In adults with clinically isolated syndrome suggestive of MS, high-dose vitamin D monotherapy reduced disease activity at 2 y
Ann Intern Med. 2025 Jul 1. doi: 10.7326/ANNALS-25-02312-JC PDF behind paywall DOI: 10.7326/ANNALS-25-02312-JC
Lucas H McCarthy 1; ACP Journal Club Editorial Team at McMaster University
High-Dose Vitamin D Monotherapy Shows Promise in Reducing Disease Activity in Clinically Isolated Syndrome
The D-Lay MS randomized clinical trial has demonstrated that high-dose vitamin D monotherapy significantly reduces disease activity in adults with clinically isolated syndrome (CIS) suggestive of multiple sclerosis 1 2 3. This landmark study provides the first robust evidence that vitamin D supplementation alone can delay disease progression in the earliest stages of MS.
Study Design and Methodology
The D-Lay MS trial was a parallel, double-blind, randomized placebo-controlled clinical trial conducted across 36 multiple sclerosis centers in France from July 2013 to December 2020 1 3. The study enrolled 316 participants aged 18 to 55 years with untreated CIS, with a median age of 34 years and 70% female participants 1 3.
Inclusion criteria were stringent and included:
- CIS duration less than 90 days from symptom onset 1 3
- Serum vitamin D concentration less than 100 nmol/L 1 3
- Diagnostic MRI meeting 2010 criteria for dissemination in space or ≥2 lesions with presence of oligoclonal bands 1 3
Participants were randomized 1:1 to receive either
100,000 IU of oral cholecalciferol (vitamin D3) or matching placebo every 2 weeks for 24 months
Primary Findings
The study's primary outcome was disease activity, defined as the occurrence of a relapse and/or MRI activity (new and/or contrast-enhancing lesions) over 24 months of follow-up 1 3.
Key results showed:
- Disease activity occurred in 60.3% of the vitamin D group compared to 74.1% of the placebo group (hazard ratio 0.66; 95% CI 0.50-0.87; P = 0.004) 1 3
- Median time to disease activity was significantly longer in the vitamin D group: 432 days versus 224 days in the placebo group (P = 0.003) 1 2 3
- This represents a 34% reduction in risk of disease activity with vitamin D supplementation 5
MRI Outcomes
All three secondary MRI outcomes showed significant benefits favoring the vitamin D group 1 3:
| MRI Outcome | Vitamin D Group | Placebo Group | Hazard Ratio | P-value |
| MRI activity | 57.1% (89 patients) | 65.3% (96 patients) | 0.71 | 0.02 |
| New lesions | 46.2% (72 patients) | 59.2% (87 patients) | 0.61 | 0.003 |
| Contrast-enhancing lesions | 18.6% (29 patients) | 34.0% (50 patients) | 0.47 | 0.001 |
The reduction in contrast-enhancing lesions was particularly striking, with a 53% reduction in the vitamin D group 6.
Clinical Outcomes
While MRI outcomes showed clear benefits, clinical outcomes showed no significant differences between groups 1 3. Specifically:
- Relapse rates: 17.9% in vitamin D group vs 21.8% in placebo group (P = 0.16) 1 3
- No significant differences in disability progression (EDSS), fatigue, quality of life, depression, or anxiety measures 7
- This suggests that while vitamin D effectively reduces subclinical disease activity detectable on MRI, it may not translate to immediate clinical symptom improvements 6.
Safety Profile
The study demonstrated that high-dose vitamin D supplementation was safe and well-tolerated 1 3 8:
- 95% of participants completed the trial 8
- Severe adverse events occurred in 11% of vitamin D group vs 9% of placebo group 2
- None of the severe adverse events were related to cholecalciferol 1 3
- No cases of vitamin D toxicity or hypercalcemia were reported 8
Clinical Implications
This study represents a significant breakthrough in early MS management for several reasons 6:
Accessibility: Vitamin D supplementation is an inexpensive, readily available intervention that could be particularly valuable in resource-limited settings or for patients with limited access to disease-modifying therapies 5.
