Vitamins and Electrolytes
New Directions in MS Research: New Therapeutic Approaches
Vitamin D is a type of hormone and a powerful mediator of immune function. The data documenting an association between low Vitamin D and high MS risk, relapses, disability, and CNS inflammation now appear to be strong, consistent, and reproducible.47 Data from a number of areas of investigation suggest that Vitamin D may be one underlying common factor that begins to make sense of the large amount of data on the geographic distribution of susceptibility to MS.
Genetically, a link appears to exist between changes in the genes involved in the synthesis of the Vitamin D hormone and the Vitamin D hormone receptor, and the risk of developing MS. The strongest genetic risk factor for MS is a specific gene (HLA DRB1*1501), whose activity appears to be influenced by Vitamin D. A study published in 2015 by Mokry and colleagues48 provided new insights about genetics and Vitamin D. This study identified four genetic variants, each correlated to a lower Vitamin D level. Using these variants and data obtained from the largest genetic association study to date of MS, conducted by the International Multiple Sclerosis Genetics Consortium, the authors found a direct relationship between the number of Vitamin D-lowering variants that an individual had and their risk for developing MS.
In animal models of MS, Vitamin D was found to directly terminate the production of disease-causing proteins, which may shed light on the mechanism of Vitamin D in MS. When Vitamin D is given to mice with EAE (an animal model of MS), it blocks the gene that encodes IL-17, stopping its production. This study also demonstrates that Vitamin D increases suppressive T cells that combat inflammation.
An important longitudinal cohort study presented in 2012 by Mowry and colleagues49 found that in people with MS, each 10 ng/ml higher Vitamin D level was associated with a 15-percent lower risk of a new T2 lesion, and a 32-percent lower risk of a gadolinium-enhancing lesion. Higher Vitamin D levels were associated with lower, but not statistically significant, relapse rates. While this was not a randomized treatment trial, it suggests that higher levels of Vitamin D may exert a protective role against MS-disease activity.
Similar data were presented in 2013, as researchers looked at how Vitamin D may play a role in MS development and disease activity on a molecular level. The BENEFIT trial studied the effects of Betaseron in patients with CIS. Blood samples were taken at various intervals, along with MRIs.
This study found that individuals with higher Vitamin D levels had lower numbers of gadolinium-enhancing lesions. These individuals generally experienced less disease activity, and genes associated with these higher Vitamin D levels appear to be involved. Studies indicate that roughly 350 genes are “significantly associated” with MS activity, and of these 350 genes, 155 are associated with Vitamin D regulation. The authors of this study explain that Vitamin D may directly and indirectly regulate gene expression in a manner that reduces MS activity.
A number of new clinical trials, mostly using Vitamin D as an add-on to existing therapies in Phase IV studies, are ongoing to assess if supplemental Vitamin D can exert such disease-modifying effects. To follow are examples of these types of investigations.
Mowry and colleagues at Johns Hopkins have initiated a multi-center clinical trial in which patients with relapsing-remitting MS will receive high-dose (5,000 IU/day) or low-dose (600 IU/day) oral Vitamin D, in addition to Copaxone.50 Patients will be evaluated for two years, and the effect of high-dose Vitamin D supplementation on the rate of MS attacks as well as on the number of new lesions and changes in brain volume on MRI will be determined. This trial is presently enrolling, with a goal of 172 participants, and is expected to run through June 2018.
A Phase II study51 investigated whether Vigantol® oil, a form of Vitamin D hormone supplement (cholecalciferol), provides any added benefit when given in conjunction with Rebif. The study had 348 participants and began in February 2011. Primary outcome measures are the mean change from baseline in the total volume of T2 lesions at week 48 and the proportion of relapse-free subjects at week 96. Secondary outcome measures include sustained disability progression, MRI measures of disease progression, proportion of subjects free from disease activity at 96 weeks, and changes in cognitive function. Although this study was completed in 2015, results are not yet available.
The French CHOLINE Phase II study52 recruited 250 individuals with RRMS who were already receiving ongoing treatment with Rebif. The aim of this study was to evaluate the efficacy and safety of supplementary treatment with Vitamin D3 in people with RRMS treated with Rebif.
The study participants were divided into two groups: one receiving Vitamin D3 100,000 IU twice monthly along with Rebif treatment, and the other group receiving placebo along with Rebif treatment. Its primary outcome measure is a reduction in relapse rate. Secondary outcome measures include: the time to a first documented relapse; the mean number of relapses per subject per year; the number of relapse-free patients after two years of treatment; MRI measures of progression and lesion load; and change in quality of life. The CHOLINE study began in January 2010 and was completed in 2015, but results have not been reported.
