University of Maryland Rounds features clinical and research updates from the University of Maryland School of Medicine and the University of Maryland Medical Center.

Intended for physicians, Rounds contains contact information to learn more about the clinical and research advances featured in each issue. It is printed three times a year and distributed monthly via email.

With vitamin D’s health benefits for conditions such as heart disease, cancer and diabetes becoming increasingly clear, a University of Maryland physician-scientist has spent years plumbing the potential role of the “sunshine vitamin” in the development, prevention or treatment of multiple sclerosis in ways that directly help his own MS patients.

Walter Royal III, MD, director of the Maryland Center for Multiple Sclerosis Treatment and Research and a professor of neurology, anatomy and neurobiology at University of Maryland School of Medicine, has long been interested in uncovering non-genetic factors, such as environment or diet, that influence MS progression. It’s a fascination that has forged a winding research trail: Dr. Royal’s lab has investigated the immune markers of MS disease progression, as well as the ways that not only vitamin D, but also vitamin A and cigarette smoke, impact immune cell behavior in this incurable autoimmune disease.

With an active roster of MS patients also under his care, Dr. Royal’s bench-to-bedside research offers him an unusual perch from which to view advancements in MS — which affects roughly 250,000 Americans — that also sets University of Maryland apart.

“There are a number of researchers interested in the link between vitamin D and MS, but I’d say we have the capability to look at the issue from a number of different dimensions,” says Dr. Royal, also the research associate director for the VA Multiple Sclerosis Center of Excellence-East in Baltimore and an author of a number of published papers on not only MS, but also topics such as neurocognitive impairment related to HIV infection. “We view it from both the basic science and clinical aspects in the context of MS, as well as other nervous system inflammatory disorders.”

Worldwide Focus on Vitamin's Role

It’s been more than a decade since the link between MS and vitamin D — typically consumed in foods and supplements, and converted to an active form in the body by enzymes and the sun’s ultraviolet light — was established in scientific literature, and the association has only strengthened since then.

Studies around the world have linked vitamin D deficiency to an increased risk of developing MS, and the acclaimed Nurses’ Health Study showed that an increased intake of vitamin D, either in food or supplements, was tied to a lower risk of MS. Other research analyzing blood samples from military personnel indicated that those with the highest levels of vitamin D had the lowest risk of developing the condition, in which the immune system attacks the fatty myelin sheath protecting nerve cells in the brain and spinal cord.

Higher vitamin D levels have been tied to lower numbers of new MS lesions in the brain as well as less brain atrophy. Although greater levels of the vitamin have not been clearly linked to a lower chance of relapse, individuals with MS have been found to have lower levels of immune activity against brain antigens.

“Vitamin D affects the immune system, regulating a number of different genes important in immune cells being activated to generate an autoimmune response,” Dr. Royal explains. “It has a number of different effects. It seems to be important in decreasing cardiac disease risk, different cancer types and diabetes, among others, and many effects are overlapping. So my interest in vitamin D is very strong, falling in line with my interest in nutrition and non-genetic environmental factors in determining MS disease course.”

Royal's Research Still Unfolding

Dr. Royal, who has spent more than 15 years investigating various aspects of MS, first observed its link to vitamin D in his own research as an offshoot of earlier work analyzing vitamin A’s role in the disease. He and colleagues found that a vitamin A deficiency was associated with higher odds of developing MS, with an analysis of relapsing-remitting MS patients showing lower levels of vitamin A in the blood of those being treated with interferon beta, one of the standard drugs used to slow MS progression.

Lower vitamin A levels in blood were associated in Dr. Royal’s research with having the relapsing-remitting form of MS, the most common type of the disease, which waxes and wanes over time. The receptor is known to be a “partner” receptor for other immune receptors involved in MS, including vitamin D. It was also found that there was altered expression of a specific vitamin A receptor subtype called retinoid X receptor (RXR). This receptor is expressed in the cytoplasm of cells, including immune cells where they receive chemical signals and then subsequently traffic into the nucleus.

The link between vitamin D and MS disease risk fueled a bevy of vitamin D-related studies by Dr. Royal and colleagues, including 2010 research showing that levels of childhood sun exposure and the intake or absence of cod liver oil supplements could predict the age of onset of MS. As with his other work, the research was enhanced by Dr. Royal’s role at the VA Multiple Sclerosis Center of Excellence-East, where he has ready access to an additional population of MS patients and databases.

“I still have a strong interest in vitamin D and MS, and there are several clinical trials currently underway at other institutions. Here at the University of Maryland and the VA, we are looking at approaches to treating patients with vitamin D analogs to see if it impacts the MS disease course,” he says. “Information along those lines is starting to come out from other studies, and I think that will be the wave of the future when it comes to assessing the effects of vitamin D and its benefits.”

Newer Focus on Effects of Smoke Exposure

Other recent research by Dr. Royal has focused on the effects of cigarette smoke on MS, with the disease risk found to increase either by smoking or exposure to second-hand smoke. A partnership with UMMC cardiologists — who were analyzing in mice the effects of cigarette smoke on rejection rates of heart transplants — found the animals’ physiological reactions similar to autoimmune responses.

“Now we’re looking at the effects of smoke itself, nicotine, and the combination of the two,” Dr. Royal says. “MS has, for some time, been thought to be a disease of an industrialized society, so this could be an important link. We have a lot of work to do.”

However, his research findings already affect MS patients he treats every day.

Vitamin D levels are often low in MS patients, and doctors typically prescribe supplements to bridge the gap. The results of Dr. Royal’s 2010 research implied that the strategy could be effective in changing the course of the disease, and that children of MS patients — who stand a higher-than-average risk of developing the disease — should also receive vitamin D supplementation. So he recommends vitamin D supplements to his patients and their families and keeps tabs on the vitamin in their blood levels through regular testing.

“My research allows me to give them advice directly based on what we’re learning at the bench,” Dr. Royal says. “Physicians would want to give vitamin D in addition to other FDA-approved MS therapies. We would hope the combination could help stabilize their disease and decrease their risk for disease progression.”

Dr. Royal can be reached at 410-328-5606.

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