Assessment, Therapy and Prevention Of Autoimmune Disease

自身免疫性疾病的评估、治疗和预防

• 批准号: 8336615
• 负责人: Frederick Miller
• 金额: $ 78.79万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8336615
• 关键词: Adolescent; Adult; Anti-Inflammatory Agents; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Cells; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Companions; Conduct Clinical Trials; Consensus; Data Analyses; Databases; Dermatomyositis; Development; Disease; Disease Outcome; Double-Blind Method; Educational Materials; Environmental Risk Factor; Epidemiologic Studies; Flare; Flow Cytometry; Future; Gene Expression; Goals; Guidelines; Heterogeneity; Idiopathic Inflammatory Myopathies; Image; Immune; Immune Targeting; Immunosuppression; Individual; International; Intervention; Investigation; Laboratory Research; Learning; Licensing; Life; Lupus; Measures; Mediating; Morbidity - disease rate; Muscle; Muscle function; Myositis; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Onset of illness; Outcome; Outcome Assessment; Outcome Measure; Pathogenesis; Patient Recruitments; Patients; Pattern; Peripheral; Play; Prevention therapy; Randomized; Randomized Controlled Clinical Trials; Refractory Disease; Rehabilitation therapy; Reporting; Resistance; Resources; Risk; Risk Factors; Role; Safety; Site; Skin; Specialist; Standardization; Syndrome; Therapeutic; Therapeutic Agents; Therapeutic Studies; Therapy Clinical Trials; Tissues; Ultraviolet Rays; Uncertainty; disease characteristic; disorder prevention; double-blind placebo controlled trial; drug efficacy; effective therapy; efficacy evaluation; experience; genetic risk factor; immune activation; immunopathology; improved; infliximab; interest; meetings; member; molecular imaging; mortality; multidisciplinary; novel; novel therapeutics; peripheral blood; placebo controlled study; prevent; prospective; rituximab; standardize measure; success; systemic autoimmune disease; tool; web site

For this project we are now focusing on the idiopathic inflammatory myopathies (IIM), also known as the myositis syndromes, as prototypic autoimmune diseases from which principles learned in these disorders may be applied generally to other diseases. The myositis syndromes are associated with substantial lifelong morbidity and mortality. Their treatment is unsatisfactory in many cases and drug efficacy evaluation is hampered by the lack of reliable and standardized measures of disease outcome. No agents are currently licensed for the treatment of IIM and few have been studied in randomized controlled clinical trials. Because of the lack of consensus on how to best measure disease in the myositis syndromes, and to enhance recruitment of patients for other studies, new disease assessment tools are being developed and validated to apply to all forms of myositis in both adults and children. We have organized a multidisciplinary collaborative group of over 200 adult and pediatric specialists with special interest in myositis, known as the International Myositis Assessment and Clinical Studies Group (IMACS) to assist in this project. The goals of IMACS are to standardize the conduct and reporting of clinical studies in all forms of IIM. Achieving these goals should enhance the consistency by which clinical trials are performed, improve the capacity to compare different treatments, and encourage development of promising novel therapeutic agents. Therapeutic studies of novel biologic agents are in progress and others are being planned to utilize these outcome measures in prospective trials. Together, and with input from the FDA, IMACS has: 1) developed and validated new tools to assess myositis disease activity and damage; 2) achieved consensus on core set outcome measures to comprehensively describe disease activity; 3) delineated preliminary definitions of improvement for use as clinical trial outcomes, which provide clinically meaningful change in combinations of the core set measures in a composite endpoint; 4) developed international consensus guidelines on details of the conduct