Table 8.

Summary of the major clinical studies evaluating the relationship between vitamin D status and multiple sclerosis (MS) risk

Source	Study design	Objective	Population (cases)	Main outcome(s)
Martinelli et al144	Retrospective study	To investigate the relationship between the vitamin D status and MS risk	100 clinically isolated syndrome (CIS) patients	CIS patients with very low (<10th percentile) and low (<25th percentile) 25(OH)D3 levels were particularly at risk of clinically definite MS
Munger et al145	Prospective, nested case-control study	To investigate the relationship between 25(OH)D3 levels and MS risk	7 million US military personnel	High circulating levels of vitamin D were associated with a lower risk of MS
Runia et al171	Prospective longitudinal study	To investigate the relationship between 25(OH)D3 levels and exacerbation risk in MS	73 patients with relapsing–remitting MS (RRMS)	Higher vitamin D levels were associated with decreased exacerbation risk in RRMS
Mirzaei et al147	Prospective study	To investigate the effect of gestational vitamin D on adult-onset MS	35,794 mothers of participants of the Nurses’ Health Study II	Higher maternal milk and vitamin D intake during pregnancy may be associated with a lower risk of developing MS in offspring
Mowry et al143	5-year longitudinal cohort study	To investigate whether vitamin D status is associated with relapse of MS	469 MS patients	Higher vitamin D levels were associated with lower relapse risk
Munger et al172	Retrospective cohort study	To evaluate the effect of dietary intake of vitamin D on risk of MS	116,671 female registered nurses	Intake of ≥400 IU/day of vitamin D from multivitamins was associated with a non-statistically significant reduced MS risk
Shaygannejad et al149	Randomized, double-blind, placebo-controlled clinical trial	To evaluate the effect of low-dose oral vitamin D on the prevention of progression of RRMS	50 RRMS patients	Adding low-dose vitamin D to routine disease-modifying therapy had no significant effect on expanded Disability Status Scale score or relapse rate
Kampman et al150	Randomized, double-blind study	To evaluate the effect of vitamin D (20,000 IU weekly for 96 weeks) on the clinical outcome of MS	35 MS patients	Supplementation with 20,000 IU vitamin D weekly did not result in beneficial effects on MS-related outcomes
Burton et al148	Randomized, prospective, controlled study	To evaluate the effect of vitamin D (40,000 IU/day over 28 weeks) on the clinical outcome of MS	49 MS patients	The trial lacked the statistical precision and design requirements to adequately assess changes in clinical disease measures
Smolders et al151	Randomized, double-blind study	To evaluate the toleration and immunoregulatory effect of vitamin D (20,000 IU/day vitamin D3 for 12 weeks) in MS	15 RRMS patients	Vitamin D supplementation increased proportion of IL-10+ CD4+ T-cells and decreased the ratio between interferon-γ+ and interleukin 4+ CD4+ T-cells