Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE)

项目概要/摘要 系统性红斑狼疮（SLE）会导致主要器官损伤并缩短相对年轻的人的寿命 人。早期诊断和治疗对于改善 SLE 患者的预后至关重要。然而， 早期治疗干预措施的循证方法以及这些措施的适当目标人群 无法采取干预措施。我们建议抗核抗体呈阳性的个体 (ANA) 以及还表现出用于分类 SLE 的其他一些特征的人，有很高的风险 进展为该疾病的完全系统形式。这些人的 ANA 水平很高 加上狼疮分类标准中的 1 或 2 个附加项目，被认为患有不完全性狼疮 红斑狼疮或 ILE。我们在“抗-ILE研究”中建议用羟氯喹（HCQ）治疗ILE患者 不完全性红斑狼疮中的疟疾”或 SMILE 试验。主要目标是确定是否 HCQ 治疗可以防止获得定义 SLE 的其他临床和免疫学特征。 主要的次要目标是确定 HCQ 治疗是否：(1) 减轻狼疮疾病活动，如 采用标准评分指标衡量； (2) 改善患者报告的结果 (3) 防止累积 免疫学异常，包括自身抗体和细胞因子，(4) 具有可接受的毒性特征。 该提案的具体目标是： 1. 在患者中进行 HCQ 与安慰剂的双盲、安慰剂对照、多中心、随机试验 与 ILE。该研究检验了以下假设：早期使用 HCQ 可以改变疾病特征，从而 导致 SLE 分类的异常积累可以显着减缓。 2. 确定 HCQ 对 ILE 患者疾病活动性和患者报告结果的影响。 3. 表征接受 ILE 治疗的患者中 HCQ 的免疫学特征。自身抗体、细胞因子和 将在多重阵列上测量趋化因子，以深入了解潜在机制。 4. 定量评估接受 HCQ 治疗的 ILE 患者眼部毒性的发生率。已全部报名 患者将在研究治疗之前和之后接受标准化眼科检查。 将制定针对该患者群体的使用和监测建议。 SMILE 试验将确定 ILE 患者是否应接受 HCQ，并将提供以下见解： 适当的目标人群，并将提出候选生物标志物来指导治疗决策。同时 SMILE 不是 Precision Medicine Initiative® 的一部分，但与其目标是一致的。这将是迈向的第一步 测试 SLE 疾病预防研究的可行性，并将在实验室中积累生物样本 存储库将可供狼疮研究界进行进一步深入的机制研究。

Project Summary/Abstract Systemic lupus erythematosus (SLE) causes major organ damage and shortens lifespan in relatively young persons. Early diagnosis and treatment are essential to improving outcomes for SLE patients. However, evidenced-based approaches to early treatment interventions and the appropriate target population for these interventions are not available. We propose that individuals who have positivity for antinuclear antibodies (ANAs) and who also exhibit some of the other features that are used to classify SLE, are at high risk of progressing to the full systemic form of this disease. These individuals, who have significant levels of ANA with 1 or 2 additional items from the lupus classification criteria, are considered to have incomplete lupus erythematosus or ILE. We propose to treat ILE patients with hydroxychloroquine (HCQ) in the “Study of Anti- Malarials in Incomplete Lupus Erythematosus” or SMILE trial. The primary objective is to determine whether HCQ treatment can prevent acquisition of additional clinical and immunologic features that define SLE. The major secondary objectives are to determine whether HCQ treatment: (1) lessens lupus disease activity as measured by standard scoring indices; (2) improves patient reported outcomes (3) prevents accumulation of immunologic abnormalities including autoantibodies and cytokines and (4) has an acceptable toxicity profile. The specific aims of this proposal are: 1. To carry out a double-blind, placebo-controlled, multicenter, randomized trial of HCQ vs. placebo in patients with ILE. The study tests the hypothesis that early use of HCQ can modify disease features so that accumulation of abnormalities leading to a classification of SLE can be significantly slowed. 2. To determine effects of HCQ on disease activity and patient-reported outcomes in patients with ILE. 3. To characterize the immunologic profile of HCQ in ILE-treated patients. Autoantibodies, cytokines and chemokines will be measured on multiplex arrays for developing insights into underlying mechanisms. 4. To quantitatively assess the incidence of ophthalmologic toxicity in HCQ-treated ILE patients. All enrolled patients will have standardized ophthalmologic examinations before and after study treatment. Recommendations for use and monitoring in this patient population will be developed. The SMILE trial will determine whether or not HCQ should be given to ILE patients, will provide insights into the appropriate target population, and will propose candidate biomarkers to guide treatment decisions. While not part of the Precision Medicine Initiative®, SMILE is consistent with its goals. It will be the first step towards testing the feasibility of disease prevention studies in SLE and will accumulate biological samples in a repository that will be available to the lupus research community for further in-depth mechanistic studies.