UPITT Rheumatoid Arthritis Combined Center (UPITT RACC)

 描述（由申请人提供）：类风湿性关节炎（RA）是一种引起滑膜炎和关节破坏的复杂炎症性疾病。疾病缓解抗风湿药物（DMARDs）的联合使用以及生物制剂的出现彻底改变了RA的治疗结果。然而，40-50%的患者对任何给定的治疗都是难治性的。定义和预测临床结果的潜在免疫机制仍不清楚。在某种程度上，这是由于缺乏关于在患者关节中激活的通路的数据， RA的不同阶段匹兹堡大学已经建立了一支由临床医生和基础和转化科学家组成的强大合作团队，该团队具有独特的优势，可以通过加速药物合作伙伴关系来满足这一需求。具体来说，我们提供了一个由匹兹堡风湿病学家组成的单一网络护理下的大型RA患者队列;在招募患者进行临床登记和研究以及伴随的样本库方面的成熟经验：大约四分之一的RA队列已经参加了我们积极的NIH资助的研究登记（RACER），通过该登记，在每次临床访视时收集临床疾病活动，实验室和血液;最先进的临床数据管理和标本跟踪系统;建立合作，提供手术样本（骨科，IRB批准），以及超声（US）引导活检，由该技术的专家进行（IRB正在进行中）;组织处理方面的专业知识，以分离淋巴细胞用于高级免疫细胞分析;在RNA-Seq方面的专业知识，包括分析人体组织（新鲜和福尔马林固定）以及生物信息学;建立工作流程，在一个站点高效快速地执行所有阶段 以优化这些宝贵样本的数据质量和完整性。在UH 2研究阶段0，我们将建立标准化的方法和可行性参数的组织收集，处理和分析。最初，我们将利用标准骨科手术（如关节置换术和滑膜切除术）中现成的滑膜组织，然后在超声引导活检样本上验证这些手术。在UH 2研究I期，我们将应用0期开发的标准化程序来确定患者样本之间的异质性，比较RA与OA以及细胞来源（血液与组织，手术与活检）。这些参数将允许进行准确的把握度分析，以确定II期所需的患者数量和分析类型。在UH 3 II期研究中，我们提出了一项对照临床研究，其中患有活动性疾病的RA患者对甲氨蝶呤或TNF抑制剂的标准一线治疗无反应，将随机接受生物治疗。将分析关节活检和血液与临床结局的关系，并应用系统生物学确定与疾病活动和治疗反应相关的因果通路激活。我们还希望参与基于第一阶段确定的途径的体外和体内验证研究，以及新兴的试点项目数据。

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a complex inflammatory disorder causing synovitis and joint destruction. Combinatorial use of disease-modifying anti-rheumatic drugs (DMARDs) as well as the advent of biologic agents has revolutionized therapeutic outcomes in RA. However, 40-50% of patients are refractory to any given therapy. The underlying immune mechanisms that define and predict clinical outcome remain unclear. In part, this is due to the paucity of data on pathways that are activated in the joint of patients at different stages of RA. The University of Pittsburgh has developed a strong collaborative team of clinicians and basic and translational scientists that is uniquely positioned to answer this nee through the Accelerated Medicines Partnership. Specifically, we offer a large cohort of RA patients under care of a single network of Pittsburgh rheumatologists; proven experience in recruiting patients for clinical registries and studies with accompanying sample banking: around one-quarter of our RA cohort are already enrolled in our active, NIH-funded research registry (RACER) through which clinical disease activity, labs, and blood are collected at each clinic visit; a state-of-the-art clinical data management and specimen tracking system; established collaborations to provide surgical samples (orthopaedics, IRB-approved), as well as ultrasound (US)-guided biopsies to be performed by specialists in this technique (IRB in process); expertise in tissue processing to isolate lymphocytes for advanced immune cell analytics; expertise in RNA-Seq, including analysis of human tissues (fresh and formalin-fixed) as well as bioinformatics; established workflow to perform all stages efficiently and rapidly at a single site to optimize data quality and integrity of these valuable samples. In UH2 Research Phase 0, we will establish standardized methods and feasibility parameters for tissue collection, processing, and analysis. Initially we will make use of readily-available synovial tissues from standard orthopaedic procedures such as joint replacement and synovectomy, and then validate these procedures on ultrasound-guided biopsy samples. In UH2 Research Phase I, we will then apply the standardized procedures developed in Phase 0 to determine heterogeneity between patient samples, compare RA versus OA and source of cells (blood vs. tissue, surgery vs. biopsy). These parameters will allow accurate power analysis to determine numbers of patients and types of analyses that are required for Phase II. In UH3 Research Phase II, we propose a controlled clinical study in which RA patients with active disease that have not responded to standard first-line therapy with methotrexate or TNF inhibitor will be randomized to receive biologic therapy. Joint biopsy and blood will be analyzed in relation to clinical outcome, and systems biology applied to determine causal pathway activation in relation to disease activity and therapy response. We also expect to participate in in-vitro and in-vivo validation studies based on pathways identified in Phase I, as well as emerging pilot project data.