The Role of Vitamin D in Systemic Lupus Erythematosus

描述(申请人提供)：维生素D是一种强大的免疫调节剂，维生素D缺乏在SLE患者中非常普遍，临床前研究表明，使用维生素D治疗自身免疫性疾病的动物模型是成功的。我们有初步数据表明，与对照组相比，高加索人SLE患者的维生素D水平显著降低，25-羟基维生素D(25(OH)D)水平较低的患者有较高的疾病活跃度的强烈趋势。来自人类类风湿性关节炎和1型糖尿病的前瞻性研究的证据表明，维生素D作为一种可改变的环境因素在自身免疫性疾病中起着重要作用。这一作用在人类系统性红斑狼疮中尚未得到很好的研究。这项建议的总体假设是，维生素D缺乏是SLE和疾病活动增加的可逆环境触发因素，补充足够剂量的维生素D以实现免疫调节作用将是安全的，并可减轻SLE患者的疾病活动。《研究发展计划》由3个目标组成。具体目标1，25(OH)D和iPTH将对来自3个纵向队列的参与者的储存血清样本进行检测，以确定与对照组相比，维生素D缺乏是否与SLE相关，以及与病例的疾病活动性和严重性相关。在具体目标2中，我们将确定保护少数非裔美国人SLE患者免受维生素D缺乏的因素，评估饮食、阳光暴露、补充剂的使用和皮肤色素。具体目标3包括在一项小规模的I期临床研究中给缺乏非洲裔美国人的SLE患者口服维生素D，以确定替代疗法的安全性、耐受性和有效剂量。还将评估疾病活动性、疾病突发、免疫学指标、炎症标志物和生活质量。从这项研究中收集的信息将被用于计划一项科学合理的更大规模的11/11期安慰剂对照试验。职业发展计划将由5个基本部分组成：(1)由研究咨询和指导委员会监督的研究项目指导；(2)各种会议；(3)负责任地开展研究的培训；(4)正式的指导培训；以及(5)进一步发展相关领域知识体系的正式课程。这些研究和职业发展目标旨在为大型数据库的横断面分析和门诊环境下临床研究研究的设计和实施提供技术培训。这些项目的实施与生物统计学和流行病学方法的正式课程相结合，旨在促进卡门博士作为一名独立的学术临床调查员的职业生涯，专注于系统性红斑狼疮和以患者为中心的研究。

DESCRIPTION (provided by applicant): Vitamin D functions as a powerful immune modulator, deficiency of vitamin D is highly prevalent among SLE patients, and preclinical studies have shown success using vitamin D to treat animal models of autoimmune disease. We have preliminary data demonstrating that Caucasian SLE patients have significantly lower vitamin D levels compared to controls, and there is a strong trend towards higher disease activity in patients with lower levels of 25-hydroxyvitamin D (25(OH)D). Evidence from prospective studies of RA and type 1 diabetes in humans suggest an important role for vitamin D as a modifiable environmental factor in autoimmune disease. This role has not been well studied in human SLE. The overall hypothesis of this proposal is that vitamin D deficiency is a reversible environmental trigger of SLE and increased disease activity, and that supplementation with doses of vitamin D sufficient to achieve immune modulatory effects will be safe and attenuate disease activity in SLE patients. The Research Development Plan consists of 3 Aims. In Specific Aim 1, 25(OH)D and iPTH will be performed on stored serum samples from participants from 3 longitudinal cohorts to determine whether vitamin D deficiency correlates with SLE compared to controls, and with disease activity and severity among cases. In Specific Aim 2, we will determine the factors that protect the minority of African American SLE patients from becoming vitamin D deficient, assessing diet, sun exposure, supplement use, and skin pigment. Specific Aim 3 involves administration of oral vitamin D to deficient African American SLE patients in a small Phase I clinical study to establish safety, tolerability, and an effective dose for replacement therapy. Disease activity, disease flare, immunologic measures, inflammatory markers, and quality of life will also be assessed. The information gathered from this study will be used to plan a scientifically sound larger scale Phase ll/lll placebo-controlled trial. The Career Development Plan will consist of 5 essential components: (1) Research projects preceptorship overseen by a research advisory and mentorship committee; (2) Meetings and conferences; (3) Training in the responsible conduct of research; (4) Formal mentorship training; and (5) Formal coursework to further develop a body of knowledge in relevant areas. These research and career development aims are designed to provide training in techniques for the cross-sectional analysis of large databases and for the design and implementation of clinical research studies in an outpatient setting. The pursuit of these projects, in conjunction with formal coursework in biostatistical and epidemiological methods, is intended to foster Dr. Kamen's career as an independent academic clinical investigator with a focus on SLE and patient-oriented research.