Influence of NT5c1A antibodies on disease progression, clinical phenotype and blood and muscle biomarkers in sporadic Inclusion Body Myositis - A prospective evaluation

项目概要 散发性包涵体肌炎 (sIBM) 是美国老年人的一种罕见疾病，会导致肌肉不对称 虚弱和严重残疾和发病。目前它无法治疗，而且人们对其知之甚少。的 随着美国 65 岁以上人口比例的增加，sIBM 的患病率可能会增加 年持续增长。 sIBM 临床试验的一个主要障碍是缺乏对 该疾病的自然史。疾病进展率是否一致仍有待确定 以及各种生物标志物是否与 sIBM 相关（抗 NT5c1A 抗体、变异 T 细胞群） 影响自然病程和疾病行为。鉴于疾病进展速度缓慢， 常规临床试验无法进行观察，此类研究需要作为 单独的独立观察研究。为了解决这些未满足的需求，我们提出了一项前瞻性研究 有四个具体目标。目标 1：首次确定 c1A 抗体是否介导疾病 sIBM 患者两年内的进展。目标 2：进行详细的形态学分析， 对从一部分获得的新鲜肌肉活检标本进行组织化学和免疫组织化学分析 sIBM 患者。目标 3：表征循环中“免疫衰老”淋巴细胞的分布 sIBM 患者的血液。目标 4：量化 sIBM 患者呼吸功能的下降情况。的 我们提出的研究的意义在于 1) 可以详细描述疾病进展 sIBM 历时两年，以及 2) 探索与以下疾病相关的许多生物标志物之间的关系 sIBM 及其对疾病行为和疾病进展的影响。完成这些目标后，我们 1) 了解疾病表型，包括呼吸系统受累模式和疾病 更好地了解 sIBM 的进展并了解血清抗体对 NT5c1A 抗体的影响 自然史和疾病行为； 2) 定义血清变异T细胞和细胞因子特征的差异 sIBM 患者及其对疾病进展和行为的影响； 3）了解肌肉病理学 sIBM患者的免疫细胞分布及其与NT5c1A抗体的关系。这些发现可能 影响 sIBM 未来的试验设计。最后，我们将创建一个由 13 个站点组成的肌炎联盟 治疗中心将准备好迅速采用任何旨在改变病程的未来临床试验 sIBM。

PROJECT SUMMARY Sporadic inclusion body myositis (sIBM) is a rare disorder of aging Americans, causing asymmetric muscle weakness and severe disability and morbidity. It is currently untreatable, and poorly understood. The prevalence of sIBM is likely to increase as the proportion of the United States population above the age of 65 years continues to grow. A major barrier to clinical trials in sIBM has been the lack of full understanding of the natural history of the disease. It remains to be determined whether the rates of disease progression is uniform and whether the various biomarkers associated with sIBM (anti-NT5c1A antibodies, variant T-cell populations) influence the natural history and disease behavior. Given the slow rate of disease progression, such observations cannot be made in the context of a routine clinical trial, and such studies need to be done as a separate stand-alone observational study. To address these unmet needs, we propose a prospective study with four specific aims. Aim 1: To determine for the first time whether c1A antibodies mediate disease progression over a two year interval in patients with sIBM. Aim 2: To perform a detailed morphological, histochemical, and immunohistochemical analysis of fresh muscle biopsy specimens obtained from a subset of patients with sIBM. Aim 3: To characterize the distribution of “immunosenescent” lymphocytes in circulating blood from patients with sIBM. Aim 4: To quantify the decline in the respiratory function of sIBM patients. The significance of our proposed study is 1) to allow for a detailed characterization of the disease progression in sIBM over a two-year period, and 2) to explore the relationship of a number of biomarkers associated with sIBM, and their influence on disease behavior and disease progression. Upon completion of these aims, we will 1) understand the disease phenotype, including pattern of respiratory involvement, and disease progression in sIBM better and understand the influence of serum antibodies to NT5c1A antibodies on the natural history and disease behavior; 2) define differences in serum variant T-cells and cytokine signatures in sIBM patients and their influence on disease progression and behavior; and 3) understand muscle pathology and immune cell distribution in sIBM patients and its relationship to NT5c1A antibodies. These findings may influence future trial design in sIBM. Finally, we will have created a thirteen-site consortium of myositis treatment centers that will be ready to adopt quickly any future clinical trials aimed at changing the course of sIBM.