By Ulrike Kaunzner, MD
Synopsis: This study by Thouvenot et al evaluated the effectiveness of high-dose vitamin D treatment on clinically isolated syndrome and early multiple sclerosis as monotherapy and reported a reduced incidence of new disease activity compared to the control group.
Source: Thouvenot E, Laplaud D, Lebrun-Frenay C, et al; D-Lay MS Investigators. High-dose vitamin D in clinically isolated syndrome typical of multiple sclerosis: The D-Lay MS randomized clinical trial. JAMA. 2025; Mar 10. doi:10.1001/jama.2025.1604. [Online ahead of print].
Vitamin D traditionally has been recognized for its role in calcium and bone metabolism. More recently, it also has been recognized for its effects on immune regulation. Interestingly, it is not a vitamin in the classic sense, since it does not necessarily need to be ingested — the body can produce it through exposure to sunlight. Synthesized in the skin upon UVB exposure and activated through sequential hydroxylation in the liver and kidneys, its active form, 1,25-dihydroxyvitamin D (calcitriol), binds to the vitamin D receptor expressed in various immune cells, including T cells, B cells, macrophages, and dendritic cells. Vitamin D3 (cholecalciferol) first is converted to 25-hydroxyvitamin D (calcidiol) in the liver and then to its active form, 1,25-dihydroxyvitamin D (calcitriol), in the kidneys. Through this pathway, vitamin D3 influences both innate and adaptive immunity, suppressing pro-inflammatory T cell subsets (Th1 and Th17) while promoting regulatory T cells.
Given these mechanisms, and consistent epidemiological evidence linking low vitamin D3 levels to increased multiple sclerosis (MS) incidence and disease activity, interest in vitamin D3 as a therapeutic adjunct in MS has grown considerably. Studies have shown that vitamin D3 deficiency increases the risk of developing MS and may lead to more severe disease progression. Supplementing with vitamin D3 has been explored as a potential treatment to reduce disease activity, particularly in patients with low baseline vitamin D3 levels. Although evidence suggests that vitamin D3 supplementation might reduce relapses and magnetic resonance imaging (MRI)-detected disease activity, its role in preventing MS or improving long-term outcomes remains inconclusive.
The D-Lay MS study by Thouvenot et al was a multicenter, double-blind, placebo-controlled Phase III trial investigating the effects of high-dose vitamin D (cholecalciferol) monotherapy in patients with clinically isolated syndrome (CIS) typical of early relapsing-remitting MS. Conducted across 36 centers in France over nearly a decade, the study enrolled more than 300 patients who recently had experienced a CIS event and met imaging and cerebrospinal fluid criteria suggestive of early MS.
Participants received either high-dose vitamin D (100,000 IU every two weeks) or placebo for up to 24 months or until signs of disease activity emerged. The treatment significantly reduced the risk of new disease activity, particularly MRI changes, compared to placebo, with the most pronounced benefits seen in individuals with severe vitamin D deficiency and no spinal cord lesions. Patients with both optic neuritis and other CIS presentations benefited, suggesting broad applicability. Although the effect on relapse rates and disability progression was limited, the efficacy of high-dose vitamin D was comparable to established therapies such as teriflunomide and interferon beta. Its immunomodulatory effects — such as possible reduction of Th17 responses and enhancement of regulatory T cell function — may underlie these findings. Compared to the PrevANZ trial, which used lower doses and showed no significant benefit, the D-Lay MS study supports a potential role for high-dose vitamin D as an affordable, well-tolerated adjunctive option in early MS.1
Commentary
This study is significant since it explores the potential use of vitamin D, a widely available and essential nutrient and vitamin, in modulating immune function and possibly influencing the disease course in patients with MS. Given its broad physiological roles, vitamin D’s effect on immune regulation offers a promising avenue for MS management. However, the study has limitations, including the potential for imprecise event detection because of the timing of MRI scans and the absence of frequent disability assessments via Expanded Disability Status Scale measures. Additionally, the secondary endpoints and subgroup analyses did not provide conclusive evidence.
Although the results are encouraging, further large-scale studies with long-term follow-up are essential to confirm these findings. The accessibility of vitamin D, particularly through cost-effective supplementation or possibly even sunlight exposure, offers a unique opportunity to intervene in the disease course, most likely as add-on therapy to currently available disease-modifying therapies (DMTs). However, larger studies could show if it offers an opportunity for regions where conventional DMTs are not easily accessible.
Ulrike W. Kaunzner, MD, is Assistant Professor of Clinical Neurology, Weill Cornell Medical College.
Reference
1. Butzkueven H, Ponsonby AL, Stein MS, et al. Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome. Brain. 2024;147(4):1206-1215.
This study by Thouvenot et al evaluated the effectiveness of high-dose vitamin D treatment on clinically isolated syndrome and early multiple sclerosis as monotherapy and reported a reduced incidence of new disease activity compared to the control group.
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