The Role of Vitamin D in Systemic Lupus Erythematosus

描述（由申请人提供）：维生素D作为一种强大的免疫调节剂发挥作用，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。我们有初步的数据表明，白人SLE患者的维生素D水平显着低于对照组，并有一个强烈的趋势，在患者的25-羟基维生素D（25（OH）D）水平较低的疾病活动。来自人类RA和1型糖尿病前瞻性研究的证据表明，维生素D作为自身免疫性疾病中可改变的环境因素具有重要作用。这种作用在人类SLE中尚未得到充分研究。该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，并且补充足以实现免疫调节作用的剂量的维生素D将是安全的，并减轻SLE患者的疾病活动。研究开发计划包括三个目标。在具体目标1中，将对来自3个纵向队列的受试者的储存血清样本进行25（OH）D和iPTH检测，以确定与对照组相比，维生素D缺乏是否与SLE相关，以及与病例中的疾病活动性和严重程度相关。在具体目标2中，我们将确定保护少数非洲裔美国SLE患者免于维生素D缺乏的因素，评估饮食，阳光照射，补充剂使用和皮肤色素。具体目标3涉及在一项小型I期临床研究中向缺乏维生素D的非裔美国SLE患者给予口服维生素D，以确定替代治疗的安全性、耐受性和有效剂量。还将评估疾病活动、疾病发作、免疫学指标、炎症标志物和生活质量。从本研究中收集的信息将用于计划一项科学合理的更大规模II/III期安慰剂对照试验。职业发展计划将包括5个基本组成部分：（1）由研究咨询和导师委员会监督的研究项目导师;（2）会议;（3）负责任地开展研究的培训;（4）正式的导师培训;（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提供大型数据库的横断面分析技术培训，以及在门诊环境中设计和实施临床研究。这些项目的追求，结合生物统计学和流行病学方法的正式课程，旨在促进Kamen博士作为一名独立的学术临床研究者的职业生涯，专注于SLE和以患者为导向的研究。

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.