Vitamin D is an essential nutrient that is the subject of emerging interest in multiple sclerosis research. Vitamin D is found in two forms: D 2 and D3, known as ergocalciferol and cholecalciferol respectively. Both of these molecules are converted to 25-hydroxyvitamin D (25(OH)D) in the body, a molecule which is measured in the blood to determine a person’s vitamin D status. 25(OH)D is then converted to 1 alpha, 25-dihydroxyvitamin D, the biologically active, hormonal form of vitamin D in the body. Vitamin D is produced by our body through exposure to sunlight, can be obtained through ingestion of supplements, and small amounts of vitamin D are in food such as oily fish, fortified dairy products, egg yolks, beef/pork liver and some cheeses 1.
For more detailed information on vitamin D, its role in health and disease prevention and its association with MS, consult our Vitamin D Fact Sheet.
Vitamin D and MS Research
Cell-based and animal studies
A growing body of evidence demonstrates that vitamin D deficiency is associated with multiple sclerosis (MS). Experimental research using cell-based and animal studies have shown that vitamin D and its metabolites can regulate the immune system by binding to vitamin D receptors that are found on certain immune cells and interacting with genes associated with autoimmunity 2. Specifically, vitamin D suppresses the activity of pro-inflammatory T cells – including T helper (Th)-1 and Th-17 cells – that secrete chemical factors that cause the damaging inflammation characteristic of MS 3,4. Vitamin D also promotes the actions of T regulatory (T-reg) cells, a protective type of immune cell that can suppress autoimmune disease5. In addition to its immune-modifying effects, vitamin D also plays a role in the repair of nervous tissue damaged by MS-related inflammation by stimulating neural stem cells to increase their numbers and rapidly mature into both neurons and myelin-forming oligodendrocytes, in turn driving remyelination6.
The link between vitamin D and MS was initially prompted by findings from population studies showing that MS is generally more common in countries further away from the equator where sunlight exposure is lower, particularly in the winter months 7. Even within the same geographic region, changes in exposure to the sun across the seasons may result in variations in MS risk in people born at different times of the year, such that the risk of MS peaks in individuals born in May and falls in those born in November in the northern hemisphere 8, while the opposite pattern is found in the southern hemisphere where the seasons are reversed 9. This seasonal trend in MS risk mirrors overall vitamin D status, which have been found to be lowest in the spring and highest in the autumn in the northern hemisphere. The link between MS risk and month-of-birth has been debated, however, and scientific opinion is divided over whether it is an actual phenomenon or a statistical anomaly 10,11.
Multiple studies have shown that the risk of developing MS is decreased with either higher blood levels of 25(OH)D or higher levels of vitamin D intake. A large cohort study of 200,000 women as part of the Nurse’s Health Study found that intake of 400 International Units (IU) of vitamin D was associated with a 40% lower risk of MS 12. In a prospective study of Canadian children and adolescents presenting with demyelination, higher 25(OH)D levels were associated with a lower risk of MS 13. A prospective study of more than 7 million US military personnel found a 51% reduction in MS risk with 25(OH)D levels of 100 nmol/L or higher 14. Another prospective study found that higher levels of 25(OH)D during late adolescence or early adulthood – generally the years just before disease onset – were associated with a lower risk of developing MS later in life 15.
Some of the strongest evidence to point towards a causal link between vitamin D and the risk of MS comes from genetic epidemiology studies. A recent study pooled genetic datasets from large European populations and used a powerful analysis method called Mendelian randomization to test the association between 25(OH)D levels and MS risk 16. The group found that genetically lowered 25(OH)D levels were associated with an increase in the risk of MS in people of European descent.
Recent research also suggests that vitamin D deficiency may not only increase the risk of developing MS but may also affect MS disease activity and clinical course. A group of researchers at the University of California examined the correlation between vitamin D status and brain lesions on an imaging scan, and found that higher 25(OH)D blood levels were associated with lower brain lesion activity 17. A follow-up study by researchers at Harvard School of Public Health that enrolled individuals with clinically isolated syndrome (over 80% of whom were eventually diagnosed with MS) with higher blood 25(OH)D levels had overall fewer active brain lesions, a slower rate of brain volume loss, lower clinical disability, fewer relapses and a slower rate of disease progression 18. They concluded that low vitamin D status early in the disease course is a strong risk factor for long-term MS disability and progression. Similarly, a study that followed a cohort of 145 participants with relapsing-remitting MS showed that higher blood 25(OH)D levels were associated with a reduced risk of relapse 19. A recent study integrating survey-based and clinical assessment data in people living with MS reported associations between latitude, deliberate sun exposure and vitamin D supplementation and specific health outcomes; specifically, vitamin D supplementation was associated positively with health-related quality of life and reduced relapse rate, while higher latitude was related to increased disability and relapse rate 20.
While the association between vitamin D status and MS risk is quite strong, it is less clear whether vitamin D supplementation can improve disease outcomes in people living with MS. Randomized, controlled clinical trials are the most scientifically rigorous method to determine the effects of vitamin D intake on MS outcomes, such as disability, brain lesions, immune cell activity, and relapse rate. Unfortunately, only a handful of studies have been conducted and the results thus far have been inconclusive. So far, three studies have revealed no significant effect of vitamin D treatment compared to the placebo control group21-23, and one study found no significant effect of high dose over low dose vitamin D 2 supplement 24.
