Vitamin D and Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease in which the immune system wrongly targets myelin, a protective sheath around nerve fibers that is important for neuronal communication.

The exact causes of MS are unclear, but multiple interconnecting factors are known to play a role. Vitamin D deficiency is an important environmental factor thought to contribute to MS development and disease progression. Some evidence suggests vitamin D supplements may be beneficial for MS patients, but more research is needed to determine its impact on disease activity.

Vitamin D is mostly known for its role in promoting calcium absorption and maintaining bone health. But the fat-soluble vitamin has many other biological functions, such as supporting brain and muscle health and reducing inflammation.

Despite its name, vitamin D acts more like a hormone. One of the main reasons for this classification is that vitamin D can be obtained from foods and directly produced in the skin after exposure to sunlight; other vitamins can only be obtained from dietary sources, such as food and supplements.

Vitamin D exists in two primary forms:

• vitamin D3, also known as cholecalciferol, which is found in animal sources and also is synthesized or produced in the skin upon sunlight exposure.
• vitamin D2, or ergocalcigerol, which comes from plants and fungi.

Both are inactive forms of the vitamin and must be converted in the liver into an intermediate molecule, called 25-hydroxyvitamin D (25[OH]D) or calcidiol. That molecule is then converted into the active product in the kidneys through a final transformative step.

The biological effects of vitamin D are mediated by its binding to vitamin D receptor proteins. These proteins are found in several tissues and cells throughout the body, including in cells from the immune system and in the central nervous system (the brain and spinal cord). After binding, this complex can interact directly with specific stretches of DNA, thereby influencing gene expression — namely, which and how much certain genes are activated.

Vitamin D is a potent immune modulator that directly affects the production, maturation, and function of several immune cell types, including those that drive autoimmunity in MS.

Some immune cells that are abnormal in MS and modulated by vitamin D include:

• B-cells, which make antibodies, including the autoantibodies or self-targeting antibodies that drive MS.
• T-cells, involved in a range of immune functions that contribute to inflammation and cell death in MS.
• dendritic cells, which are involved in regulating immune tolerance — the immune system’s ability to tolerate the body’s own cells and tissues — a feature that’s impaired in MS.

In addition to modulating immune responses, some preclinical studies suggest vitamin D may play a direct role in myelin repair by increasing the production of oligodendrocytes — the cells chiefly responsible for making new myelin in the brain and spinal cord.

Vitamin D and MS risk

The impact of vitamin D on MS risk has been extensively studied over the last decades. Research has generally established vitamin D deficiency as a risk factor for the neurodegenerative disease. Specifically, people with lower levels of the vitamin are more likely to develop MS.

The belief that vitamin D may protect from MS is supported by studies examining a variety of factors associated with vitamin D levels, from sun exposure, to vitamin D ingestion, to vitamin D exposure in the womb.

For example, MS is more common in people who live farther away from the equator — those who generally have the lowest exposure to sunlight, the main source of vitamin D. This increased risk at higher latitudes is mainly attributed to low vitamin D levels, although differences in socioeconomic factors across geographic areas also may play a role.

Lower levels of vitamin D in circulation are normally associated with a greater chance of having MS. Thus, certain genetic alterations — one study  focused on osteoporosis patients — that result in low vitamin D levels have been shown to increase MS susceptibility. Similarly, people who consume less of this vitamin through diet or supplements have a higher incidence of the autoimmune disorder.

It’s also been suggested that MS risk during adulthood is much higher in people exposed to low vitamin D levels before birth (during pregnancy), as well as in those with low levels of the vitamin in infancy.

Vitamin D and disease activity

Unlike the well-established link between vitamin D and MS risk, less is known about how natural vitamin D levels or supplementation influence MS disease activity or symptoms.

Observational studies conducted to date suggest vitamin D may protect from the development of new brain lesions, while also reducing the rate of relapses and long-term disability progression. However, clinical trials performed thus far have produced contradicting results indicating more research is needed to better understand how vitamin D impacts disease outcomes.

One of the largest trials investigating the effects of vitamin D supplementation on MS disease activity was the SOLAR Phase 2 clinical trial (NCT01285401). It enrolled more than 200 patients with relapsing-remitting multiple sclerosis (RRMS) in Europe, who were randomly assigned to receive the widely approved MS therapy Rebif (interferon beta-1a) in combination with a placebo or high-dose vitamin D3 (14,007 international units per day, or IU/day). Results showed vitamin D3 supplementation did not reduce the rate of relapses or disability progression over nearly one year, although patients in this group developed fewer lesions than those on a placebo.

Another Phase 2 study, called CHOLINE (NCT01198132) and conducted in France, examined a combination of Rebif and high-dose vitamin D3 (100,000 IU every other week) in about 180 RRMS patients with vitamin D deficiency. While the trial failed to meet its primary goal of lowering relapse rates in the overall population, those who completed the two years of vitamin D supplements did experience fewer relapses, developed fewer inflammatory lesions, and had a slower progression of disability.

The EVIDIMS Phase 2 trial (NCT01440062), conducted in Germany, enrolled more than 50 RRMS patients and compared the effects of a high (20,400 IU) versus low dose (400 IU) of vitamin D3 every other day. There were no differences between groups regarding relapse rates, disability progression, and brain lesions, though researchers noted the sample was too small to show a benefit.