of multi-center therapeutic trials for adult and juvenile IIM; and 5) developed a clinical trial and outcomes data repository to allow us to reassess and revise IMACS tools. We have created a website to consolidate all IMACS activities, including member lists and contacts, educational materials, meeting presentations, references, assessment tools and ongoing and future collaborative initiatives and studies (http://www.niehs.nih.gov/research/resources/collab/imacs/main.cfm). The therapy of myositis is focused on immunosuppression to minimize effects from immune activation and rehabilitation to improve remaining muscle function. Given the poor outcomes of myositis patients with standard therapy, novel biologic anti-inflammatory agents, which have been shown to be safe and effective for other immune-mediated diseases and have rationale for use in myositis, are reasonable candidates for study and may represent important advances in the treatment of myositis in the future. Our experience is that conducting therapeutic trials also greatly enhances recruitment to our epidemiologic investigations. We are participating as one site in the Rituximab in Myositis (RIM) trial which, is a multicenter, double-blind, placebo-controlled study that will assess the efficacy and safety of rituximab in 202 treatment-resistant dermatomyositis, polymyositis, and juvenile dermatomyositis patients. The RIM study provides us a unique opportunity to study a number of myositis features, including gene expression patterns and imaging profiles of refractory disease and how they respond to a targeted immune intervention. Identifying such molecular and imaging features may not only allow early recognition of patients requiring more aggressive treatment but could enhance our understanding of the pathogenesis of myositis and related autoimmune syndromes. The goals of this study are to define molecular and imaging characteristics of disease responsiveness to rituximab therapy and to better understand the role of B cells and their subsets in the pathogenesis of myositis. We are taking advantage of this trial to identify changes in gene expression patterns in muscle, skin and peripheral blood and the imaging features and immunopathology of muscle, skin and peripheral cells before (week 0) and after (week 16) therapy. These will also be correlated with the large number of clinical, laboratory and research variables already planned to be collected in the core RIM study. Furthermore, knowing specifically which gene expression patterns are altered in resistant patients before rituximab, and which are changed after rituximab therapy -- in conjunction with flow cytometry of peripheral cells and immunopathology of the tissues -- will help in understanding more about the pathogenesis of myositis and the possible contribution of B lymphocytes and their subsets. We are also collaborating with Paul Plotz and Mark Gourley in NIAMS on a randomized, double-blind, placebo-controlled trial of infliximab in myositis using the IMACS outcome criteria. We have completed this study and are analyzing data from the trial. The identification of environmental risk factors for autoimmune diseases offers the hope of preventing some of these disorders by exposure avoidance in genetically susceptible individuals. Investigations underway in our companion study ES101074-10, Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease, which is focused on identifying environmental risk factors for autoimmune conditions, may offer approaches to disease prevention. Exposures that are known to be important in inducing disease exacerbations in established disease may be triggers for disease onset as well. One example is our recent finding that ultraviolet radiation, known to induce exacerbations of lupus and dermatomyositis, likely plays an important role in the development of dermatomyositis and related autoantibodies. Studies to assess the efficacy of exposure avoidance in reducing myositis disease flares should be benefited from the validated outcome measures we are developing.

