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

描述(申请人提供)：临床隔离综合征(CIS)是发生在中枢神经系统(CNS)内的孤立脱髓鞘事件。据估计，在经历CIS的个体中，30-70%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%的人以CIS为首发症状。CIS的临床特征，如它是单灶性还是多灶性的，以及在CIS发生时临床上无症状的中枢神经系统病变的数量，确实可以预测以后转化为MS的风险。然而，关于环境因素如何影响这一进展，人们了解很少。维生素D缺乏、EB病毒感染和吸烟都被确定为多发性硬化症(MS)的危险因素；这里提出的研究将检查这些因素是否也预测CIS向MS的转化，以及这些因素是否影响临床测量的MS早期进展和中枢神经系统病变的变化。这项研究将包括三项大型随机安慰剂对照试验的参与者，该试验旨在观察各种药物在延迟或防止CIS向MS转化方面的效果：用于新出现的多发性硬化症的初始治疗(Benefit)的倍他芬/倍他隆，用于早期多发性硬化症的口服Cladriine(ORACLE)，以及用于早期多发性硬化症的REBIF灵活剂量(RELECTION)。这些试验总共包括1600多名被诊断为独联体的参与者。这些试验中的所有参与者都提供了多个血液样本，并在临床和磁共振成像方面进行了转换为多发性硬化症的跟踪调查。此外，那些患有多发性硬化症的人继续受到关注。具体地说，这项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)是否增加了从CIS向MS转化的风险，以及它们是否增加了进展，如扩展的残疾状态量表、MS功能复合体和MS疾病过程早期的MRI参数变化所衡量的。在统计分析中将使用到事件的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来检查维生素D水平、EBV抗体效价或吸烟状况是否预测从CIS向MS的转化或在疾病过程的早期影响进展。

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.