic targets, and new biomarkers; and 2) disease mechanisms inherent to progression of SjD from non-SjD to SjD, and from “early SjD” to “advanced SjD”.