Editor’s note: This is the third story in a three-part report examining the question "Should vitamin D supplements be recommended for MS patients?", which was a topic discussed at this year's Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Here, we take an in-depth look at the arguments presented against vitamin D supplementation. *** Should vitamin D supplements be recommended for MS? "No," is the answer of Joost Smolders, MD, PhD, neurologist at the Dutch Canisius Wilhelmina Hospital and a researcher at the Netherlands Institute for Neuroscience (NIN). Not generally advisable. As an opponent to vitamin D supplementation in this ECTRIMS session, Smolders explained why he thinks it is not generally advisable to give to people with multiple sclerosis (MS). Some serious questions "require clarification before we really can confidently advise vitamin D supplements to our patients, with the goal to improve their long-term disease outcomes," he said. In several groups of patients, "low 25(OH)D [25-hydroxyvitamin D] levels predict the risk of relapses, and predict the risk of MRI [magnetic resonance imaging] lesions," but this has not been seen for all MS patients, Smolders emphasized. "Low vitamin D levels do not predict outcomes in all people with MS." In addition, studies in progressive MS are really lacking, he said. Why do people with MS have worse outcomes on MRI and relapse activity when they have low vitamin D levels? "There can be various explanations for this," Smolders said. "The most favorable hypothesis is that vitamin D has a dampening effect on the disease process of MS. This would also mean there could be a beneficial effect in supplementing vitamin D to your patients. But there are some other plausible mechanisms, for which there is some support in the literature." Plausible explanation: inflammation. "One of them is that inflammation by itself may lower vitamin D levels," Smolders said. He explained that if you stimulate white blood cells grown in the lab, they start to consume the vitamin D present in the culture system, lowering its levels. This "may also occur in vivo [in a living organ or organism]," he said. To support this hypothesis, Smolders and colleagues conducted a study in which healthy male volunteers were infused with lipopolysaccharide, or LPS, a bacterial sugar known to induce a "massive inflammatory response." Levels of vitamin D during the infusions and right after were followed. Results from nine healthy participants showed that during LPS-induced inflammation, "there is a small drop in 25D levels, which stays that low until we end treatment with LPS," Smolders said. "If this is also the case in humans on a normal situation, then low 25(OH)D levels should be associated with a range of inflammatory diseases." This is actually the case, he said. Low vitamin D levels have been associated with allergies, asthma, chronic infections, acute infections, and also autoimmune diseases, such as type 1 diabetes, lupus, and rheumatoid arthritis. Are these illnesses associated with low vitamin D and disease activity as in MS? It appears so. A recent study in people with Crohn's disease (an autoimmune disorder characterized by chronic inflammation of the bowels) showed that patients "with active disease also had lower 25D levels, which recovered when disease went into remission." Yet, whether inflammation lowers vitamin D levels in MS is still "a bit uncertain," Smolders said. Using brain tissue collected from deceased MS patients, Smolders and his team showed that in active, inflammatory MS lesions, the enzymatic machinery that metabolizes 25(OH)D into 1,25(OH)2D (the active form of vitamin D) has increased levels and is more active. "These data do not prove that inflammation-dependent loss of 25(OH)D explains all these associations, but at least shows that this is a plausible mechanism," Smolders said. Plausible explanation: sunlight's effect on MS risk. According to Smolders, another plausible explanation for the link between low vitamin D levels and poorer MS outcomes may result from deficient sunlight exposure. Plus, as UV light is the main source of vitamin D production in the human body, the low vitamin D levels observed could be a collateral effect of low sun exposure. More than 10 years ago, a study showed that "an increasing level of MS-related disability, as reflected by higher EDSS scores, was associated not only with lower vitamin D levels, but also with a lower amount of sunlight exposure," a link already seen at a stage when walking ability was not impaired, the researcher said. This shows that any MS-related outcome associated with increased disability and vitamin D "could be confounded by sunlight exposure;" moreover, sunlight exposure by itself can have "direct immunosuppressive effects in the human skin," Smolders noted. According to him, vitamin D-independent sunlight effects can be important. A recent study followed patients after a first demyelinating event (also referred to as clinically isolated syndrome, CIS), up to five years, and revealed that those pre-exposed to more sunlight "had a lower risk to convert to MS, and also a lower risk of subsequent relapses — and this was all independent of 25(OH)D measures," he said. Overall, "this could suggest that not vitamin D supplementation, but rather UV light exposure could be explored as a therapy for people early in their disease," Smolders said. Actually, a first attempt to test this potential therapy was performed already. A clinical trial assessed the feasibility of UV light phototherapy in people with CIS, and showed that 70% of those receiving phototherapy converted to MS, compared with 100% in the group with no phototherapy. However, this difference was not statistically significant. Despite these results, Smolders thinks the data really call on additional studies to be performed on this topic. Premature data on vitamin D impact on disease course. What is the effect of vitamin D on the MS disease course? Some genetic studies propose that variations associated with lower vitamin D levels also are associated with an increased risk of developing MS. A study in children with MS "showed that having an increased load of SNPs [small, point genetic variations] associated with lower 25(OH)D levels were also associated with a higher risk of relapses," suggesting a "biological effect of vitamin D on the disease process," Smolders said. Hower, these studies do not offer "a quantitive estimate of the effect of vitamin D supplementation. These studies do not tell us how much vitamin D we should supplement, and whether this results in a clinically relevant, meaningful improvement in the lives of people with MS," he added. To answer these questions, it is important to conduct well-designed clinical trials, but several of the completed or ongoing trials are flawed by limitations. Patients start with different baseline vitamin D levels, and receive different supplementation doses. Plus, in terms of patient sample, these trials "were all quite small," he said. The bottom-line conclusion is that clinical trial researchers who used MRI or relapse activity as their efficacy outcome measures "did not meet their primary endpoints," Smolders emphasized. Although some of the secondary goals suggest a benefit of vitamin D supplements, this is not enough to have "sufficient confidence to apply this on a large scale on people with MS." According to the researcher, the data available so far "are too premature to confidently advise vitamin D supplements to people with MS, with the aim to improve their long-term disease outcomes. We cannot fully interpret the associations found, and we currently do not know whom we should supplement, and with how much vitamin D." The only situation in which Smolders advocates for vitamin D supplementation is for MS patients with low vitamin levels "to prevent the loss of bone mineral density," he said.