Mechanisms of Lupus Disease Transition and Hydroxychloroquine Immune Modulation

不完全性红斑狼疮或SILE患者的抗疟疾药物研究是首次进行的预防研究 系统性红斑狼疮，将240名自身抗体携带者和至少一名临床患者随机分组 狼疮的特征是接受羟氯喹(HCQ)或安慰剂来评估延迟或预防的能力 制定新的临床标准或过渡到SLE分类。每季度对个人进行评估 狼疮或其他自身免疫性风湿病的新的血清学或临床证据的发展，以及 获得了标准样品。本申请中建议的辅助研究将利用资源 来自这一新的临床试验，增加了分析所需的新的关键样本，以测试特定的 狼疮发病机制的假说和确定HCQ如何改变调节失调的潜在机制 人类的自身免疫系统。本申请中的研究集中在三个关键假设上， 已在现场建立并确认在狼疮中发现后的疾病分类和意志 确定这些途径中的哪一条对疾病的发生和发病至关重要。存在自身抗体 几乎所有的系统性红斑狼疮患者均可发病，且常发生在临床症状或疾病分类前数年。 使用新的基于芯片的自身抗原和多肽阵列，实验将评估HCQ对 开发新的自选品种，并确定多样化的程度和时机，以应对 有新的临床症状积累或SLE疾病分类。干扰素表达增加 反应基因在系统性红斑狼疮中也很常见，与疾病活动性和自身抗体的增加有关 制作。对来自军队和家庭收藏品的系列样本进行回顾分析的结果 后来发展成狼疮的人支持干扰素途径在疾病前是调节失调的 发病时在分类附近强化程度最大。干扰素活性，全血基因签名，可溶 介体和TLR/干扰素刺激的反应将在我们将收集的系列样本中进行评估 这项试验和分析与详细的方案驱动的临床表型有关。氢氧化钠对人体健康的影响 这些干扰素反应，以及这些反应中的变化随着额外的 红斑狼疮的临床特征，将进行评估。最后，自身抗体通过网织反应刺激干扰素的产生。 低密度中性粒细胞的频率和功能将在新鲜的系列样本上进行测试，以确定 他们与狼疮症状的时间相关性增加。最后，一组血清学标记已经被 在回顾分析中被确定为与未来SLE发病密切相关的患者将通过以下方法进行测试 新获得的生物标记物集用于预测额外狼疮标准的累积以及使用 这项研究的新数据进一步完善了识别系统性红斑狼疮高危人群的能力 为实施预防战略和/或进一步完善的、与生物有关的预防制定工作 审判。

The Study of anti-Malarials in Incomplete Lupus Erythematosus or SMILE is the first prevention study for systemic lupus erythematosus, randomizing 240 individuals with autoantibodies and at least one clinical feature of lupus to receive either hydroxychloroquine (HCQ) or placebo to assess the ability to delay or prevent the development of new clinical criteria or transition to classified SLE. Individuals are assessed quarterly for development of new serologic or clinical evidence of lupus, or other autoimmune rheumatic diseases, and standard samples are obtained. The ancillary studies proposed in this application will leverage the resources from this novel clinical trial with the addition of new critical samples required for analyses to test specific hypotheses of lupus pathogenesis and to identify potential mechanisms of how HCQ modifies the dysregulated autoimmune system in humans. The studies within this application focus on three critical hypotheses which have been established and confirmed in the field to be found in lupus after disease classification and will establish which of these pathways are critical to disease onset and pathogenesis. Autoantibodies are present in nearly all SLE patients and often occur years before the onset of clinical symptoms or disease classification. Using novel chip-based autoantigen and peptide arrays, experiments will assess the impact of HCQ on development of new autospecificities, and determine the degree and timing of diversification in response to accumulation of new clinical symptoms or SLE disease classification. Increased expression of interferon responsive genes is also common in SLE and associated with increased disease activity and autoantibody production. Results from retrospective analyses of serial samples from military and family collections of individuals who subsequently develop lupus support that interferon pathways are dysregulated before disease onset with greatest enhancement near classification. Interferon activity, whole blood gene signatures, soluble mediators and TLR/interferon stimulated responses will be assessed in the serial samples we will collect from this trial and analyzed in relation to the detailed protocol-driven clinical phenotyping. The influence of HCQ on these interferon responses, as well as the changes in these responses with the accumulation of additional lupus clinical features, will be assessed. Finally, autoantibody stimulated interferon production through netosis and the frequency and function of low density neutrophils will be tested on fresh serial samples to determine their temporal association with lupus symptom accrual. Finally, serologic sets of markers which have been identified to associate strongly with future onset of SLE in retrospective analyses will be tested with these newly available biomarker sets for the ability to predict accumulation of additional lupus criteria, as well as use the new data from this study to further refine the ability to identify individuals at the highest risk of SLE development for implementation of prevention strategies and/or further refined, biologically-relevant prevention trials.