A recently completed Phase 3 trial called VIDAMS (NCT01490502), which enrolled 172 participants in the U.S., also showed no benefits of high-dose (5,000 IU/day) over low-dose vitamin D (600 IU/day), although a trend was observed for lower relapse rates and reduced relapse severity in the low-dose group.

As with other measures of MS activity, the impact of vitamin D on MS relapses is not well-established, and a better understanding of this association has been hampered by studies with small sample sizes or lacking appropriate control groups.

Some observational studies have demonstrated people with lower levels of vitamin D have a more active disease course, including a higher relapse rate. In the studies that showed an association, the risk of relapses was reduced by 14%–34% for each increase of 10 nanograms per milliliter (ng/mL) in vitamin D levels.

However, in clinical trials examining vitamin D supplementation, the benefits have been less evident. Some trials have shown a significant reduction in the annual rate of relapses with the use of supplements, but most either failed to detect a significant effect or showed only a trend toward fewer relapses. A review study examining nine published trials found no effects of vitamin D supplementation on relapse rates.

The active form of vitamin D is called calcitriol, or 1,25-dihydroxyvitamin D. However, the most accurate way to determine how much vitamin D is in the body is by measuring its precursor molecule 25(OH)D in the blood.

There are several reasons for this. Compared with calcitriol, 25(OH)D stays in circulation for longer periods of time and is found at much higher levels, enabling doctors to more accurately detect small changes in vitamin D levels. Also, as an individual becomes deficient in vitamin D, the body sends signals that increase the production of calcitriol. That results in patients having normal or elevated calcitriol levels even when actual vitamin D levels are below the optimal range.

Optimal vitamin D

Experts haven’t yet reached a consensus on what is considered an optimal vitamin D level or for defining vitamin D deficiency. Most physicians currently make their clinical assessments and recommendations based on existing guidelines from the Institute of Medicine, or from the Endocrine Society. These guidelines both date back more than a decade.

In both guidelines, people are considered to be deficient in vitamin D if their 25(OH)D blood levels fall below 20 ng/mL. However, while the Institute of Medicine committee determined levels above that threshold are sufficient, the Endocrine Society recommends patients have levels of at least 30 ng/mL.

The guidelines from the Endocrine Society, issued in 2011, further categorize vitamin D status for children and adults as:

• Ideal: 40-60 ng/mL
• Sufficient: at least 30 ng/mL
• Insufficient: 21-29 ng/mL
• Deficient: 20 ng/mL or less

The two guidelines also do not agree on the recommended daily intake of vitamin D. To ensure levels are consistently ideal for maintaining bone health, the Institute of Medicine, in its 2011 publication, recommends  people ingest at least 600 IU (15 micrograms, mcg) daily, via supplements or other dietary sources.

On the other hand, the Endocrine Society recommends 1,500 to 2,000 IU per day for adults and 1,000 IU for children. These levels are recommended to maintain optimal health in the bones and other organs. For those with vitamin D deficiency, the recommendation is to take a higher dose of 10,000 IU daily until the deficiency is corrected.

There are no specific guidelines for people with MS.

Aptly called the “sunshine vitamin” due to its source, vitamin D is mostly obtained from sunlight. More specifically, it comes from a certain spectrum of ultraviolet light present in sunlight — type B ultraviolet light, or UVB.

It is estimated that whole-body sun exposure for 20 minutes during the summertime equates to a production of more than 10,000 IU of vitamin D. However, the amount of vitamin D produced in response to sunlight depends on several individual factors, including skin color, age, and use of sunscreen. It’s also impacted by environmental factors — like season and latitude — that influence UVB exposure.

It is therefore difficult to determine how much sun exposure is needed to maintain adequate vitamin D levels. Some experts recommend approximately 5–30 minutes of sun exposure, at least twice a week, to guarantee sufficient vitamin D levels.

Food

Vitamin D also can be obtained through diet, although there aren’t many foods that are naturally rich in this vitamin. Diet is considered a poor source of vitamin D compared to sun exposure, as most foods provide only about 40–400 IU of the vitamin per serving.

Foods naturally rich in vitamin D include:

• fatty fish, such as trout, salmon, mackerel, and sardines;
• egg yolks;
• beef liver; and
• shiitake mushrooms.

Other foods, such as cereals, milk, orange juice, and cheese, are often fortified with vitamin D to increase the dietary availability of this vitamin.

Supplements

Dietary supplements are another main source of vitamin D. In addition to fish liver oils, these supplements are commonly available in pills that contain either vitamin D2 or vitamin D3.

Vitamin D supplements are available in multiple strengths and may be administered at various intervals  depending on the individual’s needs. They often are recommended by physicians to people with vitamin D deficiency or with a health condition that may benefit from extra vitamin D.

Some studies suggest vitamin D supplements may be beneficial for people with MS, but there are no guidelines recommending a specific strength, formulation, or dosing frequency in these patients.

While vitamin D is a naturally occurring molecule, having levels above 100 ng/mL can be associated with certain side effects. Most adverse reactions are caused by a rise in calcium levels (hypercalcemia), as the excess vitamin D promotes a greater absorption of this mineral in the intestines.

Side effects associated with too much vitamin D may include:

• digestive problems such as vomiting, nausea, and stomach pain;
• excessive urination and dehydration;
• muscle weakness;
• psychological disturbances, including hallucinations and confusion;
• kidney complications; and
• heart problems.

Vitamin D toxicity is unlikely to occur from sun exposure and diet. It may develop after taking very high doses of vitamin D supplements, particularly when these are combined with calcium supplements.