Seasons in the sun: The relationship between vitamin D and MS
By Erik Greb
About one in every three patients with multiple sclerosis (MS) uses complementary medicine in addition to conventional disease-modifying therapy. Besides treatments that require a provider, such as acupuncture and chiropractic therapy, complementary medicine encompasses special diets, herbs, and supplements. Some patients take vitamin D in the belief that it not only promotes general health but also may counteract the effects of MS. Researchers are trying to determine whether this belief is justified.
Interest resulted from epidemiologic studies
Among the observations that first sparked interest in the relationship between vitamin D and MS was that the prevalence and incidence of MS increases with distance from the equator. MS is more prevalent in the United Kingdom, for example, than in Venezuela. Other epidemiologic studies demonstrate that the relationship between prevalence and latitude holds within individual countries as well.
Investigators proposed UV light exposure as a potential explanation for this association. “Vitamin D requires UV light exposure for its biosynthesis into active forms of vitamin D,” said Daniel Ontaneda, MD, MSc, associate professor of neurology at the Cleveland Clinic.
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Further epidemiologic studies indicated that serum vitamin D levels are lower in people who develop MS later, compared with people who do not, said Bernhard Hemmer, MD, director of the neurology clinic at the Technical University of Munich.
In addition to these epidemiologic observations, “experimental studies suggested that vitamin D has a role in immune function, as shown in experimental autoimmune encephalomyelitis [EAE] models,” said Iris V. Marin Collazo, MD, a neurologist at the Mayo Clinic in Jacksonville, Fla. In MS, the immune system breaks down the myelin sheath that covers nerves. EAE is the model that MS researchers use to conduct animal studies. “Since then, multiple studies have addressed the role of vitamin D in MS. Large studies, such as one by Munger et al., including nurses and military personnel found that those with higher level of vitamin D have lower risk of developing MS,” said Dr. Marin Collazo.
Dr. Daniel Ontaneda
Establishing an association is one thing, but “demonstrating causality is a little bit more difficult, especially because vitamin D is something that we’re exposed to throughout our lives,” said Dr. Ontaneda. “When we measure [vitamin D] in an MS patient, we’re measuring it in a snapshot.” This technique may not provide a reliable indication of a patient’s vitamin D level over a longer period.
Vitamin D modulates the immune system
Vitamin D regulates more than 200 genes and affects several bodily systems. It has direct effects on the immune system and the CNS, although the direct effects in the brain are not as clear. Studies suggest that vitamin D offers neuroprotection and promotes brain growth factors. “More importantly, we think that indirect effects on the immune system are what determine the benefits of vitamin D in MS,” said Dr. Ontaneda.
Dr. Bernhard Hemmer
The current hypothesis is that vitamin D exerts most of its influence on MS through immune-mediated mechanisms. Specifically, vitamin D influences the balance between proregulatory and proinflammatory helper T cells. Low levels of vitamin D appear to promote a proinflammatory immune response. Epidemiologic data indicate that patients with MS have lower vitamin D levels than matched healthy controls, said Dr. Ontaneda. “Even within patients with MS, it turns out that people who have lower levels of vitamin D have more measures of inflammation and inflammatory disease activity.”
Among vitamin D’s other effects on the immune system are its roles in lymphocyte activation and proliferation and in the production of antibodies, said Dr. Marin Collazo.
Low vitamin D levels may be related to lifestyle changes during the prodromal phase of MS, rather than a cause. “There is a prodromal phase before the first symptoms of MS occur,” said Dr. Hemmer. “During this phase, patients do behave differently than controls. These differences occur 5 or even more years before disease onset. Different behavior might also affect sun exposure and, thus, vitamin D levels.”
Data indicate potential effects on MS
Several investigations, such as those by Mowry et al. and Ascherio et al., have found that vitamin D improves clinical and radiographic outcomes in patients with MS. A large, international cohort study that included 2,000 subjects found that intentional sun exposure and higher doses of vitamin D supplementation were associated with lower levels of disability. “A longitudinal study including 469 patients with MS found that those with higher levels of vitamin D have lower risk of new T2 hyperintensities or gadolinium-enhancing lesions on MRI,” said Dr. Marin Collazo. “Another cohort study found that the levels of vitamin D in patients with clinically isolated syndrome were inversely associated with risk of conversion to MS, disease progression, and new radiographic activity.”
