Efficacy Measures for Pediatric Lupus Studies

描述(申请人提供)：儿童期起病的系统性红斑狼疮(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。在如何全面衡量CSLE是否发生了临床相关变化的知识方面存在着根本的差距。这使得新药的测试变得非常困难。我们研究的长期目标是通过开发和传播结果指标来改善CSLE的预后，这些指标将促进生物标记物的发现，促进翻译研究，并进行临床试验来测试CSLE新药的疗效。这一应用程序的目标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。需要检验的中心假设是，CSLE核心集合变量(疾病活动、疾病活动的MD分级、患者的幸福感等级、身体功能、蛋白尿、损伤、生长和发育)最适合定义CSLE的疾病症状，并且可以使用相同的CSLE核心集合变量来制定缓解标准。我们建议通过以下具体目标来检验中心假说和实现研究目标：1)按照美国风湿病学会质量测量委员会的建议，采用共识形成方法和统计学方法相结合的方法，制定并前瞻性地验证疾病爆发的标准；2)建立“儿童关节炎风湿学研究联盟(CARA)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已建立队列的数据和新收集的100名具有极端CSLE表型的患者的信息，以获得关于CSLE核心变量(&gt；750患者-年的随访；n&gt；400)的发生、缓解和相关变化的真实患者信息。在与专业学会的密切合作中，并通过使用协商一致的方法(Delphi，名义群体技术)、数据挖掘技术和其他统计方法，将制定定量验证的耀斑标准和疾病缓解的初步标准。我们将为这项研究改进我们的基于网络的数据管理系统。在NIH资助的卓越中心和CCHMC风湿病临床试验单位的支持下，这项应用的预期结果是FLARE标准，可以很容易地用作CSLE临床试验的疗效衡量标准和CSLE缓解的初步标准。收集的数据将作为CARRA儿童狼疮登记处的基础，并将开发一个多功能的基于网络的狼疮研究管理系统，并向儿科风湿病社区提供。这具有重大意义，因为定量验证的FLARE标准将促进疾病修改药物的临床试验，而缓解标准对于测试目前正在开发的最有效的新药至关重要。基于Web的学习管理节省了成本和时间，促进了未来的协作研究。与公共卫生的相关性：正如最近出版的NIAMS长期研究计划所建议的那样，通过利用NIH资助的英才中心的专业知识，拟议的研究将增强生物医学和临床研究人员的“工具箱”，并作为一个场所，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