对于这个项目，我们现在重点关注特发性炎症性肌病（IIM），也称为肌炎综合征，作为典型的自身免疫性疾病，从这些疾病中学到的原理可以普遍应用于其他疾病。肌炎综合征与大量的终生发病率和死亡率相关。在许多情况下，他们的治疗效果并不令人满意，并且由于缺乏可靠和标准化的疾病结果衡量标准，药物疗效评估受到阻碍。目前还没有药物被批准用于治疗 IIM，并且很少有药物在随机对照临床试验中进行过研究。 由于对于如何最好地测量肌炎综合征中的疾病以及加强招募其他研究的患者缺乏共识，新的疾病评估工具正在开发和验证，以适用于成人和儿童的所有形式的肌炎。我们组织了一个由 200 多名对肌炎特别感兴趣的成人和儿科专家组成的多学科协作小组，称为国际肌炎评估和临床研究小组 (IMACS)，以协助该项目。 IMACS 的目标是标准化所有形式的 IIM 临床研究的实施和报告。实现这些目标应提高临床试验的一致性，提高比较不同治疗方法的能力，并鼓励开发有前景的新型治疗药物。新型生物制剂的治疗研究正在进行中，其他研究也正在计划在前瞻性试验中利用这些结果指标。 在 FDA 的帮助下，IMACS 已经：1）开发并验证了新工具来评估肌炎疾病活动和损害； 2）就全面描述疾病活动性的核心结果指标达成共识； 3) 描述了用作临床试验结果的改进的初步定义，其在复合终点中的核心集测量组合中提供了具有临床意义的变化； 4) 制定了关于成人和青少年IIM多中心治疗试验细节的国际共识指南； 5) 开发了临床试验和结果数据存储库，使我们能够重新评估和修订 IMACS 工具。我们创建了一个网站来整合所有 IMACS 活动，包括成员名单和联系人、教育材料、会议演示、参考资料、评估工具以及正在进行和未来的合作计划和研究 (http://www.niehs.nih.gov/research/resources/collab/imacs/main.cfm)。 肌炎的治疗重点是免疫抑制，以尽量减少免疫激活和康复的影响，以改善剩余的肌肉功能。鉴于肌炎患者的标准治疗效果不佳，新型生物抗炎药物已被证明对其他免疫介导的疾病安全有效，并且具有用于治疗肌炎的合理性，因此是合理的研究候选者，并且可能代表未来肌炎治疗的重要进展。我们的经验是，进行治疗试验也大大增加了我们流行病学调查的招募。 我们作为一个中心参与利妥昔单抗治疗肌炎 (RIM) 试验，这是一项多中心、双盲、安慰剂对照研究，将评估利妥昔单抗对 202 名难治性皮肌炎、多发性肌炎和青少年皮肌炎患者的疗效和安全性。 RIM 研究为我们提供了一个独特的机会来研究许多肌炎特征，包括难治性疾病的基因表达模式和影像学特征，以及它们对靶向免疫干预的反应。 识别这些分子和影像特征不仅可以早期识别需要更积极治疗的患者，还可以增强我们对肌炎和相关自身免疫综合征发病机制的理解。 本研究的目的是确定疾病对利妥昔单抗治疗反应的分子和影像学特征，并更好地了解 B 细胞及其亚群在肌炎发病机制中的作用。 我们正在利用这项试验来确定肌肉、皮肤和外周血液中基因表达模式的变化，以及治疗前（第 0 周）和治疗后（第 16 周）肌肉、皮肤和外周细胞的成像特征和免疫病理学。 这些也将与已计划在 RIM 核心研究中收集的大量临床、实验室和研究变量相关。 此外，具体了解耐药患者在利妥昔单抗治疗前哪些基因表达模式发生了改变，以及利妥昔单抗治疗后哪些基因表达模式发生了改变——结合外周细胞的流式细胞术和组织的免疫病理学——将有助于更多地了解肌炎的发病机制以及 B 淋巴细胞及其亚群的可能贡献。 我们还与 NIAMS 的 Paul Plotz 和 Mark Gourley 合作，使用 IMACS 结果标准进行一项英夫利昔单抗治疗肌炎的随机、双盲、安慰剂对照试验。我们已经完成了这项研究并正在分析试验数据。 识别自身免疫性疾病的环境风险因素为遗传易感个体避免暴露来预防某些疾病提供了希望。我们的配套研究 ES101074-10“环境/遗传风险因素和自身免疫性疾病的发病机制”中正在进行的调查，重点是确定自身免疫性疾病的环境风险因素，可能会提供疾病预防的方法。已知对于诱发已确定疾病的疾病恶化很重要的暴露也可能是疾病发作的触发因素。一个例子是我们最近发现，已知可诱发狼疮和皮肌炎恶化的紫外线辐射，可能在皮肌炎和相关自身抗体的发展中发挥重要作用。评估避免暴露在减少肌炎疾病发作方面的功效的研究应该受益于我们正在开发的经过验证的结果测量。