Skeletal Myopathy in Systemic Sclerosis: Devising a Classification Schema Predictive of Outcomes

项目总结 系统性硬化症(SSC)中的骨骼肌病与残疾和死亡率的增加有关。没有 对SSc相关性肌病的共识分类，可用于为 了解硬皮病的肌肉疾病。我们知道有病理的、血清学的和结局的 在定义SSc中肌病的不同亚型时，异质性可能是有用的。我们的初步数据 证明(1)SSc的肌肉组织病理学是不同的，(2)纤维化性肌病患者 预后不佳，尤其是心源性死亡；(3)在高级MRI上有强烈的信号摄取 弥散加权和张量成像及T2图在SSc相关性肌病中的应用 与常规肌肉MRI相比，可能提示疾病相关的早期变化。这份K23建议书 我将首先建立一个肌病队列(目标1)，设计一个分类方案，并测试其在预测Long 长期结果，如轨迹、心肺疾病、残疾、死亡率和治疗 反应性(目标2)，检测和量化晚期肌肉上与疾病相关的早期肌肉变化 磁共振成像(AIM 3)。本申请表旨在为医学硕士、医学助理教授Julie Paik颁发K23奖项。 约翰霍普金斯大学风湿病学系。她的长期职业目标是成为一名 在观察性队列研究的背景下，硬皮病肌肉疾病的主要临床研究员，州 ART成像生物标记物和临床试验方法学。她设计这一分类的短期目标 SCHEMA将为SSC中外部肌病队列的验证提供一个新的黄金标准，并为 未来研究的框架，旨在了解生物机制和开发治疗试验 使用量化肌肉核磁共振等可测量的结果。这项提议占了富人的便宜 约翰霍普金斯硬皮病中心的资源和基础设施，该中心最近被指定为精密中心 2018年卓越人物奖。她的指导团队包括劳拉·悍马博士和弗雷德里克·威格利博士，两人都是 安德鲁·曼曼博士是SSC和临床流行病学方面的知名专家，是国际公认的 肌炎专家斯科特·泽格博士是生物统计学和流行病学研究的领先者。白居易博士 她的咨询委员会招募了重要的成员，由具有特定经验的导师和合作者组成 与该提案相关的专业知识，并完全支持白博士的研究和职业目标。这些 包括迈克尔·雅各布斯博士(高级放射成像)、劳拉·法亚德博士(肌肉骨骼放射学)、 Andrea Corse(肌肉组织病理学)，Tom Lloyd博士(包涵体肌炎的分类模式)，以及 阿米·沙阿博士(硬皮病转化研究)。这项K23奖项将使白博士获得所需的技能 分析和开发硬皮病骨骼肌病的分类方案，开发专业知识 先进的肌肉核磁共振分析，并建立她的临床试验技能集，最终支持未来的R01提案。

PROJECT SUMMARY Skeletal myopathy in systemic sclerosis (SSc) is associated with increased disability and mortality. There is no consensus classification of SSc-associated myopathy that can be utilized to lay the groundwork for understanding muscle disease in scleroderma. We know that there is pathological, serological, and outcome heterogeneity that may be informative in defining distinct subsets of myopathy in SSc. Our preliminary data demonstrate that (1) muscle histopathology is heterogeneous in SSc, (2) patients with a fibrosing myopathy have poor outcomes, in particular cardiac death, and (3) there is intense signal uptake on advanced MRI imaging such as diffusion weighted and tensor imaging and T2 mapping in SSc-associated myopathy which may indicate early disease related changes when compared to conventional muscle MRI. This K23 proposal will first establish a Myopathy cohort (Aim 1), devise a classification schema and test its utility in predicting long term outcomes such as trajectory, cardiopulmonary disease, disability, mortality, and treatment responsiveness(Aim 2), and detect and quantify early disease related muscle changes on advanced muscle MRI (Aim 3). This application is for a K23 award for Julie Paik, MD, MHS, Assistant Professor of Medicine in the Division of Rheumatology at the Johns Hopkins University. Her long term career goal is to become a leading clinical investigator in scleroderma muscle disease in the context of observational cohort studies, state of the art imaging biomarkers, and clinical trial methodology. Her short term goal of devising this classification schema will provide a new gold standard for the validation of external myopathy cohorts in SSc and lay the framework for future studies directed at understanding biological mechanism and developing a therapeutic trial using measurable outcomes such as quantitative muscle MRI. This proposal takes advantage of the rich resources and infrastructure at the Johns Hopkins Scleroderma Center, a recently designated Precision Center of Excellence in 2018. Her mentoring team includes Dr. Laura Hummers and Dr. Fredrick Wigley, both renowned experts in SSc and clinical epidemiology, Dr. Andrew Mammen is an internationally recognized myositis expert, and Dr. Scott Zeger a leader in bio statistical and epidemiological research. Dr. Paik has recruited vital members to her Advisory Committee, composed of mentors and collaborators who have specific expertise relevant to the proposal and are fully supportive of Dr. Paik’s research and career goals. These include Dr. Michael Jacobs (advanced radiological imaging), Dr. Laura Fayad (musculoskeletal radiology), Dr. Andrea Corse (muscle histopathology), Dr. Tom Lloyd (classification schemas in inclusion body myositis), and Dr. Ami Shah (scleroderma translational research). This K23 award will allow Dr. Paik to gain the skills needed to analyze and develop a classification schema of skeletal myopathy in scleroderma, develop expertise in advanced muscle MRI analysis, and build her clinical trial skill set to ultimately support a future R01 proposal.