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

描述（由申请人提供）：临床孤立综合征（CIS）是发生在中枢神经系统（CNS）内的脱髓鞘孤立事件。据估计，30-70%经历过CIS的人会继续发展为多发性硬化症（MS），而在所有MS患者中，约80%的患者发病时有CIS。CIS的临床特征，如CIS是单灶性还是多灶性，以及CIS发生时临床无症状的中枢神经系统病变的数量，确实可以预测后来转化为ms的风险。然而，对于环境因素如何影响这一进展，我们知之甚少。维生素D不足、eb病毒感染和吸烟都被认为是多发性硬化症（MS）的危险因素；本文提出的研究将检验这些因素是否也能预测CIS向MS的转化，以及这些因素是否会影响临床和通过中枢神经系统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，研究各种药物对延迟或防止从CIS到MS的转化的影响：倍他龙/倍他龙用于新出现的多发性硬化症初始治疗（BENEFIT），口服克拉德滨用于早期多发性硬化症（ORACLE），以及瑞比夫灵活给药用于早期多发性硬化症（REFLEX）。总的来说，这些试验包括1600多名被诊断为CIS的参与者。这些试验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进行了转化为多发性硬化症的跟踪。此外，那些发展为多发性硬化症的人继续被跟踪。具体来说，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（表明当前吸烟）是否会增加CIS向MS转化的风险，以及它们是否会增加进展，通过扩展残疾状态量表、MS功能复合指数和MRI参数的变化来衡量，在MS疾病过程的早期。统计分析将使用时间事件分析和混合效应模型。作为这些试验的常规部分收集的大量信息为检查维生素D水平、EBV抗体滴度或吸烟状况是否预测CIS向MS的转化或影响疾病早期进程提供了理想的机会。

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.