On the other hand, three studies have demonstrated benefit of vitamin D supplementation on MS outcomes, although the type of benefit (reduction in brain lesions vs. fewer relapse events) depended on the study 25-27. For example, one study evaluating the safety of high dose vitamin D 3 showed preliminary evidence of reduced relapses and decreased immune cell activity 25. Another study found that vitamin D3 supplementation in participants with optic neuritis and low 25(OH)D levels could reduce the risk of conversion to MS and marginally reduce the number of brain lesions 26. Finally, participants in a randomized, double blind, controlled trial given vitamin D 3 as an add-on to their treatment with disease-modifying therapies experienced a decrease in the number of brain lesions along with a marginal decrease in disability accumulation 27.
In terms of safety, none of the clinical trials have reported adverse events such as toxicity at any of the tested doses of vitamin D 2 or D3, and only one study resulted in mild adverse events when participants were given the active hormonal form (calcitriol) 28.
Further clinical trials to determine the efficacy of vitamin D as a treatment for MS are ongoing. The EVIDIMS (Efficacy of Vitamin D Supplementation in MS) trial is a phase II pilot study evaluating the effects of high-dose vitamin D 3 supplementation brain lesion activity, inflammation, clinical disability and quality of life. Similarly, the VIDAMS (Vitamin D to Ameliorate MS) trial is a large-scale study evaluating the efficacy of high-dose vitamin D 3 in reducing relapse rate and disease activity in the brain while improving quality of life. These are two of several ongoing studies that examining this important question.
Challenges with vitamin D research
One of the major challenges facing researchers examining the link between vitamin D and MS is that many of the studies thus far have been observational in nature. Observational studies produce correlational evidence rather than causal evidence. However, in such studies background factors that may not be anticipated and controlled for and can, thus, muddy our understanding of how vitamin D relates to MS. In other words, most observational studies cannot determine whether vitamin D deficiency results from something to do with MS or whether MS results from low vitamin D status. For example, interpretation of studies examining the relationship between vitamin D status and clinical disability are complicated by the observation that participants with a high degree of disability are more likely to remain indoors, thus reducing their exposure to sunlight 29. Therefore, although it is helpful to know that people with MS are at a higher risk of vitamin D deficiency, these studies do not allow us to draw conclusions about whether low vitamin D status results in MS-related disability, or whether individuals with greater disability receive less sunlight exposure and produce less vitamin D.
Randomized, controlled clinical trials are the gold standard for determining the causal link between a specific intervention and disease outcome, and there are a number of both completed and ongoing studies seeking to determine if vitamin D supplementation is an effective method of treating MS symptoms and progression. However, it is difficult to reconcile the various findings of these studies, since they often use different doses and formulations of vitamin D – for instance, vitamin D 2 versus D3 – and many have been small or short-term, which can make it difficult to draw statistically significant conclusions. Only when evidence stemming from scientifically robust clinical trials is available will we be able to determine if vitamin D supplementation is a safe and effective intervention for people living with MS.
Canadian research on vitamin D and MS
Canadian Collaborative Project on Genetic Susceptibility to MS
- Investigators: Dr. George Ebers (University of Oxford); Dr. Dessa Sadovnick (UBC)
- Summary: The Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS) was a Canada-wide study involving 15 MS clinics and over 30,000 MS patients and their family members. The primary goal of the study was to identify genes which are linked to the onset and development of MS, as well as determine how environmental factors influence the role of genes in MS. In 2009 the CCPGSMS group published a study demonstrating that vitamin D can influence expression of a gene which has been strongly linked to MS – via a vitamin D receptor. This was one of the first pieces of evidence showing that a primary environmental risk candidate – a deficiency of vitamin D – and the gene most strongly associated with MS risk, are directly linked and interact.
Prospective Study of the Clinical Epidemiology, Pathobiology, and Neuroimaging features of Canadian Children with Acquired Demyelinating Syndromes (PD-ADS Study)
- Investigators: Dr. Brenda Banwell (Hospital for Sick Children); Dr. Amit Bar-Or (Montreal Neurological Institute); Dr. Dessa Sadovnk (UBC); Dr. Doug Arnold (Montreal Neurological Institute); Dr. Ruth Ann Marrie (University of Manitoba)
- Summary: The PD-ADS Study was funded in 2004 and then a phase 2 was launched in 2010. Overall the objectives of the study were to define the clinical features, population patterns, disease progression, and imaging features of acquired demyelinating syndrome (ADS) in children in Canada, in order to determine predictive risk factors for MS. A focus of phase II has been to determine the impact of the environment on immune activity and whether this interaction affects the development of pediatric MS. The Vitamin D status in the body were observed and the results of this work 13 showed that children with low vitamin D status were more susceptible to developing MS, as were those with previous infection with EBV and a genetic predisposition towards MS.
What does this mean for Canadians?
