The Effect of Vitamin D Supplements on Clinical and Para-Clinical Outcomes in Patients With Multiple Sclerosis: Protocol for a Systematic Review

Background: Multiple sclerosis (MS) is an inflammatory disease, which has a wide range of effects on patients. There are controversies regarding the role of vitamin D in clinical and laboratory improvements in MS patients. Objective: The aim of this systematic review protocol is to evaluate the efficacy of vitamin D supplements on relapse rate, gadolinium-enhancing lesions of magnetic resonance imaging (MRI)


Background
Multiple sclerosis (MS) is an inflammatory progressive disorder of the central nervous system, which affects women more than men [1]. The annual incidence of the disease has increased, and environmental and genetic factors are considered important in disease development [2][3][4].
Smoking, Epstein-Barr virus infection, habitat latitude, and vitamin D status are among the environmental factors associated with disease risk [5,6].
Previous studies have demonstrated that a longer duration of sunlight exposure, decreasing latitude of residence, and a vitamin-rich diet are associated with a lower risk of developing MS [7][8][9].
Vitamin D, which is a modulator of calcium and phosphorus, plays an important role in bone formation and maintenance as well as having anti-inflammatory, antiproliferation, and immune intonation functions [10]. The regulation of gene expression in immune cells is thought to explain vitamin D's immune effects on cells [11].
Experimental studies have shown that vitamin D administration could slow down experimental autoimmune encephalomyelitis progression [12,13]. In humans, lower vitamin D status has been reported at the time of relapse in MS patients as compared with the relapse-free period [14][15][16]. Some previous studies showed that vitamin D supplements were not effective in reducing MS-related relapses [17,18], whereas others revealed that vitamin D supplements were helpful in reducing relapse rates and MRI lesions in MS patients [19,20].
A systematic review and meta-analysis conducted previously showed that vitamin D supplementation was not beneficial to control MS relapses (odds ratio 0.98, 95% CI 0.45-2.16) by including 5 randomized clinical trials (RCTs) [21].
The main goal of this systematic review and meta-analysis will be to evaluate the effectiveness of vitamin D supplementation on clinical and para-clinical outcomes in patients with multiple sclerosis

Primary Objective
The primary objective was to identify the efficacy of vitamin D supplement administration in patients with MS on relapse rates.

Secondary Objectives
The secondary objectives were the following:

Study Characteristics
We will include RCTs, being single-blinded or double-blinded or open-label trials in which relapse rate was one of the main outcomes after vitamin D supplement therapy. The articles that had been published in the English language will be included.
Cohort studies, case-control studies, and any other types of studies will be excluded.

Types of Participants
We will include studies with adult participants (aged more than 18 years) with the relapsing-remitting (RR) form of the disease (as we want to assess the effect of the intervention on relapse rate).

Control Group
The control group should be patients who received placebo (color, shape, and smell similarity with the vitamin D supplements).

Types of Intervention
We considered interventions as vitamin D supplements (any doses) whereas controls should have received placebos.

Outcome Assessment
The primary outcome assessment will be carried out by a report of relapse, which is characterized by attacks of new or increasing neurologic symptoms (such as double vision, blurred vision, numbness, the lack of balance, memory loss, muscle cramping secondary to spasticity, bladder, bowel, and sexual dysfunction, bilateral facial weakness or trigeminal neuralgia, nystagmus, and intention tremor, and heat intolerance). The secondary outcomes will be assessed by comparing the number of gadolinium-enhanced plaques before and after the treatment, level of cytokines (tumor necrosis factor and interleukins) before and after the treatment, and progression of disability measured with the Expanded Disability Status Scale (EDSS).

Information Sources
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Search Strategy
A search strategy was developed, and it will be used to search in all databases. The search keywords are as following:

Study Records
In total, 2 independent researchers will independently assess the articles. All obtained articles will be screened by title and abstract, and selected articles will be considered as eligible, not eligible, or may be eligible.
Articles that are considered as not eligible by both researchers will be excluded and others will be searched for by obtaining the full text. Eligible and may be eligible articles will be assessed independently, and in the case of a disagreement, a session for solving the disagreement will be held. The researchers will extract the data from papers and in the case of incomplete/unclear information, surveys will be sent to the authors.

Data Items
Data regarding the name of authors, year of publication, number of patients, journal title, date, demographic data, method of intervention, dose of vitamin D supplement, duration of the study, frequency of relapses during the study, mean vitamin D levels at baseline and at the end of the study, type of control, number of baseline and final gadolinium enhanced plaques in MRI, and mean levels of cytokines and EDSS at baseline and the end of the study will be extracted by 2 independent researchers and will be recorded.

Assessment of Risk of Bias in Included Studies
On the basis of the Cochrane Collaboration Risk of Bias assessment tool, 2 researchers will assess the risk of bias in each study [22]. Thus, each article will be categorized into low risk, high risk, and unclear risk. In the case of a disagreement, a discussion to reach an agreement will be held.

Data Synthesis
When adequate studies are included, the meta-analysis will be performed by considering the relapse, the number of gadolinium-enhanced plaques, and the level of cytokines and disability (which is assessed by means of EDSS) as the main outcome. For all of the main outcomes, mean differences and standardized mean differences will be applied. In the case of missing SD or SE, it will be calculated directly using the data where possible. If adequate studies are retrieved, a subgroup analysis will be carried out.

Subgroup Analysis
A subgroup analysis will be carried out according to sex, age, and EDSS.

Results
This systematic review was started in September 2017, and the search process is completed. The articles are retrieved and are under review by 2 independent researchers. The findings of this systematic review will determine the effectiveness of vitamin D supplements on the prevention of MS relapses, MRI findings, and cytokines. The results of this systematic review will be published in a peer-reviewed journal.

Discussion
MS is a disabling disease and nearly 85% of patients present with the RR form [23]. Relapses are not predictable and have negative impacts on a patient's quality of life [24].
Since 1970, vitamin D has been considered as an important factor in MS development. Studies showed that the prevalence of MS is higher in regions with less exposure to ultraviolet light [25]. Other studies demonstrated that higher levels of serum vitamin D levels are associated with less disease activity in patients and by each doubling of serum level of this vitamin, the risk of relapse decreased by 27% [16]. Vitamin D supplements were considered to be useful for the reduction of disease-related MRI lesions, disability, and reduced relapse rates during the study period [17], but there is no consistent finding on the effectiveness of vitamin D supplements in all those studies. This may be because different studies administered different doses of supplements and they assessed the effects on different outcomes.
The results of this systematic review could be helpful for clinicians to understand the best dose of vitamin D supplement for patients with MS.

Conflicts of Interest
None declared.