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 autoimmunity¹. 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^2–4. Through its protective effect against Th-1 and Th-17 cells⁵, vitamin D can reduce the extent of clinical disability in a MS mouse model⁶. Vitamin D also promotes the actions of T regulatory (T-reg) cells, a protective type of immune cell that can suppress autoimmune disease⁷. 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 remyelination^8–10. Combined, the immunomodulation and oligodendrocyte enhancement properties of vitamin D has shown to suppress the MS-like disease in mice¹¹.

Observational Studies

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 months¹². Supporting this link, a study conducted in Australia evaluated sun exposure and vitamin D levels with conversion to MS in individuals that experienced first symptoms of MS called clinically isolated syndrome (CIS). The study concluded that pre-onset sun exposure could be protective against conversion from CIS to MS¹³. 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 hemisphere¹⁴, while the opposite pattern is found in the southern hemisphere where the seasons are reversed¹⁵. 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 birth month has been debated, however, and scientific opinion is divided over whether it is an actual phenomenon or a statistical anomaly^16,17. Furthermore, research has shown an association between low vitamin D levels during winter months and increased number of relapses¹⁸. Similarly, a cross-sectional study determined that seasonal variation of 25(OH)D serum levels were reversely associated with clinical disease activity¹⁹. Interestingly, a retrospective study in Germany observed that vitamin D supplementation would be more efficient in winter/early spring, as it reduced the quarterly relapse rate in this season²⁰.

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 for different populations. A large cohort study of 200,000 women as part of the Nurse’s Health Study found that intake of 400 IU of vitamin D was associated with a 40 per cent lower risk of MS²¹. In another prospective study, Canadian children and adolescents presenting with demyelination had higher 25(OH)D levels, which were associated with a lower risk of MS²². Supporting this study, a powerful analysis method called Mendelian randomization was performed on pediatric-onset MS patients demonstrating that decreased vitamin D levels was associated with an increased risk of pediatric-onset MS in non-Hispanic white individuals²³. A U.S. prospective study of more than 7 million military personnel found a 51 per cent reduction in MS risk with 25(OH)D levels of 100 nmol/L or higher²⁴. 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 life²⁵.

Some of the strongest evidence to point towards a causal link between vitamin D and the risk of MS comes from genetic epidemiology studies. One study pooled genetic datasets from large European populations and used Mendelian randomization to test the association between 25(OH)D levels and MS risk²⁶. 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.

Another Mendelian randomization on a large population found that vitamin D deficiency could be the cause of MS, independent of other established risk factors²⁷. More recent studies revealed that variations in vitamin D-related genes could cause lower vitamin D levels and MS risk^28,29.

Some research also suggests that vitamin D deficiency may not only increase the risk of developing MS but may also affect 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 activity³⁰. A follow-up study by researchers at Harvard School of Public Health that enrolled individuals with CIS (over 80 per cent 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 progression³¹. 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 relapse³². Another 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 certain 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 rate³³. A Brazilian study on 136 MS patients also concluded an association between vitamin D deficiency (defined as < 20 ng/mL) and disease progression³⁴. Finally, a prospective study of 36 patients diagnosed with optic neuritis reported that neuronal and possibly axonal loss was associated with vitamin D deficiency³⁵.

Clinical Trials

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.

To date, four studies have revealed no significant therapeutic effect of vitamin D compared to the placebo control group^36–39, and one study found no significant effect of high-dose vs low dose vitamin D₂ supplement⁴⁰. In addition to these studies, SOLAR,a double-blind trial, randomly assigned either high-dose vitamin D or placebo (mock drug) to 229 people with MS. High-dose vitamin D was ineffective in changing disease activity, measured through relapses, disability progression and lesions. Similarly, the CHOLINE clinical trial failed to meet its primary outcome measure of change in the number of relapses following high-dose vitamin D compared to placebo.

Conversely, five studies have demonstrated benefit of vitamin D supplementation on MS outcomes, although the type of benefit depended on the study^41–45. The first study evaluated the safety of high-dose vitamin D₃ and showed preliminary evidence of reduced relapses and decreased immune cell activity⁴¹. 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 lesions⁴². In a third study, participants in a randomized, double-blind, controlled trial given vitamin D₃ 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 accumulation⁴³. The fourth study investigated natalizumab-treated participants with insufficient serum 25(OH)D levels and were advised to take vitamin D supplements which resulted in a significant decrease in annualized relapse rate⁴⁴. Finally, a study looking into the cognitive effects of vitamin D supplementation on participants administered interferon-beta showed improvements on some tests that measured visuospatial memory and mild cognitive impairment, however, was ineffective on other measures of cognition⁴⁵.

None of the clinical trials have reported adverse events such as toxicity at any of the tested doses of vitamin D₂ or D₃, and only one study resulted in mild adverse events when participants were given the active hormonal form (calcitriol)⁴⁶.

Further clinical trials to determine the efficacy of vitamin D as a treatment for MS are ongoing. The Efficacy of Vitamin D Supplementation in MS (EVIDIMS) trial is a phase II pilot study evaluating the effects of high-dose vitamin D₃ supplementation on brain lesions, inflammatory activity, disability progression and quality of life. Similarly, the Vitamin D to Ameliorate MS (VIDAMS) trial is a large-scale study evaluating the efficacy of high-dose vitamin D₃ in reducing relapse rate and disease activity in the brain while improving quality of life. These are two of several ongoing studies examining this important question.

• Click here to visit the news updates archive on vitamin D research in MS.

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 can, 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 sunlight⁴⁷. 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 treatment for MS symptoms and progression. However, it is difficult to reconcile the various findings of these studies, since they often use different dosing and formulations of vitamin D (D₂ 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 Contributions to Vitamin D and MS

Canadian Collaborative Project on Genetic Susceptibility to MS (2003-2007)

• 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) (2004-present)

• 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 II 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 was observed and the results of this work²³showed that children with low vitamin D status were more susceptible to developing MS, as were those with previous infection with Epstein–Barr virus and a genetic predisposition towards MS.

What does this mean for Canadians?

There are several things that all Canadians can do to maintain healthy levels of vitamin D:

• Talk to your healthcare provider about having your vitamin D levels checked. Your healthcare provider will be able to offer 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 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 healthcare provider 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 contain natural sources of vitamin D: fortified products such as milk, egg yolks, and oily fish like salmon, trout and sardines.

Vitamin D and MS Recommendations

The Multiple Sclerosis Society of Canada has launched evidence-based recommendations on vitamin D supplementation that can help people affected by MS make informed decisions about their health.

To develop these recommendations, the Society convened a panel of scientific and clinical experts as well as representatives from other national MS Societies and an individual living with MS to discuss the available evidence on the link between vitamin D and MS. Fruitful discussions between the panel of experts led to the development of evidence-based statements which formed the basis of the recommendations.

The MS Society recommendations provide information about the general role of vitamin D in the human body as well as reference the Health Canada recommendations, including sources of vitamin D. The purpose of these recommendations is to provide the suggested daily intake of vitamin D for various populations affected by MS including the at-risk population (children and adults with a biological relative diagnosed with MS), and individuals diagnosed with MS. In addition to the recommended daily intake of vitamin D, information on maintaining vitamin D levels is provided. Vitamin D levels are measured through a blood test. Comorbid conditions such as osteoporosis and vitamin D toxicity are also discussed in the recommendations.

Resources:

• Vitamin D and MS Recommendations (healthcare providers and scientific community)
• Vitamin D and MS Recommendations (patient community)

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