Efficacy Measures for Pediatric Lupus Studies

描述（由申请人提供）：儿童期系统性红斑狼疮（cSLE）是一种严重的自身免疫性疾病，迫切需要更好的药物来降低其死亡率。如何全面衡量cSLE是否发生了临床相关的变化，在知识上存在根本性的空白。这使得新药的测试非常困难。我们研究的长期目标是通过开发和推广预后指标来改善cSLE的预后，这些指标将促进生物标志物的发现，促进转化研究，并进行临床试验来测试新的cSLE药物的疗效。本应用程序的目的是前瞻性地验证疾病爆发的标准，并制定疾病缓解的标准，同时为未来的cSLE研究建立一个通用的电子数据管理框架。待验证的中心假设是，cSLE核心组变量（疾病活动性、疾病活动性的MD评分、患者幸福感评分、身体功能、蛋白尿、损伤、生长和发育）最适合定义cSLE的疾病发作，同样的cSLE核心组变量可用于制定缓解标准。我们建议通过追求以下具体目标来检验中心假设并实现研究目标：1)根据美国风湿病学会质量测量委员会的建议，通过共识形成方法和统计方法的结合，制定并前瞻性地验证疾病发作的标准2)建立“儿童关节炎风湿病研究联盟（CARRA）儿科狼疮登记处，目的是制定cSLE疾病缓解的初步标准。实现这些目标的方法是使用来自定义明确的建立队列的数据和新收集的100例极端cSLE表型患者的信息，以获得关于耀斑发生、缓解和cSLE核心变量相关变化的真实患者信息（750例患者-年随访；400例患者-年随访）。在与专业协会的密切合作下，通过使用共识方法（德尔菲、名义群体技术）、数据挖掘技术和其他统计方法，将制定定量验证的疾病发作标准和疾病缓解的初步标准。本研究将改进基于网络的数据管理系统。在美国国立卫生研究院资助的卓越中心和CCHMC风湿病临床试验单位的支持下，该应用程序的预期结果是耀斑标准，可以很容易地用作cSLE临床试验的疗效测量和cSLE缓解的初步标准。收集到的数据将作为CARRA儿童狼疮登记的基础，一个多功能的基于网络的狼疮研究管理系统将被开发并提供给儿童风湿病学社区。这是重要的意义，因为定量验证的耀斑标准将促进疾病改善药物的临床试验，而缓解标准对于测试目前正在开发的最有效的新药物至关重要。基于网络的学习管理节省了成本和时间，促进了未来的合作研究。与公共卫生的相关性：正如最近公布的NIAMS长期研究计划所建议的那样，通过利用美国国立卫生研究院资助的卓越中心的专业知识，拟议的研究将增强生物医学和临床研究者的“工具箱”，并通过开发更好的药物来改善cSLE儿童的生活质量和预后

DESCRIPTION (provided by applicant): Childhood-onset Systemic Lupus Erythematosus (cSLE) is a severe autoimmune disease and better medications are urgently needed to decrease its mortality. There is a fundamental gap in the knowledge of how to comprehensively measure whether clinically relevant changes in cSLE have occurred. This makes the testing of new drugs very difficult. The long-term goal of our research is to improve the prognosis of cSLE through the development and dissemination of outcome measures that will facilitate biomarker discovery, promote translational research, and the conduct of clinical trials to test the efficacy of new cSLE drugs. The objectives of this application are to prospectively validate criteria of disease flare and to develop criteria of disease remission, while establishing a common electronic data management framework for future cSLE studies. The central hypothesis to be tested is that the cSLE core set variables (disease activity, MD rating of disease activity, patient rating of well-being, physical function, proteinuria, damage, growth & development) are best suited to define disease flares in cSLE and that the same cSLE core set variables can be used to develop remission criteria. We propose to test the central hypothesis and achieve he study objectives by pursuing the following specific aims: 1) To develop and prospectively validate criteria of disease flare by a combination of consensus formation methodology and statistical approaches as is recommended by the American College of Rheumatology Committee on Quality Measures 2) To establish a "Childhood Arthritis Rheumatology Research Alliance (CARRA) Pediatric Lupus Registry with the goal of develop preliminary criteria of disease remission in cSLE. The approach to achieving these aims is to use data from well-defined established cohorts and newly collected information of 100 patients with extreme cSLE phenotypes to obtain real-patient information on the occurrence of flares, remission and the related changes in the cSLE core variables (>750 patient-years of follow-up; n>400). In close collaborations with Professional societies and by using consensus methodology (Delphi, nominal group technique), data mining techniques, and other statistical approaches quantitatively validated criteria of flare and preliminary criteria of disease remission will be developed. Our web-based data management systems will be improved for this study. Supported by NIH-funded Centers of Excellence and the CCHMC Rheumatology Clinical Trial Unit, the expected results of this application are flare criteria that can readily be used as efficacy measures of clinical trials in cSLE and preliminary criteria of remission for cSLE. The collected data will serve as the foundation for a CARRA Pediatric Lupus Registry, and a versatile web-based Lupus Study Management System will be developed and made available to the pediatric rheumatology community. This is of major significance because quantitatively validated flare criteria will facilitate clinical trials of disease modifying drugs, while remission criteria are critical to test the most potent new medications that are currently being developed. Web-based study management is cost & time saving and promotes future collaborative research. RELEVANCE TO PUBLIC HEALTH: As is suggested by the recently published NIAMS Long-Term Research Plan and by leveraging the expertise of NIH-funded Centers of Excellence, the proposed research will enhance the "tool box" of biomedical & clinical investigators and serve as a venue to improve the quality of life and prognosis of children with cSLE through the development of better drugs