Vitamin D status, supplementation, and multiple sclerosis: a systematic review and meta-analysis.

Background: Multiple sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder of the central nervous system and a leading cause of disability among young adults. The disease exhibits considerable heterogeneity in clinical progression, with some patients experiencing more aggressive disease activity and a rapid decline in quality of life. Vitamin D plays a key role in immune regulation, and evidence suggests that its deficiency constitutes a significant environmental risk factor for immune-mediated conditions such as MS. While there are controversies regarding the role of serum 25(OH)D in MS as well as vitamin D3 supplements in controlling relapse and disability improvement during treatment. Therefore, our current meta-analysis aims to examine the relationship between serum 25(OH)D levels-and their modulation through supplementation-and multiple sclerosis. Methods: Comprehensive literature review was performed from conception to November 17, 2025, employing various online databases including PubMed, Cochrane Library, Web of Science, and EMBASE. The relevant studies about MS and serum 25-hydroxyvitamin D (25(OH)D) level or vitamin D3 supplementation. This meta-analysis incorporated 40 research examining the correlation between serum 25(OH)D levels and multiple sclerosis, as well as 22 studies investigating the effects of vitamin D3 supplementation on multiple sclerosis. Results: 1) The 25(OH)D levels in patients with MS were significantly lower than those in healthy controls. In the analysis of disease subtypes, patients with relapsing-remitting MS (RRMS) had significantly higher 25(OH)D levels than those with secondary progressive MS (SPMS), but no significant difference was observed compared to patients with primary progressive MS (PPMS). Additionally, RRMS patients had significantly lower 25(OH)D levels during relapse than during remission. No significant seasonal fluctuation in 25(OH)D levels was observed in MS patients; 2) Multivariable-adjusted analysis comparing the highest versus lowest serum 25(OH)D categories revealed that higher serum 25(OH)D levels were associated with a lower risk of MS onset and lower disability scores (EDSS), but no significant association was found with disease activity. 3) In the intervention analysis, overall, vitamin D3 supplementation did not significantly reduce the annualized relapse rate (ARR) or improve EDSS scores. However, subgroup analysis indicated that high-dose vitamin D3 supplementation significantly reduced the ARR, whereas low-dose supplementation showed no such effect. Multivariable-adjusted analysis further confirmed that vitamin D3 supplementation was significantly associated with a reduced risk of MS relapse, and this benefit was similarly observed only in the high-dose supplementation group. Conclusions: This systematic analysis confirms that patients with MS exhibit significantly lower serum 25(OH)D levels compared to healthy controls, with notable reductions observed during clinical relapses. A clear gradient exists across disease subtypes, with RRMS patients showing higher levels than those with SPMS. An inverse correlation was demonstrated between serum 25(OH)D levels and both the risk and severity of MS. Critically, while high-dose vitamin D3 supplementation is associated with a reduced ARR and overall relapse risk, neither supplementation compared to placebo nor dosage comparison significantly affected relapse rates during the study period or final disability scores. These findings suggest a complex, dose-dependent role of vitamin D in modifying relapse risk without a clear impact on short-term disability progression in established MS. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/login, identifier CRD420251273119.