NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

项目摘要 Stevens-Johnson综合征（SJS）和中毒性表皮坏死松解症（TEN）是严重的、危及生命的 免疫介导的药物不良反应代表同一疾病的严重程度范围。1 目前尚无针对SJS/TEN的循证标准治疗。预防工作已 由HLA I类等位基因HLA-B*15：02之间的强关联推动，这导致了 在许多东南亚国家，具有成本效益的治疗前遗传筛查计划。2，3然而， 该HLA等位基因在欧洲裔美国人、西班牙裔美国人和美国人中的患病率较低（<1%）， 美国人和非洲裔美国人，以及缺乏目前定义的HLA与药物的关联 在美国，通常使用并与SJS/TEN相关的药物留下了许多证据空白， 实施障碍。4这项研究的科学前提是，最有效的治疗将 影响SJS/TEN介导的细胞免疫应答、相关生物标志物和临床结局。我们 已经组装了北美治疗表皮坏死松解综合征（NATIENS）研究， 美国22个研究中心组成的一组，进行首次多中心双盲双模拟 环孢素或依那西普或支持治疗的随机对照评估。受控 设计将提供在每个治疗组中采集和测定多个样本的机会， 急性期和恢复期，目的是发现新的预防战略， 诊断和针对性治疗。我们将使用集成的多组学，单细胞和高通量 确定遗传基础、免疫病理学和抗原特异性的体外筛选方法 药物诱导的SJS/TEN。在具体目标1中，我们将为SJS/TEN建立临床上最有效的治疗方法 通过NATIENS多中心、双盲、双模拟随机对照试验， 在5个入组年内招募267名患者，以确定依那西普和/或环孢霉素是否 对于测量的完全上皮再形成的主要结局，其获益超过支持性治疗。具体目标 我们将使用全基因组测序、高分辨率HLA测序、转录组学和细胞因子分析 确定预测SJS/TEN风险和结局的遗传和生物标志物。在第三阶段，我们将 研究急性SJS/TEN中皮肤、水疱液和外周血细胞的免疫表型， 单细胞RNA和蛋白质表达。使用泡罩中占优势的T细胞受体（TCR） 我们将使用高通量体外筛选方法来鉴定CD 8+识别的特异性表位。 SJS/TEN组织损伤部位的T细胞。5我们的研究将是第一个双盲研究， SJS/TEN的管理和机制的随机对照设计。这将导致新的方法 预防，诊断和治疗SJS/TEN，并将为严重的研究创建路线图和证据基础。 免疫介导的药物不良反应和其他免疫介导的疾病。

PROJECT SUMMARY Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are severe, life-threatening immunologically mediated adverse drug reactions representing the same disease across a spectrum of severity.1 There is currently no evidence-based standard of care treatment for SJS/TEN. Preventive efforts have been fueled by strong associations between the HLA Class I allele HLA-B*15:02 which has led to implementation of cost-effective pre-treatment genetic screening programs in many Southeast Asian countries.2,3 However, the lower prevalence (<1%) and negative predictive value of this HLA allele in European American, Hispanic American, and African American populations, and the lack of currently defined HLA associations with drugs commonly used and associated with SJS/TEN in the United States has left many evidence gaps and implementation hurdles.4 The scientific premise of this study is that the most efficacious treatment will impact cellular immune responses mediating, related biomarkers and clinical outcomes of SJS/TEN. We have assembled the North American Therapeutics in Epidermal Necrolysis Syndrome (NATIENS) study, a group of 22 sites across the United States to conduct the first multicenter double-blind double dummy randomized controlled assessment of cyclosporine or etanercept or supportive care. The controlled design will afford the opportunity to collect and assay multiple samples in each treatment arm, in both the acute and convalescent phase, with the aim to discover new strategies for prevention, early diagnosis and targeted treatment. We will use integrated multi-omic, single-cell and high-throughput in-vitro screening approaches to determine the genetic basis, immunopathology and antigen specificity of drug-induced SJS/TEN. In Specific Aim 1 we will establish the most clinically effective therapy for SJS/TEN through the NATIENS multi-centered, double-blind double-dummy randomized controlled trial with a planned accrual of 267 patients over 5 enrollment years to determine whether etanercept and/or cyclosporine have benefit over supportive care for the measured primary outcome of complete re-epithelialization. In Specific Aim 2 we will use genome-wide sequencing, high-resolution HLA sequencing, transcriptomic, and cytokine profiling to identify genetic and biological markers that predict risk and outcome for SJS/TEN. In Specific Aim 3 We will study the immune phenotype of cells in the skin, blister fluid and peripheral blood in acute SJS/TEN based on single-cell RNA and protein expression. Using the dominantly represented T-cell receptor (TCR) in the blister fluid we will use a high throughput in-vitro screening approach to identify specific epitopes recognized by CD8+ T cells at the site of SJS/TEN tissue damage.5 Our study will be the first to examine in a double-blind randomized controlled design both management and mechanisms of SJS/TEN. This will lead to new ways to prevent, diagnosis and treat SJS/TEN, and will create a roadmap and evidence-base for studies of serious immunologically-mediated adverse drug reactions and other immunologically-mediated diseases.