Vitamin D, cigarette smoking, EBV infection and risk of MS progression

描述（由申请方提供）：临床孤立综合征（CIS）是发生在中枢神经系统（CNS）内的孤立脱髓鞘事件。据估计，30-70%的经历CIS的个体将继续发展为多发性硬化症（MS），并且在所有MS患者中，约80%的患者以CIS作为其发作事件。CIS的临床特征，如CIS时是否为单灶性或多灶性以及临床无症状CNS病变的数量，确实预测了后来转化为MS的风险。然而，关于环境因素如何也可能影响这种进展，目前尚不清楚。维生素D不足、EB病毒（EBV）感染和吸烟都被确定为多发性硬化（MS）的危险因素;本文提出的研究将检查这些因素是否也预测CIS转化为MS，以及这些因素是否影响临床和CNS病变变化测量的早期MS进展。这项研究将包括三个大型随机安慰剂对照试验的参与者，这些试验研究了各种药物对延迟或预防从CIS向MS转化的影响：Betaferon/Betaseron在新发多发性硬化症中的初始治疗（BENEFIT），口服克拉屈滨在早期多发性硬化症中的作用（ORACLE），以及Rebif灵活剂量在早期多发性硬化症中的作用（REFLEX）。总的来说，这些试验包括超过1，600名被诊断患有CIS的参与者。这些试验中的所有参与者都提供了多个血液样本，并通过临床和磁共振成像跟踪了MS的转化。此外，那些发展MS的人继续被跟踪。具体而言，本研究的目的是检查血清25-羟基维生素D水平低，EBV抗体升高或血清可替宁水平升高（指示当前吸烟）是否会增加从CIS转化为MS的风险，以及它们是否会增加MS疾病过程早期的进展，如扩展残疾状态量表，MS功能复合量表和MRI参数变化所测量的。统计分析中将使用至事件发生时间分析和混合效应建模。作为这些试验的常规部分收集的丰富信息提供了一个理想的机会，可以检查维生素D水平，EBV抗体滴度或吸烟状态是否预测从CIS到MS的转换或影响疾病过程早期的进展。 公共卫生相关性： 多发性硬化症（MS）是一种慢性进行性疾病，对受影响者及其家庭和社会的生活质量有很大的负面影响。经历临床孤立综合征（CIS）的个体患MS的风险增加。目前MS的风险因素，包括维生素D营养不足，爱泼斯坦-巴尔病毒感染或吸烟，是否预测从CIS转化为MS尚不清楚。了解这些环境因素在早期MS进展中的作用可能会导致新的预防和治疗策略。

DESCRIPTION (provided by applicant): Clinically isolated syndromes (CIS) are isolated events of demyelination that occur within the central nervous system (CNS). It is estimated that between 30-70% of individuals who experience a CIS will go on to develop multiple sclerosis (MS), and that of all patients with MS, about 80% had a CIS as their onset episode. Clinical features of the CIS, such as whether it was monofocal or multifocal and number of clinically silent CNS lesions at the time of the CIS, do predict risk of later conversion to MS. However, little is understood about how environmental factors may also influence this progression. Vitamin D insufficiency, infection with Epstein-Barr virus (EBV), and cigarette smoking have all been identified as risk factors for developing multiple sclerosis (MS); the study proposed here will examine whether these factors also predict CIS conversion to MS and whether these factors influence early MS progression as measured clinically and by changes in CNS lesions. This study will include participants in three large randomized placebo controlled trials of the effect of various drugs on delaying or preventing conversion from CIS to MS: the Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) the Oral Cladribine in Early multiple sclerosis (ORACLE), and the Rebif Flexible Dosing in early multiple sclerosis (REFLEX). Collectively, these trials include over 1,600 participants who were diagnosed with CIS. All participants in these trials have provided multiple blood samples and have been followed for conversion to MS both clinically and by magnetic resonance imaging. Further, those who develop MS continue to be followed. Specifically, the aims of this study are to examine whether low serum 25-hydroxyvitamin D levels, elevated antibodies against EBV, or elevated serum cotinine levels (indicative of current smoking) increase the risk of conversion from CIS to MS and whether they increase progression, as measured by the Expanded Disability Status Scale, the MS Functional Composite, and changes in MRI parameters, early in the MS disease process. Time to event analysis and mixed effects modeling will be used in the statistical analysis. The wealth of information collected as a routine part of these trials provides an ideal opportunity to examine whether vitamin D levels, EBV antibody titers, or cigarette smoking status predict conversion from CIS to MS or influence progression early in the disease process. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a chronic progressive disease with a large negative impact on the quality of life of those affected, their families, and society. Individuals who experience a clinically isolated syndrome (CIS) are at an increased risk of developing MS. Whether current risk factors for MS, including insufficient vitamin D nutrition, infection with Epstein-Barr virus, or cigarette smoking, predict conversion from CIS to MS is not known. Understanding the role of these environmental factors in early MS progression may lead to new prevention and therapeutic strategies.