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

项目摘要 散发性包涵体肌炎（sIBM）是美国老年人的一种罕见疾病， 虚弱和严重残疾及发病。它目前无法治疗，而且人们对其了解甚少。的 sIBM的患病率可能会随着美国65岁以上人口的比例增加而增加 年继续增长。sIBM临床试验的一个主要障碍是缺乏对 疾病的自然史。疾病进展的速度是否一致还有待确定 以及是否与sIBM相关的各种生物标志物（抗NT5c1A抗体，变异T细胞群） 影响自然史和疾病行为。鉴于疾病进展缓慢， 不能在常规临床试验的背景下进行观察，此类研究需要作为一种 单独的独立观察性研究。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。目的1：首次确定c1A抗体是否介导疾病 在sIBM患者中，两年内的进展。目的2：进行详细的形态学， 组织化学和免疫组织化学分析的新鲜肌肉活检标本获得的一个子集， sIBM患者目的3：研究"免疫衰老"淋巴细胞在循环中的分布特点， sIBM患者的血液。目的4：量化sIBM患者呼吸功能的下降。的 我们提出的研究的意义是：1）允许详细描述疾病进展， sIBM在一个为期两年的时间，和2）探索的关系，一些生物标志物与 sIBM及其对疾病行为和疾病进展的影响。在实现这些目标后，我们 将1）了解疾病表型，包括呼吸系统受累模式，以及疾病 更好地了解NT5c1A抗体的血清抗体对sIBM进展的影响， 自然史和疾病行为; 2）定义血清变体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;以及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未来试验设计。最后，我们将创建一个13个位点的肌炎联合体， 治疗中心，将准备迅速采用任何未来的临床试验，旨在改变的过程中， 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.