Update: Risk Factors
American Academy of Neurology meeting report
SAN DIEGO—Life in the Western world has changed dramatically over the past 50 years. We spend more time indoors, eat more processed foods, have children later, and, unfortunately, fall prey to more autoimmune diseases than ever before. Could the changes in our lifestyle be contributing to the higher disease rate? At last month’s meeting of the American Academy of Neurology, researchers presented work that provided an update on risk factors for MS and indicated how these risk factors might help inform future therapies for MS.
Genes clearly influence one’s risk for MS and other autoimmune diseases, but the rapid growth in the rate of MS suggests that environmental factors must be involved as well (see “Nature, Nurture”). One clue came from the realization that those who live at higher latitudes—and see less sunshine—are at higher risk for MS. George Ebers, recipient of the John Dystel Prize at this year’s meeting, spoke about his extensive work indicating that vitamin D is the biological mediator at play (see “The Sunshine Suspect”). “If your shadow is taller than you are tall, you can’t make vitamin D,” Ebers said. The highest rate of MS in the world is now found in Scotland, where most people can’t make vitamin D even in the summer, he said. High rates of MS are also found throughout northern Europe, Canada, the northern United States, and New Zealand. A clue pointing to vitamin D insufficiency as a risk factor came from studies of half-siblings raised in the same or different households but in the same region. The work revealed that “the environment acts at a population level, because those [half-siblings] reared together versus apart had the same risk” for MS, Ebers said.
Many mysteries remain about vitamin D, according to Ebers. An as-yet-unexplained finding is that women are increasingly more susceptible than men to MS. “The sex ratio has been steadily changing from about one to one at the turn of the last century to over three to one in Canada today,” Ebers said. In Scotland, the rate of MS has tripled in that time in women while the rate in men hasn’t nearly kept pace. In Mediterranean Europe, he said, there’s still a much lower sex ratio, suggesting that the climb in women might be related to vitamin D deficiency. Why would lower levels of vitamin D have a greater adverse effect on women than men? That’s not known yet—and in fact the biological function of vitamin D remains poorly understood even in healthy systems, according to Ebers.
A study from Per Solberg Sorensen and colleagues at Copenhagen University in Denmark sought to address another factor that might underlie the growing discrepancy between the sexes: the tendency for modern women to have fewer children and have them later in life than their grandmothers did. Since 1970, the MS rate has doubled in Danish women while the rate in men has held steady. In many countries, first author Melinda Magyari said, “there is a general tendency for an increasing female-to-male ratio.” Could more childless years be increasing women’s risk of autoimmune disease? The researchers compared each of more than 1400 MS patients drawn from the Danish Multiple Sclerosis Registry to 25 randomly selected, matched control subjects from the Danish Civil Registration System, for a total of more than 30,000 people. They found that, within the 5 years preceding disease onset, MS patients “had significantly fewer childbirths than controls,” Magyari said. Other factors such as lifestyle and contraceptive methods were ruled out as contributing factors. “Pregnancy has a biological protective effect lasting up to 5 years,” she concluded, but added, “there may be unknown factors that independently increase the risk of MS and reduce fertility.”
Other groups also appear to be at a disadvantage when it comes to MS, which might also be rooted in vitamin D deficiency. A research group led by Omar Khan from Wayne State University in Detroit, Michigan, examined the relationship between vitamin D status and disease progression in African-American and Caucasian MS patients. African-American patients had a significantly higher level of disability and a greater lesion load than Caucasians. (MS has previously been established to have a more aggressive course in blacks than whites.) African-American patients had significantly lower vitamin D levels, and in both groups, a vitamin deficiency correlated with worse symptoms.
To look more closely at the effects of vitamin D, Jodie Burton and colleagues at the University of Calgary, Canada, asked whether vitamin D might help protect against neurodegeneration as well as inflammation, a role that had been previously established in many different studies. The researchers studied patients with optic neuritis in one eye, a condition commonly associated with MS that involves inflammation of the optic nerve during an attack, followed by its neurodegeneration in a separate biological process that becomes evident within 6 months. Optic neuritis provides a way to study inflammation and neurodegeneration independently of one another. The scientists used a technique called optical coherence tomography to measure swelling in the nerve during the acute, inflammatory phase, and then to measure retinal nerve fiber layer (RNFL) thickness 6 months later. Thinning of the RNFL in the affected eye would be an indication of neurodegeneration. Patients who were deficient in vitamin D had more acute inflammation and more degeneration 6 months after the attack than did patients who had sufficient levels of vitamin D.
