Pros and Cons: Vitamin D Supplementation in Multiple Sclerosis

Several observations have contributed to the association of vitamin D status and multiple sclerosis (MS) pathogenesis. Previous studies have linked MS to sun exposure based on geographic relationship to the equator, lower levels of vitamin D, and to the genes that encode enzymes in the vitamin D pathway.¹

“There is compelling evidence that vitamin D status is an important determinant of MS outcomes, including new MRI lesions, relapses, and accumulation of disability.  In particular, most individuals with MS have vitamin D levels well below those that appear to be optimal for MS treatment,” Alberto Ascherio, MD, MPH, DrPH, Professor of Medicine at Harvard Medical School and Brigham and Women’s Hospital in Boston, MA, told Neurology Advisor.

Several new studies have attempted to further elucidate the relationship of vitamin D status and MS development and progression.

For instance, Elias S. Sotirchos, MD, of the Department of Neurology at Johns Hopkins University School of Medicine in Baltimore, MD, and colleagues conducted a pilot study to understand the immunologic impact and safety of high (10 400 IU) and low (800 IU) dose cholecalciferol supplementation in relapsing-remitting MS.

They found a reduction in interleukin-17 +CD4+ T cells (P=.016), effector memory CD4+ T cells (P=.021), and CD161+CD4+ T cells (P=.03) in the high-dose group. The high-dose treatment group also demonstrated increases in naïve CD4+ T cells (P=.04) and central memory CD4+ T cells (P=.018). The supplementation did not come without adverse events, including nausea (n=3), hypercalcemia (n=1), and increased spot urine calcium:creatinine ratio (n=14).

Dr Sotirchos and colleagues further noted that single nucleotide polymorphisms in the gene for CD161 and CD4+IL-17+ T cells have been linked to the development of MS. “Thus, our finding that high-dose cholecalciferol leads to a decrease in the proportion of CD4+IL-17+ T cells in the peripheral blood of patients with MS suggests that this may be a major mechanism underlying the possible therapeutic role of vitamin D in MS,” the wrote.²

Previous studies have examined Vitamin D status in patients treated with interferon-β. Dalia Rotstein, MD, of the Partners Multiple Sclerosis Center at Brigham and Women’s Hospital in Boston, MA, and colleagues wanted to further examine its impact on clinical and MRI outcomes in patients treated with fingolimod, glatiramer acetate (GA), and interferon (INF).

In the interferon/glatiramer group, they found that a longer time to relapse or new gadolinium-enhancing lesions was associated with higher 25(OH)D levels (P for trend-0.042, HR=.77). This association was also found in the interferon subgroup (P=.012. HR=.58) but not in the glatiramer group (P=.50, HR=.89).

Likewise, both the interferon and glatiramer acetate groups demonstrated improvement in new gadolinium-enhancing lesions with a more prominent effect in the interferon group (59% hazard reduction with IFN vs 43% reduction with GA). No significant associations were found for relapses or change in disability. Notably, a higher 25(OH)D in patients treated with fingolimod was associated with a longer time to the combined outcome (HR=.48, P=.016) and relapse (HR=.50, P=.046).

Dr Rotstein hypothesized that the differences in efficacy may be related to their underlying mechanisms of actions. For instance, they note fingolimod acts peripherally and sequesters T-lymphocytes to decrease T-cells in the CNS and interferon promotes T_H2 responses. Vitamin D is involved in T-regulatory cell differentiation, T_H2 responses, and monocyte inhibition and “GA shares each of these immune mechanisms with vitamin D” and consequently the effects may be redundant.³

In a letter to the editor published in the Journal of Neurological Sciences, Yara Dadalti Fragoso, MD, of the Department of Neurology and MS Reference Center in Brazil, cautioned on the use of high doses of Vitamin D.

In 21 patients of which most discontinued disease-modifying drugs, Dr Fragoso noted the daily dose of cholecalciferol ranged from 8000 IU to 150 000 IU per day for an average of 1 year. Worsening in the form of relapses and new MRI lesions was reported in 17 patients. Further, 10 patients had worsening of their disability. Moreover, this group of patients reported severe hypercalcemia (n=5), tonic-clonic seizures (n=2), kidney failure (n=3), nephrocalcinosis (n=3), and nephrolithiasis (n=2). Ionic calcium levels of 13.8 mg/mL and 16.8 mg/mL were reported in cases with renal abnormalities. Although there were no deaths, 3 patients required intensive care.

Dr Fragoso suggested that because MS is characterized by relapses and remission, when patients are in a remission period there may be a tendency to “overvalue their state and enthusiastically correlate it with anything that seems to fit.”⁴

“Most MS patients are likely to benefit from vitamin D supplementation.  In reasonable dosages (up to 3000 IU/day) vitamin D is extremely safe, so the fact that there are still some uncertainties concerning the optimal levels should not be an obstacle to supplementation,” Dr Asherio said.  “Although we know enough to correct the vitamin D insufficiency that is common in MS, further research remains important to determine the optimal vitamin D levels and possible interactions of vitamin D with immunomodulatory drugs, including the new oral agents that are now commonly used as first line treatment.”

References

1. Rolf L, Muris AH, Hupperts R, Damoiseaux J. Illuminating vitamin D effects on B-cells – the multiple sclerosis perspective. Immunology. 2015; doi:10.1111/imm.12572.
2. Sotirchos ES, Bhargava P, Eckstein C, et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology. 2015; doi:10.1212/WNL.0000000000002316.
3. Rotstein DL, Healy BC, Malik MT, et al. Effect of vitamin D on MS activity by disease-modifying therapy class. Neurol Neuroimmunol Neuroinflamm. 2015; doi: 10.1212/NXI.0000000000000167.
4. Fragoso YD, Adoni T, Damasceno A, et al. Unfavorable outcomes during treatment of multiple sclerosis with high doses of vitamin D. J Neurol Sci. 2014;346(1-2):341-2.