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Vitamin D Supplementation Shows Benefits in Multiple Sclerosis, but Questions Remain

Web Exclusives: Value-Based Care - April 2017 - Multiple Sclerosis
Caroline Helwick

Orlando, FL—A growing body of evidence supports vitamin D as a dietary factor associated with multiple sclerosis (MS). The question remains, however, whether low serum levels of vitamin D may predispose patients to MS, or whether low levels are a part of the disease, and whether supplementation is really protective. Regardless, the data are suggestive enough to make vitamin D supplementation part of MS management, according to Ellen Mowry, MD, Associate Professor of Neurology, Johns Hopkins University, Baltimore, MD, who discussed the topic at the 2017 Americas Committee for Treatment and Research in Multiple Sclerosis meeting.

Two major prospective studies have concluded that levels of serum vitamin D are related to a diagnosis of MS. One study included US military personnel,1 and the other was a study of patients from northern Sweden.2 Both studies measured serum 25-hydroxyvitamin D and showed a 50% to 60% reduced risk for MS among individuals with the highest levels.

The protective threshold was approximately 40 ng/mL. Whether this indicates a preventive effect, per se, is not clear. If it does, how much vitamin D is optimal, and when in the life span should it be given, and for how long? These are unanswered questions, said Dr Mowry.

Vitamin D Is Prognostic

Early exposure to sufficient vitamin D levels is important. In fact, protection may actually begin in utero. A 2016 study from Finland showed that low maternal levels (<12 ng/mL) is associated with an increased risk for MS in their offspring.3 Another recent case-control study of newborns showed a 47% reduced risk for MS for babies in the highest quintiles at birth.4 A study of pediatric-onset MS showed a 34% reduced risk for MS relapse for every 10-ng/mL increase of serum vitamin D.5

Evidence of inflammatory activity, in the form of magnetic resonance imaging changes, is also linked to vitamin D levels, according to Dr Mowry’s own studies. For every 10 ng/mL of serum vitamin D, gadolinium-enhancing lesions were reduced by 32% and new T2 lesions were reduced by 15% in a study that adjusted for age, sex, ethnicity, smoking status, and the use of disease-modifying therapies.6 In another study, Dr Mowry found that higher levels of serum vitamin D correlate with less loss of gray matter, which is a marker for brain atrophy.7

Benefit Harder to Show in Randomized Trials

The limitation of these findings, she acknowledged, is that most of the data come from observational studies. Although some randomized trials have demonstrated an association, others have not.

In one study of 66 patients with relapsing-remitting MS, those who were randomized to 20,000 IU of vitamin D3 weekly for 1 year experienced significantly fewer enhancing T1 and new T2 lesions and a trend for lower disability scores.8 A number of other randomized trials, however, have not shown significant benefits in terms of reduced rates of relapse and disability.

“Most have been small pilot studies, and while they have shown no impact, they have been small studies of short duration,” Dr Mowry pointed out.

She added that she is encouraged by the results of in vivo experiments demonstrating reductions in multiple inflammatory markers with vitamin D supplementation.9 “The change in these markers mimics treatment with interferon,” Dr Mowry commented.

In the large SOLAR trial, which evaluated the addition of vitamin D3 oil as an add-on to interferon beta-1a, a trend was observed for fewer relapses with vitamin D3 than with placebo, and there were significantly fewer new gadolinium-enhancing or T2 lesions observed with treatment.10

Dr Mowry hopes to confirm the benefit of vitamin D supplementation in a new trial she is leading—Vitamin D to Ameliorate Multiple Sclerosis (VIDAMS)—which will randomize patients who received glatiramer acetate to also receive oral vitamin D3 as either 5000 IU daily or 600 IU daily. It is not clear how high of a dose is needed for a protective effect, she said.

Other randomized trials are also evaluating vitamin D3 supplementation, including the CHOLINE, VITADEM, EVIDIMS, PrevANZ, and D-Lay-MS studies. The doses of vitamin D3  in these studies range from 4000 IU daily to 100,000 IU daily.

Supplementation Is Advised

“Randomized trials will provide critical information about the role of vitamin D supplementation in people with MS,” she said. In the meantime, it is good practice to prescribe supplementation, according to Dr Mowry and other experts speaking at the session.

Dr Mowry advised aiming for serum 25-hydroxyvitamin D levels of 40 ng/mL to 60 ng/mL, which can usually be achieved with doses of 2000 IU to 4000 IU daily. “Carefully consider risks versus benefits in those at risk for excess vitamin D,” she added. “In an otherwise healthy person, 5000 IU/day gets most patients into the normal range.”

Some specialists at the session said they simply prescribe 5000 IU of vitamin D daily to all patients, although other specialists indicated that some patients may need up to 15,000 IU daily. Vitamin D3 is preferred over vitamin D2, which is less potent.

Despite the benefits shown or suggested for vitamin D supplementation, Dr Mowry added a note of caution. “The safety and efficacy of vitamin D supplements for MS, or for its prevention, is still not really known.”


References

  1. Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296:2832-2838.
  2. Salzer J, Hallmans G, Nyström M, et al. Vitamin D as a protective factor in multiple sclerosis. Neurology. 2012;79:2140-2145.
  3. Munger KL, Åivo J, Hogell K, et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. JAMA Neurol. 2016;73:515-519.
  4. Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: a population-based case-control study. Neurology. 2017;88:44-51.
  5. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010;67:618-624.
  6. Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72:234-240.
  7. Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016;23:327-332.
  8. 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;83:565-571.
  9. Sotirchos ES, Bhargava P, Eckstein C, et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology. 2016;86:382-390.
  10. Smolders J, Hupperts R, Vieth R, et al. High dose cholecalciferol (vitamin D3) oil as add-on therapy in subjects with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a. Presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 14-17, 2016; London, United Kingdom.
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