There are a few proactive things that all Canadians can do to maintain healthy levels of vitamin D:
- Talk to your physician about having your vitamin D levels checked. Your physician will also be able to provide you guidance on acceptable levels of vitamin D intake for your specific health circumstances.
- If you are an adult or adolescent (age 9 and up), consider taking up to 4000 International Units (IU) supplement of vitamin D per day during the winter or if you are at risk of low sun exposure. The risk of vitamin D toxicity is extremely rare; however, with supplements, there is the potential that vitamin D could build up to toxic levels. Supplements taken as directed and up to 4000 IU/day for adults would not lead to toxicity. This is not intended as medical guidance, so it is recommended that you speak with your physician about appropriate levels of vitamin D intake.
- Enjoy the sun safely. Sun exposure is an important source of vitamin D, but excessive sun exposure is the main cause of skin cancer. Exposure time required to make sufficient vitamin D is less than the amount of time needed for skin to redden and burn. In Canada, vitamin D from sunlight can only be synthesized in your skin during the spring and summer months, around midday, from 10am – 2pm, when the UV index is above 3 and your shadow is shorter than your height. Regularly going outside for a matter of minutes around the middle of the day without sunscreen for a ‘D-Break’ should be enough. It is important to note that vitamin D produced in the skin from solar UVB exposure does not lead to vitamin D toxicity.
- Eat foods that are natural sources of vitamin D: fortified products such as milk, egg yolks, and oily fish like salmon, trout and sardines.
The MS Society of Canada thanks Dr. Heather Hanwell for her scientific consultation on this document.
Resources and References
- National Institutes of Health. Vitamin D Professional Fact Sheet. http://ods.od.nih.gov/factsheets/VitaminD-HealthPr... Available at. Accessed June 1, 2015.
- Handel AE, Sandve GK, Disanto G, et al. Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease. BMC Med. 2013;11:163.
- Bhargava P, Gocke A, Calabresi PA. 1,25-Dihydroxyvitamin D3 impairs the differentiation of effector memory T cells in vitro in multiple sclerosis patients and healthy controls. J Neuroimmunol. 2015;279:20-24.
- Mattner F, Smiroldo S, Galbiati F, et al. Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D(3). Eur J Immunol. 2000;30(2):498-508.
- Correale J, Ysrraelit MC, Gaitán MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain. 2009;132(Pt 5):1146-1160.
- Shirazi HA, Rasouli J, Ciric B, Rostami A, Zhang GX. 1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Exp Mol Pathol. 2015;98(2):240-245.
- Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr Scand Suppl. 1960;35(147):132-147.
- Willer CJ, Dyment DA, Sadovnick AD, et al. Timing of birth and risk of multiple sclerosis: population based study. BMJ. 2005;330(7483):120.
- Staples J, Ponsonby AL, Lim L. Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis. BMJ. 2010;340:c1640.
- Dobson R, Giovannoni G, Ramagopalan S. The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. J Neurol Neurosurg Psychiatry. 2013;84(4):427-432.
- Fiddes B, Wason J, Sawcer S. Confounding in association studies: month of birth and multiple sclerosis. J Neurol. 2014;261(10):1851-1856.
- Munger KL, Zhang SM, O'Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60-65.
- Banwell B, Bar-Or A, Arnold DL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol. 2011;10(5):436-445.
- Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838.
- Salzer J, Hallmans G, Nyström M, Stenlund H, Wadell G, Sundström P. Vitamin D as a protective factor in multiple sclerosis. Neurology. 2012;79(21):2140-2145.
- Mokry LE, Ross S, Ahmad OS, et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med. 2015;12(8):e1001866.
- Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240.
- Ascherio A, Munger KL, White R, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014;71(3):306-314.
- Simpson S, Taylor B, Blizzard L, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010;68(2):193-203.
- Jelinek GA, Marck CH, Weiland TJ, Pereira N, van der Meer DM, Hadgkiss EJ. Latitude, sun exposure and vitamin D supplementation: associations with quality of life and disease outcomes in a large international cohort of people with multiple sclerosis. BMC Neurol. 2015;15:132.
- Kampman MT, Steffensen LH, Mellgren SI, Jørgensen L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler. 2012;18(8):1144-1151.
- Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest. 2011;40(6):627-639.
- Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H. Effects of adjunct low-dose vitamin d on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult Scler Int. 2012;2012:452541.
- Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011;77(17):1611-1618.
- Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74(23):1852-1859.
- Derakhshandi H, Etemadifar M, Feizi A, et al. Preventive effect of vitamin D3 supplementation on conversion of optic neuritis to clinically definite multiple sclerosis: a double blind, randomized, placebo-controlled pilot clinical trial. Acta Neurol Belg. 2013;113(3):257-263.
- Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(5):565-571.
- Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(9):1294-1296.
- Thouvenot E, Orsini M, Daures JP, Camu W. Vitamin D is associated with degree of disability in patients with fully ambulatory relapsing-remitting multiple sclerosis. Eur J Neurol. 2015;22(3):564-569.
- Ramagopalan SV, Maugeri NJ, Handunnetthi L, et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 2009;5(2):e1000369.