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. 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 Mowry and colleagues 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 individuals had and their risk for developing MS.
An important longitudinal cohort study presented in 2012 by Mowry and colleagues 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.
Meanwhile, the SOLAR study randomized 229 individuals who were on high-dose interferon beta-1a therapy either to high-dose Vitamin D3 (14,000 IU daily) or placebo. Originally, the study was planned to be 96 weeks, but because of challenges with recruitment, the study was 48 weeks. The primary endpoint of the study was disease-activity-free (DAF) status at week 48. DAF was defined as having no relapses, no new MRI lesions, and no worsening of disability.
This study did not find a difference in DAF status between the high-dose vitamin D3 group and the placebo group. While no difference was seen in the relapse rate, a 32-percent decrease was found in the number of new lesions in the Vitamin D3 group versus the placebo group. It is possible that the small study size precluded more significant results. The finding of a decrease in new lesion formation in the Vitamin D3 group is intriguing and deserves further study. However, as evidenced by the SOLAR study, in order to definitively answer the question of whether Vitamin D3 has a protective role in MS, it will be critical to design studies that are large enough and able to obtain full recruitment.
The French CHOLINE Phase II study 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 individuals 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. Mowry and colleagues at Johns Hopkins are currently running a multi-center clinical trial in which people 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.67
Participants 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 ongoing.
One trial of particular interest that is currently running in Australia and New Zealand, PrevANZ, is a Phase II study looking at whether Vitamin D supplementation can decrease a person’s risk for developing MS after a first demyelinating event (CIS). Although the associations between MS and Vitamin D deficiency have been well-documented, it is still not clear if giving a patient Vitamin D supplementation can actually impact the course of the condition.
Another study, reported at the ECTRIMS-ACTRIMS Meeting in 2017, followed 200 individuals with MS during a period of 12 months. The study assessed how Vitamin D levels affected quality of life as measured by a standardized questionnaire developed specifically for people with MS. At baseline, 92 percent of the participants had a Vitamin D level at or below 30 ng/mL, and so were given supplements to raise those levels. The study found that increasing Vitamin D levels was associated with significant improvement in self-reported quality of life across all areas measured by the questionnaire.68
Although 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 consult their physician before making any changes to their treatment plan.
A pilot trial of lipoic acid supplementation reported a positive result in SPMS in 2016. Researchers from Oregon conducted a two- year study that followed 27 individuals with MS who were given lipoic acid, and 24 patients who were given placebo. Lipoic acid is a readily available antioxidant supplement thought to aid the function of mitochondria, which are cell structures that break down nutrients to create energy.
After 96 weeks, the researchers found that the participants in the lipoic acid group had significantly less brain-volume loss and were able to walk faster than the placebo group. Overall, the drug was well-tolerated, though stomach symptoms were higher in the lipoic acid group. Two patients in the lipoic acid group had kidney issues during the trial, however, a kidney doctor thought this was unrelated to the lipoic acid treatment.69
Accelerated brain-volume loss has been linked to worsening in progressive MS. The findings of this trial suggest that lipoic acid may offer neuro-protection by slowing down this process. Larger studies will have to be completed to see whether lipoic acid works, not only to slow down brain loss as seen on MRI, but also to slow down the clinical progression of MS.
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 individuals 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 individuals were randomized to high-dose biotin or placebo.
The primary endpoint of the study was defined as the proportion of participants 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 participants in the MD1003 arm showing an improvement of EDSS or T25FW at nine months and confirmed at 12 months, compared to none of the people 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 were 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 that they would be virtually undetectable in clinical practice. MD1003 was well-tolerated. The overall incidence of adverse events was similar across the two groups.70
However, a smaller, single-center Italian study reported in October 2017 raised potential concerns about use of biotin in progressive forms of multiple sclerosis. The investigators followed 41 individuals with either PPMS (39 percent of the participants) or SPMS (61 percent) who were treated with 300 mg daily of biotin. Following a mean treatment period of 13.7 months, the annualized relapse rate for the group increased from 0.10 in the prior year to 0.27 on treatment. Nine patients – or 22 percent of the group – had relapses during the treatment period, with some having more than one relapse during that time. Most of the relapses required treatment with steroids, and four left residual disability. Seven of the 41 patients had MRI evidence of disease activity. In 28 of the participants who took biotin for 12 months or more, only one had an improvement in EDSS score, while the score remained stable in 17 of the participants (61 percent of the group), and worsened in 10 individuals (35 percent of the group).71 Again, these results are from a study conducted at a single center and with a small number of patients, but the findings are troubling nonetheless.
A Phase III study (SP12) involving 600 individuals with progressive MS will hopefully clarify the concerns and questions raised by the Italian study. The study began in late 2016 and will include people with either PPMS or SPMS who have shown signs of worsening in the past two years. Participants will be given either high-dose biotin (100 mg three times daily) or placebo, and will be followed for 15 months to see if differences in progression or walking speeds are observed in the biotin group as compared to the placebo. Following the initial 15-month study, both groups will then be given the high-dose biotin and followed for an additional 12 months.