Ganesh Aravind, Apel Sabrina, Metz Luanne, Patten Scott
Resident, Clinical Neurosciences, University of Calgary, 1403 29 Street NW Calgary, Alberta, Canada T2N 2T9.
Undergraduate Medical Education, University of Calgary, 33 Discovery Rise SW Calgary, Alberta, Canada T3H 4N6.
Mult Scler Relat Disord. 2013 Oct;2(4):281-306. doi: 10.1016/j.msard.2012.12.008. Epub 2013 Feb 12.
Given that vitamin D has a role in immunomodulation, and its levels appear to correlate with the development of Multiple Sclerosis (MS), it is conceivable that vitamin D may also influence disease activity in MS patients. In this regard, we conducted a systematic review investigating the evidence for: (1) the role of vitamin D in disease activity in MS, and (2) the therapeutic supplementation of vitamin D in MS.
A comprehensive search of Medline, Embase, Pubmed, clinical trials registries, and conference proceedings, followed by screening and application of inclusion and exclusion criteria, yielded 57 studies for detailed appraisal. Following careful data extraction, studies addressing the role of vitamin D in disease activity were appraised on the basis of common epidemiological principles, while those involving vitamin D supplementation were assessed for potential bias using Cochrane guidelines. The overall evidence was interpreted in the context of the Bradford-Hill criteria of causation, and the number needed to treat (NNT) to prevent one patient from relapsing over a year was calculated for each supplementation study examining relapse rate.
RESULTS/DISCUSSION: Both cross-sectional and longitudinal studies have fairly consistently demonstrated a strong positive correlation between vitamin D deficiency and subsequent relapse and/or disability in patients with MS. As well, there appears to be a negative correlation between vitamin D levels and inflammatory markers in MS patients, suggesting that vitamin D modifies serum cytokines to a more anti-inflammatory profile. Therefore, vitamin D fulfills the Bradford-Hill criteria for strong and consistent association, biological plausibility, and coherence. However, the criteria of temporality, dose-response, and experimental evidence are yet to be adequately met, although there is preliminary evidence from longitudinal studies and randomized clinical trials (RCTs) of supplementation that vitamin D can attenuate the autoimmune response in patients, and potentially reduce relapse rates and burden of disease. Currently published data on relapse prevention with vitamin D indicates the possibility of small NNTs in the range of 1.36-25.00, but they arise from very heterogeneously designed studies.
Ultimately, the current evidence does not permit inference of a causal relationship between vitamin D deficiency and disease activity in MS. Vitamin D supplementation appears to be a promising treatment worthy of further exploration, but owing to the paucity of RCTs with placebo or comparator arms, the evidence is not definitive and appropriate dosing remains uncertain.
鉴于维生素D在免疫调节中发挥作用，且其水平似乎与多发性硬化症（MS）的发展相关，因此可以推测维生素D也可能影响MS患者的疾病活动。在这方面，我们进行了一项系统综述，调查以下方面的证据：（1）维生素D在MS疾病活动中的作用，以及（2）MS中维生素D的治疗性补充。
全面检索Medline、Embase、Pubmed、临床试验注册库和会议论文集，随后筛选并应用纳入和排除标准，得到57项研究进行详细评估。经过仔细的数据提取后，根据常见的流行病学原则对探讨维生素D在疾病活动中作用的研究进行评估，而对涉及维生素D补充的研究则使用Cochrane指南评估潜在偏倚。在因果关系的布拉德福德 - 希尔标准背景下解读总体证据，并为每项研究复发率的补充研究计算防止一名患者在一年内复发所需治疗人数（NNT）。
结果/讨论：横断面研究和纵向研究均相当一致地表明，MS患者维生素D缺乏与随后的复发和/或残疾之间存在强烈的正相关。此外，MS患者的维生素D水平与炎症标志物之间似乎存在负相关，这表明维生素D可将血清细胞因子调节为更具抗炎性的状态。因此，维生素D符合布拉德福德 - 希尔标准中关于强且一致的关联、生物学合理性和连贯性的要求。然而，时间顺序、剂量反应和实验证据等标准尚未得到充分满足，尽管纵向研究和补充剂随机临床试验（RCT）有初步证据表明维生素D可减弱患者的自身免疫反应，并可能降低复发率和疾病负担。目前关于维生素D预防复发的已发表数据表明，NNT可能在1.36 - 25.00的较小范围内，但这些数据来自设计非常异质的研究。
最终，目前的证据不允许推断MS中维生素D缺乏与疾病活动之间存在因果关系。维生素D补充似乎是一种值得进一步探索的有前景的治疗方法，但由于缺乏有安慰剂或对照臂的RCT，证据并不确凿，合适的剂量仍不确定。
