High-dose vitamin D may quell clinically isolated syndrome of MS

Supplementation with high-dose vitamin D in patients with clinically isolated syndrome (CIS) typical for multiple sclerosis (MS) helps lower disease activity, as shown in the D-Lay MS trial.

Over 24 months of follow-up, disease activity was observed less frequently among patients who received oral cholecalciferol 100,000 IU every 2 weeks than among those who received placebo (60.3 percent vs 74.1 percent; hazard ratio [HR], 0.66, 95 percent confidence interval [CI], 0.50–0.87; p=0.004). [JAMA 2025;doi:10.1001/jama.2025.1604]

Vitamin D supplementation delayed the onset of disease activity, with a median of 432 days as opposed to 224 days with placebo. The number needed to treat to prevent one case of disease activity with high-dose vitamin D over the 24-month study period was 7.2 (95 percent CI, 4.1–29.0).

Results for all three secondary MRI outcomes were also more favourable in the vitamin D group than in the placebo group, with fewer patients showing MRI activity (57.1 percent vs 65.3 percent; HR, 0.71, 95 percent CI, 0.53–0.95; p=0.02), new lesions (46.2 percent vs 59.2 percent; HR, 0.61, 95 percent CI, 0.44–0.84; p=0.003), and contrast-enhancing lesions (18.6 percent vs 34.0 percent; HR, 0.47, 95 percent CI, 0.30–0.75; p=0.001).

No significant between-group difference was observed in other outcomes such as relapse, disability, fatigue, quality of life, and depression and anxiety symptoms.

Ancillary analysis

Often, MS begins with a CIS—an acute event involving the central nervous system, such as optic neuritis, transverse myelitis, or brainstem syndromes, the investigators said. “However, CIS does not always convert to MS.”

The definition of disease activity used in the primary analysis aligned with the 2005 McDonald criteria’s definition of risk for conversion to relapsing-remitting MS. Given the 2017 update to the McDonald criteria, which enabled earlier and more precise MS diagnosis, an ancillary analysis of disease activity was performed in the subgroup of patients meeting the 2017 criteria prior to treatment. [Lancet Neurol 2018;17:162-173]

The findings were consistent with those of the primary analysis. Compared with placebo, vitamin D was associated with a lower risk of disease activity during the follow-up period (HR, 0.66, 95 percent CI, 0.49–0.89; p=0.007). The same was true for MRI activity (HR, 0.71, 95 percent CI, 0.51–0.97; p=0.03), occurrence of new/enlarging lesions (HR, 0.59, 95 percent CI, 0.42–0.83; p=0.003), and occurrence of contrast-enhancing lesions (HR, 0.49, 95 percent CI, 0.30–0.81; p=0.006).

Therapeutic alternative

Of note, the effect of high-dose vitamin D on disease activity was pronounced for participants without spinal cord lesions at diagnosis (HR, 0.23 vs 0.85; p=0.01 for interaction), those with severe vitamin D deficiency (HR, 0.33 vs 0.78; p=0.03 for interaction), and those with normal BMI at baseline (HR, 0.53 vs 0.95; p=0.048).

As for safety, 33 serious adverse events occurred in 30 patients during the study, including 17 (10.9 percent) in the vitamin D group and 13 (8.8 percent) in the placebo group, none of which were suggestive of hypercalcemia or related to cholecalciferol. Mild hypercalcemia (calcium level of 2.6–2.88 mmol/L) was reported in two patients in the placebo group at 3 and 12 months, with similar urinary calcium/creatinine ratios on spot sample results during follow-up. There were no reports of kidney failure and moderate or severe hypercalcemia (calcium level >2.88 mmol/L).

“[The findings] suggest that cholecalciferol could represent an inexpensive therapeutic alternative, with low risk of adverse events, after a CIS, especially in populations with limited access to disease-modifying therapies,” the investigators said.

With cholecalciferol also shown to reduce disease activity in relapsing-remitting MS patients using the most recent McDonald criteria, vitamin D supplementation could be beneficial for all early-stage relapsing-remitting MS, but only after thorough screening to exclude those with hypercalcemia risk factors like sarcoidosis and tuberculosis, they added.

Future studies may evaluate vitamin D as an add-on therapy in the therapeutic strategy for managing MS, according to the investigators.

D-Lay MS 

D-Lay MS included 316 adults (median age 34 years, 70 percent women) with CIS duration less than 90 days, serum vitamin D concentration less than 100 nmol/L, and diagnostic MRI meeting 2010 criteria for dissemination in space or two or more lesions and presence of oligoclonal bands, enrolled from July 2013 to December 2020.

The patients were randomly assigned to receive oral cholecalciferol 100,000 IU (n=163) or placebo (n=153) every 2 weeks for 24 months. Of these patients, 303 took at least one dose of the study drug and were included in the primary analysis, with 288 completing the 24-month trial.

A total of 257 patients (85 percent) received high-dose intravenous methylprednisolone pulse therapy, and 247 (89 percent) fulfilled the requirements for relapsing-remitting MS diagnosis. The median vitamin D level at diagnosis was 45 nmol/L, with 68 (22.4 percent) having severe vitamin D deficiency (<30 nmol/L).