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: 8522158
• 负责人: MARC C. LEVESQUE
• 金额: $ 28.23万
• 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/8522158
• 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）。这些罕见疾病会导致严重发病并可能导致死亡。一种新的治疗肌炎以及其他自身免疫性疾病的方法是B细胞耗竭（BCD）治疗与生物制剂，利妥昔单抗。我们研究了利妥昔单抗在最近完成的临床试验肌炎称为利妥昔单抗在肌炎（RIM）的研究。RIM研究是有史以来在AI炎症性肌肉疾病中进行的第一个也是最大的对照临床试验。利妥昔单抗改善肌炎和其他AI疾病的机制尚不清楚，本研究旨在确定利妥昔单抗在肌炎中的作用机制。通过这样做，我们不仅将了解BCD在肌炎中的作用方式，还将了解它总体上改善AI疾病的机制。本申请中拟定的研究将使用从200例肌炎患者的RIM队列中前瞻性采集的标本完成; RIM队列包括成人和儿童肌炎患者（PM、DM和JDM）。与收集的标本一起，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、前瞻性收集的临床数据相关联，为我们提供肌炎的无与伦比的数据集。免疫系统在所有AI疾病中都会受到影响，本研究旨在研究免疫系统的三个主要分支以及利妥昔单抗如何影响T细胞，B细胞和先天免疫反应。通过这种方式，该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）：炎症性肌肉疾病，包括多发性肌炎、成人皮肌炎和青少年皮肌炎，会导致严重的健康问题，并可能导致死亡。最近的研究表明，利妥昔单抗是一种有效的治疗肌炎患者。本申请将使用RIM研究中接受利妥昔单抗治疗的肌炎受试者采集的样本确定利妥昔单抗的作用机制。

项目成果

Interferon-regulated chemokine score associated with improvement in disease activity in refractory myositis patients treated with rituximab.

干扰素调节的趋化因子评分与接受利妥昔单抗治疗的难治性肌炎患者的疾病活动性改善相关。

• 发表时间: 2015
• 期刊: Clinical and experimental rheumatology
• 影响因子: 3.7
• 作者: LópezDePadilla,ConsueloM;Crowson,CynthiaS;Hein,MollyS;Strausbauch,MichaelA;Aggarwal,Rohit;Levesque,MarcC;Ascherman,DanaP;Oddis,ChesterV;Reed,AnnM
• 通讯作者: Reed,AnnM

Biologic predictors of clinical improvement in rituximab-treated refractory myositis.

• DOI: 10.1186/s12891-015-0710-3
• 发表时间: 2015-09-17
• 期刊: BMC musculoskeletal disorders
• 影响因子: 2.3
• 作者: Reed AM;Crowson CS;Hein M;de Padilla CL;Olazagasti JM;Aggarwal R;Ascherman DP;Levesque MC;Oddis CV;RIM Study Group
• 通讯作者: RIM Study Group