But these studies, of course, have limitations. The main limitation is that vitamin D levels change throughout life, depending on sun exposure and vitamin D supplementation, but vitamin D often is measured at a single time point. “I might say I’m going to assign a group to only take 800 IU of vitamin D, and then I’m going to assign another group to take 5,000 or 10,000 IU of vitamin D a day,” said Dr. Ontaneda. “Then a person in the group who was randomized to 800 IU spends a day at the beach. All of a sudden, your exposure changes completely. That’s one of the inherent difficulties about conducting a trial with vitamin D: controlling your exposure variable.”
Furthermore, a patient could begin taking vitamin D supplementation, but changes in the body during the time before supplementation, and the clinical implications of these changes, are not known, Dr. Ontaneda added. “Did that [period before supplementation] have long-lasting effects on the immune system? Could that confer risk in MS that might not be significantly changed with supplementation, once the diagnosis is made?”
When Munger et al. examined the blood of pregnant women, they found that maternal levels of vitamin D predicted the child’s risk of MS. Babies born to women who were pregnant during the spring and summer have a lower risk of MS than babies born to women who were pregnant during the winter. “The question is, if one performs a 2-year clinical trial and gives somebody vitamin D supplementation, how likely is that short course to mitigate long-standing effects?” asked Dr. Ontaneda. “The effects might last a little bit longer than what we can adjust for in a clinical trial.”
The question remains to be settled
Many studies have failed to demonstrate an effect of vitamin D supplementation on MS outcomes. “The SOLAR trial did not find positive results regarding disease activity on [patients] treated with high-dose vitamin D versus placebo after 1 year,” said Dr. Marin Collazo. “The CHOLINE trial did not find that high doses of vitamin D would lead to lower annualized relapse rate.”
The effect of vitamin D on MS is still an open question, but a large, ongoing clinical trial sponsored by the National MS Society could shed additional light on it, said Dr. Ontaneda. In the study, patients are treated with a low or high dose of vitamin D in addition to glatiramer acetate. This multicenter study probably is one of the largest to date that has investigated the relationship of vitamin D to MS, he added. The researchers adjusted their methodology to avoid the difficulties that other studies have encountered. “If, despite those methodological steps, you still don’t have a positive trial, that’s when you ask yourself: ‘Are we ever going to be able to answer this question?’” said Dr. Ontaneda.
Large, longitudinal controlled studies would help to settle the question, said Dr. Marin Collazo. Investigators might choose to randomize participants to a level of vitamin D rather than a dose. This approach could help reduce variations in exposure.
In the future, researchers will be able to examine large amounts of longitudinal data to determine the risk of MS according to vitamin D level. Such research would integrate health and medical records, including consecutive measures of vitamin D levels over time, in a large observational study. This method “is probably going to be one of the promising avenues for future research,” said Dr. Ontaneda.
That’s one of the inherent difficulties about conducting a trial with vitamin D: controlling your exposure variable.
Should patients with MS take vitamin D?
“Despite the contradictory evidence, neurologists should consider advising patients with MS to take daily vitamin D supplementation,” said Dr. Marin Collazo. “I usually recommend a maintenance dose of between 2,000 and 5,000 IU daily.”
“Our practice at the Mellen Center at the Cleveland Clinic is that we typically would check the level and then prescribe vitamin D, based on where that level is,” said Dr. Ontaneda. Vitamin D does not have significant side effects and is well tolerated if the target level remains within a safe range, which is comparatively wide, he added.
“High doses of vitamin D over an extended period of time can result in toxicity, therefore baseline and routine monitoring of vitamin D levels in serum should be considered,” said Dr. Marin Collazo.
“High-dose vitamin D has not been investigated in proper trials, although some people promote such a treatment,” said Dr. Hemmer. “I usually discuss vitamin D with the patient and test vitamin D serum levels. If the patient has low levels, I discuss with her or him the level of evidence, and if the patient still wants vitamin D, I prescribe it.”
The range of vitamin D levels that is considered normal may be too low, since it was established through observations of a population that works indoors and has limited sun exposure. “We tend to target levels above a normal level,” but below the level of toxicity, said Dr. Ontaneda.
“Our prevailing view is that vitamin D does have a role [in MS], but it might be difficult to demonstrate that in a clinical trial,” he continued. “And it might be that vitamin D has long-standing effects that, despite supplementation, we might not be able to overcome completely.”
Ascherio A et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014;71(3):306-14.
Mowry EM et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-40.
Munger KL et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-8.
Munger KL et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. JAMA Neurol. 2016;73(5):515-9.
Smolders J et al. An update on vitamin D and disease activity in multiple sclerosis. Review CNS Drugs. 2019;33(12):1187-99.