Now that vitamin D insufficiency has been established as a risk factor for MS, can supplementation be used as therapy? A team led by Peter Calabresi at Johns Hopkins University in Baltimore, Maryland, took the first step toward answering this question with a study aimed at establishing the safety of high-dose vitamin D. The randomized pilot study’s 40 subjects, all with relapsing-remitting MS, received either a low dose (800 IU) or high dose (10,400 IU) of daily vitamin D for 6 months. (For comparison, the recommended daily allowance of vitamin D for those 70 years of age and younger is 600 IU.) Both doses of the supplement were safe and well tolerated in the study, and only a handful of subjects withdrew due to real or perceived side effects. An important finding, said first author Elias Sotirchos, was that subjects receiving the high dose had nearly doubled their levels of vitamin D in the blood by the end of the study, whereas those on the low dose saw only a very small increase. The effect of the supplement on vitamin D levels was “much more powerful and robust in the high-dose group, and that’s what we think will be necessary [for therapeutic use] in MS patients,” Sotirchos said.
Only two patients experienced a relapse during the study—one each from the high- and low-dose groups—but Sotirchos pointed out that the pilot investigation was not designed to measure clinical effects. Other ongoing clinical trials that are properly powered to see disease effects will better answer questions about whether high doses of vitamin D can improve outcomes. Sotirchos reported preliminary findings showing that markers of Th17 cells—a type of T helper cell that is known to contribute to MS pathology—decreased in patients receiving the high but not the low dose of vitamin D. The next step for the researchers will be to further analyze cytokine production and gene-expression patterns in the patients.
David Hafler, a neuroimmunologist at Yale University, said, “It’s clear that vitamin D and sunlight are likely to be one factor in disease. What are the others?” He and others in the field are finding one answer he said surprised him: salt intake (see “Salt Sampler”). “Diet and dietary influences may be much more important than certainly I ever thought was possible,” Hafler said. He presented findings from a body of work published last month (Kleinevietfeld et al., 2013). “The effect of salt on human cells in a test tube is dramatic,” Hafler said. The researchers isolated unspecialized human T cells and grew them in a salty solution mixed to mimic the cellular environment that would result from a high-salt diet. Compared to cells in a control solution, cells exposed to high salt were more likely to develop into pathogenic Th17 cells and express pro-inflammatory molecules like interleukin 17 (IL-17). In a related presentation, Ralf Linker, a collaborator at the University of Erlangen-Nuremberg, Germany, showed data from mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. After inducing EAE, the scientists fed mice either a normal or high-salt diet. Salt-gobbling mice developed earlier and more severe disease symptoms than did those on the standard diet; the salty foods seemed to act through the same pathway outlined in the human cells. Linker concluded, “A high-sodium diet aggravates neuroinflammation via IL-17-related mechanisms.” But diet doesn’t radically change the salt levels in the bloodstream, so how could it affect the cellular environment? Probably not globally, Linker said, but locally. The team suspects that the microenvironment of the small intestine might facilitate a change in the immune cells.
Can we reduce our disease risk by lowering our salt intake? That remains to be seen, Hafler said, but “we know [a low-salt diet] is good for your health anyway, and now the research hints” that it could lower MS risk. “These are things we can do that are clearly logical,” he said. Here’s hoping that by identifying risk factors, scientists can help reduce the odds of developing MS and other autoimmune diseases—and potentially identify new treatment strategies.
Key open questions
- Can high doses of vitamin D prevent MS or improve the outcome in established disease?
- What are the cellular mechanisms by which vitamin D protects against MS, or by which vitamin D deficiency increases vulnerability?
- Can people lower their risk for MS—or can those with the disease improve outcomes—by eating a diet low in sodium?