Timing: The intervention was most effective when initiated very early in the disease course, highlighting the importance of early identification and treatment of CIS 9.
Patient Selection: Patients most likely to benefit had severe vitamin D deficiency at baseline, normal BMI, and no spinal cord lesions 5.
Future Directions: The results support further investigation of vitamin D as add-on therapy to conventional disease-modifying treatments 1 6.
Study Limitations
While promising, the study has several limitations:
- The study population was limited to patients with vitamin D deficiency at baseline 1
- Long-term outcomes beyond 24 months were not assessed 1
- The study was conducted primarily in France, which may limit generalizability to other populations 1
- Clinical symptoms and disability measures showed no significant improvement despite MRI benefits 1
Conclusion
The D-Lay MS trial provides compelling evidence that high-dose vitamin D monotherapy can significantly reduce disease activity in CIS and early relapsing-remitting MS
1 2 6. With a 34% reduction in disease activity risk and nearly doubling the time to disease progression, vitamin D supplementation represents a safe, accessible intervention that could complement existing MS therapies 5. These findings support routine vitamin D assessment and supplementation in patients with CIS, particularly those with vitamin D deficiency, and warrant further investigation into optimal dosing strategies and combination therapies 6.
References
- https://jamanetwork.com/journals/jama/fullarticle/2831270
- https://www.medpagetoday.com/neurology/multiplesclerosis/114587
- https://pubmed.ncbi.nlm.nih.gov/40063041/
- https://practicalneurology.com/news/high-dose-vitamin-d-monotherapy-reduced-disease-activity-in-cis-and-early-relapsing-remitting-ms
- https://hcn.health/hcn-trends-story/high-dose-vitamin-d-may-stop-cis-early-rrms-new-disease-activity/
- https://www.emjreviews.com/neurology/news/vitamin-d-significantly-reduces-ms-disease-activity-landmark-trial-shows/
- https://www.charcot-ms.org/files/ID-33-Manon-Rival.pdf
- https://www.medscape.com/viewarticle/high-dose-vitamin-d-linked-lower-disease-activity-cis-2024a1000h4r
- https://www.ucihealth.org/about-us/news/2025/06/vitamin-d-multiple-sclerosis
- https://multiplesclerosisnewstoday.com/news-posts/2024/09/20/ectrims-2024-high-dose-vitamin-d-delay-progression-ms/
- https://www.jwatch.org/na58563/2025/03/25/testing-vitamin-d-supplementation-early-multiple-sclerosis
- https://pmc.ncbi.nlm.nih.gov/articles/PMC5990512/
- https://rheumnow.com/news/d-lay-trial-high-dose-vitamin-d-retards-multiple-sclerosis
- https://jamanetwork.com/journals/jama/article-abstract/2831270
- https://medicalxpress.com/news/2025-03-highdose-vitamin-d-significantly-disease.html
- https://clinicaltrials.gov/study/NCT01817166
- https://www.nhs.uk/medicines/colecalciferol/side-effects-of-colecalciferol/
- https://www.healthline.com/nutrition/vitamin-d-side-effects
- https://jamanetwork.com/journals/jamaneurology/fullarticle/1815002
- https://www.webmd.com/drugs/2/drug-179480/is-d-10-000-oral/details
- https://practicalneurology.com/news/high-dose-vitamin-d-monotherapy-reduced-disease-activity-in-cis-and-early-relapsing-remitting-ms/2473817/
See related in VitaminDWiki
- Overview MS and vitamin D
- Multiple Sclerosis slowed by bi-weekly 100,000 IU of Vitamin D (Note: Same amount daily reverses MS) - March 2025 same study
- Multiple Sclerosis non-drug treatment – Vitamin D is the most popular (Austria – 42% of MSers in the study) – March 2025 same study
- CIS (MS) reduced 36% by two capsules of 50,000 IU of Vitamin D taken biweekly – RCT March 2025 same study
- A New Role for Vitamin D (Multiple Sclerosis) - March 2025
- Comparing High-dose vitamin D therapies
- Vitamin D fights Multiple Sclerosis, Autoimmune, etc. - Dr. Coimbra video and transcript March 2025