Please note that while no major safety issues have been reported with these larger daily doses of Vitamin D3 (such as 5,000 to 10,000 IU/day), as with all medications and supplements, individuals should always consult their physician before making any changes to their treatment plan.
Biotin is a vitamin involved in key steps of energy metabolism and fatty acid synthesis, though most people think of it as being “good for hair and nails.” Among other actions, biotin activates an enzyme in myelin synthesis. Using this hypothesis and building upon data from a small, open-label pilot study, MD1003, a high-dose biotin preparation of 300 mg per day, was studied in a Phase III trial of patients diagnosed with SPMS or PPMS. (This dose is hundreds of times higher than what can typically be purchased as a supplement of this vitamin.) In a relatively small study, 154 patients were randomized to high-dose biotin or placebo.
The primary endpoint of the study was defined as the proportion of patients who improved at nine months, with a confirmation of the improvement at 12 months. Improvement was defined as either a decrease in EDSS (Expanded Disability Status Scale) or an improvement in T25FW (timed 25-foot walk) of at least 20 percent.
The primary endpoint was met, with 12.6 percent of patients in the MD1003 arm showing an improvement of EDSS or T25FW at nine months and confirmed at 12 months, compared to none of the patients in the placebo arm. The primary endpoint was supported by secondary analyses showing evidence for a decrease in the risk of disease progression. These numbers are encouraging, although it is important to note that the decrease in disability experienced by the MD1003 group, and the disease progression seen in the placebo group, were both so small, they would be virtually undetectable in clinical practice. MD1003 was well-tolerated. The overall incidence of adverse events was similar across the two groups. One patient treated with MD1003 died from suicide; however, this event was not considered to be related to the drug.
These results suggest a possible therapeutic effect of high-dose biotin in progressive MS, and merit further study. Noting that the dose of biotin studied would require taking hundreds of commercially available vitamin pills, it is not generally recommended that patients begin such a regimen at the present time. Studies also need to determine if any toxic effects could result from taking such high doses of this vitamin.
An array of recent research ranging from molecular studies to animal models and even some preliminary human data, has implicated levels of dietary salt – sodium chloride, or NaCl – as potentially affecting MS outcomes. In research presented in 201353, high dietary salt was found to increase autoimmune neuro-inflammation by markedly boosting a Th17 helper T-cell-driven autoimmune response in EAE (an animal model of MS). Th17 is an immune-system cell (lymphocyte) involved with the inflammation that causes damage to the myelin and nerves with MS. This Th17-boosting property of dietary salt was also seen in humans.
In a separate study,54 higher-salt consumption was associated with increased clinical and MRI disease activity in people with MS. Seventy patients with RRMS were followed over two years, tracking sodium intake. This was in conjunction with clinical and MRI assessment every three-to-six months or at the time of relapse. Researchers found that individuals with high-sodium intake had 3.4-times greater odds of developing a new lesion on the MRI, and on average, had eight more T2 lesions on MRI. MS relapse rates were higher among those with high-sodium intake as well.
In 2015, many additional studies were published showing a connection between salt and MS.55 Krementsov and colleagues fed high-salt and low-salt diets to three genetically different groups of mice and compared their EAE disease course. The researchers showed that in certain strains of mice, high-salt diets led to worsening of EAE. Furthermore, in one strain of mice, this effect was gender-specific, occurring only in females. Because the investigators did not find an alteration in the Th1/Th17 ratio mentioned above, they postulated that the salt caused an increased permeability of the blood-brain barrier leading to attacks by the immune system.
Two other studies were able to show a change in immune cells after exposure to high-salt environments. Hafler and colleagues showed changes in a cell type important for the regulation of the immune system called the “Treg” cell. The Treg cell is thought to play a key role in suppressing those cells that might initiate autoimmune disease. The researchers found the effect of decreased Treg function both in individual cells exposed to high salt as well as in mice fed a high-salt diet.56
Muller and colleagues looked at a different type of immune cell that is important in MS: the macrophage. A macrophage is a type of white blood cell that works to ingest and destroy foreign substances. In cells, they found that a certain type of macrophage was less able to block the autoimmune activities of damaging T cells in a high-salt environment. In mice, they found that a high-salt diet led to decreased abilities of macrophages to aid in wound healing.
The theory that salt may increase MS inflammation remains to be proven, and interventional studies will need to be performed to establish causality. However, this theory could have far-reaching practical dietary implications for individuals with MS.