Mechanisms of Response and Relapse in Rituximab-treated Myositis Patients

利妥昔单抗治疗肌炎患者的缓解和复发机制

• 批准号: 8146973
• 负责人: MARC C. LEVESQUE
• 金额: $ 29.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-22 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146973
• 关键词: Adult; Adult Dermatomyositis; Affect; Antigen-Presenting Cells; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Cell Development; B-Lymphocytes; Biological; Blood; Cell Count; Cell physiology; Cessation of life; Childhood; Clinical; Clinical Data; Clinical Trials; Controlled Clinical Trials; Controlled Study; Data Set; Dermatomyositis; Disease; Effectiveness; Flow Cytometry; Freezing; Funding; Gene Expression; Genes; Health; Immune; Immune response; Immune system; Immunoglobulin Class Switching; Immunoglobulins; Immunologics; Inflammatory Response Pathway; Interferon Type I; Interferons; Interleukin-17; Laboratories; Lead; Learning; Lymphoid; MS4A1 gene; Measurement; Measures; Mediating; Memory B-Lymphocyte; Morbidity - disease rate; Muscle; Myositis; Natural Immunity; Patients; Pemphigus; Peripheral Blood Mononuclear Cell; Polymyositis; Production; Rare Diseases; Receptor Activation; Regulatory T-Lymphocyte; Relapse; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Sampling; Serum; Source; Specimen; Statistical Models; Structure; Study Subject; Systemic Lupus Erythematosus; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; TALL-1 protein; Testing; Th1 Cells; Th2 Cells; Time; Toll-like receptors; Uncontrolled Study; United States National Institutes of Health; Work; arm; base; chemokine; cohort; cytokine; desmoglein 1; effective therapy; improved; mortality; novel; peripheral blood; public health relevance; research study; response; rituximab; time use; transcriptional intermediary factor 1

DESCRIPTION (provided by applicant): Autoimmune (AI) inflammatory muscle diseases (myositis) include polymyositis (PM), adult dermatomyositis (DM) and juvenile dermatomyositis (JDM). These rare diseases cause significant morbidity and can lead to death. One of the more novel treatments for myositis as well as other autoimmune diseases is B cell depletion (BCD) therapy with a biologic agent, rituximab. We studied rituximab in a recently completed clinical trial in myositis termed the Rituximab in Myositis (RIM) Study. The RIM Study is the first and largest controlled clinical trial ever performed in AI inflammatory muscle disease. The mechanism(s) by which rituximab improves myositis and other AI diseases is unclear and this study proposes to determine rituximab's mechanism of action in myositis. By doing so, we will not only learn how BCD works in myositis, but also the mechanism by which it improves AI disease in general. The studies proposed in this application will be completed using specimens that were prospectively collected from the RIM cohort of 200 myositis patients; the RIM cohort included both adult and pediatric patients with myositis (PM, DM and JDM). In conjunction with the specimens collected, valuable clinical information was also obtained so that the laboratory results from the experiments that are performed can be correlated with accurate, prospectively collected clinical data to provide us with an unmatched dataset in myositis. The immune system is affected in all AI diseases and this study proposes to examine the three major arms of the immune system and how rituximab affects T cell, B cell and innate immune responses. In this way, this proposal will also determine the relevant abnormal immune mechanisms that mediate myositis. PUBLIC HEALTH RELEVANCE (provided by applicant): Inflammatory muscle diseases including polymyositis, adult dermatomyositis and juvenile dermatomyositis cause significant health problems and can lead to death. Recent studies indicate that rituximab is an effective therapy for myositis patients. This application will determine the mechanisms by which rituximab works using samples collected from myositis subjects treated with rituximab in the RIM study.

描述(由申请人提供)：自身免疫(AI)炎症性肌肉疾病(肌炎)包括多发性肌炎(PM)、成人皮肌炎(DM)和青少年皮肌炎(JDM)。这些罕见的疾病会导致严重的发病率，并可能导致死亡。肌炎和其他自身免疫性疾病的一种更新的治疗方法是使用生物制剂利妥昔单抗的B细胞耗竭(BCD)疗法。我们在最近完成的一项名为利妥昔单抗肌炎(RIM)研究的肌炎临床试验中研究了利妥昔单抗。RIM研究是有史以来对AI炎症性肌肉疾病进行的第一次也是最大规模的临床对照试验。利妥昔单抗改善肌炎和其他人工智能疾病的机制(S)尚不清楚，本研究建议确定利妥昔单抗治疗肌炎的作用机制。通过这样做，我们不仅将了解BCD如何在肌炎中发挥作用，而且还将了解它改善AI疾病的一般机制。本申请中建议的研究将使用从200名肌炎患者的RIM队列中前瞻性收集的样本来完成；RIM队列包括患有肌炎(PM、DM和JDM)的成人和儿童患者。结合收集的标本，还获得了有价值的临床信息，以便进行的实验的实验室结果可以与准确的、预期收集的临床数据相关联，为我们提供无与伦比的肌炎数据集。免疫系统在所有人工智能疾病中都会受到影响，这项研究建议检查免疫系统的三个主要手臂，以及利妥昔单抗如何影响T细胞、B细胞和先天性免疫反应。如此一来，这一建议还将确定介导肌炎的相关异常免疫机制。 公共卫生相关性(由申请人提供)：包括多发性肌炎、成人皮肌炎和青少年皮肌炎在内的炎症性肌肉疾病会导致严重的健康问题，并可能导致死亡。最近的研究表明，利妥昔单抗是治疗肌炎的一种有效方法。这项应用将使用从RIM研究中使用利妥昔单抗治疗的肌炎受试者收集的样本来确定利妥昔单抗的作用机制。