Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece; Department of Biostatistics and Epidemiology, Imperial College London, London, UK.
Lancet Neurol. 2015 Mar;14(3):263-73. doi: 10.1016/S1474-4422(14)70267-4. Epub 2015 Feb 4.
The cause of multiple sclerosis is believed to involve environmental exposure and genetic susceptibility. We aimed to summarise the environmental risk factors that have been studied in relation to onset of multiple sclerosis, assess whether there is evidence for diverse biases in this literature, and identify risk factors without evidence of biases.
We searched PubMed from inception to Nov 22, 2014, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and multiple sclerosis. For each meta-analysis we estimated the summary effect size by use of random-effects and fixed-effects models, the 95% CI, and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2) (defined as large for I(2)≥50%), evidence of small-study effects (ie, large studies had significantly more conservative results than smaller studies), and evidence of excess significance bias (ie, more studies than expected with significant results).
Overall, 44 unique meta-analyses including 416 primary studies of different risk factors and multiple sclerosis were examined, covering a wide range of risk factors: vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers. 23 of 44 meta-analyses had results that were significant at p values less than 0·05 and 11 at p values less than 0·001 under the random-effects model. Only three of the 11 significant meta-analyses (p<0·001) included more than 1000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (I(2)<50%), small-study effects (p for Egger's test >0·10), or excess significance (p>0·05). These were IgG seropositivity to Epstein-Barr virus nuclear antigen (EBNA) (random effects odds ratio [OR] 4·46, 95% CI 3·26-6·09; p for effect size=1·5 × 10(-19); I(2)=43%), infectious mononucleosis (2·17, 1·97-2·39; p=3·1 × 10(-50); I(2)=0%), and smoking (1·52, 1·39-1·66; p=1·7 × 10(-18;)I(2)=0%).
Many studies on environmental factors associated with multiple sclerosis have caveats casting doubts on their validity. Data from more and better-designed studies are needed to establish robust evidence. A biomarker of Epstein-Barr virus (anti-EBNA IgG seropositivity), infectious mononucleosis, and smoking showed the strongest consistent evidence of an association.
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多发性硬化症的病因被认为与环境暴露和遗传易感性有关。我们旨在总结与多发性硬化症发病相关的环境危险因素，评估该文献中是否存在不同偏见的证据，并确定没有偏见证据的危险因素。
我们从建立到 2014 年 11 月 22 日在 PubMed 中进行了检索，以确定观察性研究的系统评价和荟萃分析，这些研究检查了环境因素与多发性硬化症之间的关联。对于每个荟萃分析，我们使用随机效应和固定效应模型估计了汇总效应大小、95%置信区间和 95%预测区间。我们估计了研究间的异质性，用 I²（定义为 I²≥50%为大）表示（定义为 I²≥50%为大）、小研究效应的证据（即，大研究的结果比小研究的结果更保守），以及过度显著偏差的证据（即，具有显著结果的研究比预期的研究更多）。
总共检查了 44 项独特的荟萃分析，其中包括 416 项不同危险因素和多发性硬化症的主要研究，涵盖了广泛的危险因素：疫苗接种、合并症、手术、创伤事件和事故、环境因素暴露以及生化、感染和肌肉骨骼生物标志物。44 项荟萃分析中有 23 项在随机效应模型下的 p 值小于 0·05 时有显著结果，11 项在 p 值小于 0·001 时有显著结果。在 11 项显著荟萃分析中（p<0·001），只有 3 项包括超过 1000 例病例，95%预测区间排除了零值，并且没有提示存在大的异质性（I²<50%）、小研究效应（Egger 检验 p 值>0·10）或过度显著（p>0·05）。这些结果包括 EBV 核抗原（EBNA）IgG 血清阳性（随机效应比值比[OR]4·46，95%CI 3·26-6·09；p 值为效应大小=1·5 × 10(-19)；I²=43%）、传染性单核细胞增多症（2·17，1·97-2·39；p=3·1 × 10(-50)；I²=0%）和吸烟（1·52，1·39-1·66；p=1·7 × 10(-18)；I²=0%）。
许多与多发性硬化症相关的环境因素研究都存在疑问，这些疑问对其有效性提出了质疑。需要更多和设计更好的研究来提供确凿的证据。爱泼斯坦-巴尔病毒（抗-EBNA IgG 血清阳性）、传染性单核细胞增多症和吸烟的生物标志物显示出与多发性硬化症最强的一致关联证据。
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