Vitamin D and Multiple Sclerosis: A Comprehensive Review

Vitamin D and Multiple Sclerosis: A Comprehensive Review Neurol Ther (2018) 7:59–85 https://doi.org/10.1007/s40120-017-0086-4 REVIEW Vitamin D and Multiple Sclerosis: A Comprehensive Review . . Martina B. Sintzel Mark Rametta Anthony T. Reder Received: October 10, 2017 / Published online: December 14, 2017 The Author(s) 2017. This article is an open access publication limitations identified in this review recognize ABSTRACT the need for larger controlled clinical trials to establish vitamin D supplementation as the Numerous observational studies have suggested standard of care for MS patients. Though there that there is a correlation between the level of is increasing evidence indicating that lower serum vitamin D and MS risk and disease vitamin D levels are associated with increased activity. To explore this hypothesis, a literature risk of MS and with greater clinical and brain search of large, prospective, observation studies, MRI activity in established MS, the impact of epidemiological studies, and studies using new vitamin D supplementation on MS activity approaches such as Mendelian randomization remains inadequately investigated. was conducted. Available data and ongoing research included in this review suggest that the level of serum vitamin D affects the risk of Keywords: Autoimmune disease; Health developing MS and also modifies disease activ- outcomes; Mendelian randomization; Multiple ity in MS patients. Newer Mendelian random- sclerosis; Optic neuritis; Pregnancy; Relapsing- ization analyses suggest there is a causal remitting MS (RRMS); Supplementation; relationship between low vitamin D level and Vitamin D the risk of MS. Post-hoc evaluations from two phase 3 studies, BENEFIT and BEYOND, support the findings of observational trials. Study INTRODUCTION Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/ Knowledge of the widespread effects of vitamin F5FCF060794BDA24. D on skeletal and non-skeletal functions, including immune functions, has developed M. B. Sintzel considerably over the past 3 decades. Higher Medical Communication Services, Erlenbach, levels of vitamin D are associated with reduced Zurich, Switzerland risk for developing multiple sclerosis (MS), and M. Rametta with reduced clinical activity in established MS, Bayer HealthCare Pharmaceuticals, Whippany, NJ, including decreased risk of relapse and reduc- USA tion in disease activity on brain MRI [1, 2]. A. T. Reder (&) Vitamin D supplementation may diminish the Department of Neurology, University of Chicago, risk of MS in the general population, as well as Chicago, IL, USA in children of mothers supplemented before e-mail: areder@neurology.bsd.uchicago.edu 60 Neurol Ther (2018) 7:59–85 and during pregnancy [3]. In the information exposure for 20 min for a light-skinned person that follows, we will summarize the available during the summer months will produce data on vitamin D, with a focus on vitamin D’s upwards of 10,000 IU of vitamin D [7, 10]. effects on the risk of onset of MS and on the However, UVB exposure and vitamin D pro- disease course of MS. duction through the skin may be reduced with increased skin pigmentation, age, use of sun- screen, and environmental factors such as win- Sources, Metabolism, and Biological ter season, high latitude, pollution, cloud cover, Functions of Vitamin D and ozone levels [7]. For instance, sun exposure during most of the winter at latitudes Vitamin D is a lipid-soluble vitamin, but acts above * 33 North (e.g., Atlanta, GA, USA; like a hormone. Unlike a vitamin, which is an Casablanca, Morocco) and below * 33 degrees essential organic compound that cannot be South (e.g., Santiago, Chile; New South Wales, synthesized by the body and must be ingested, Australia; Southern Cape of Africa) provides vitamin D can be synthesized [4]. The active minimal, if any, vitamin D production [11]. form of vitamin D, 1,25-dihydroxyvitamin D Both forms of vitamin D, cholecalciferol, and (1,25[OH] VD), also known as calcitriol (Fig. 1) ergocalciferol are biologically inactive and [5] has chemical similarities to typical hor- undergo an enzymatic transformation in the mones such as testosterone, estrogen, and cor- liver to 25(OH)D (calcidiol). Stimulated by tisol [6]. The main sources of vitamin D are parathyroid hormone, 25(OH)D goes through a sunlight, diet, and supplementation (Fig. 2)[7]. second hydroxylation in the kidney or other UVB in the 290–315-nm range photolyses tissues to 1,25(OH) VD (also known as calcitriol 7-dehydrocholesterol in the skin to form pre- if derived from vitamin D3), which is the active vitamin D3, which then isomerizes to vitamin metabolite (Figs. 1 and 2)[5, 7]. 1,25(OH) VD D3 or cholecalciferol [8]. Foods rich in vitamin has a half-life of several hours, while 25(OH)D D include fatty fish (e.g., salmon, mackerel), cod has a relatively long half-life (20–60 days), and liver oil, egg yolk, and shiitake mushrooms. The thus more accurately exemplifies the overall plant form of vitamin D is called vitamin D2 or vitamin D stores in the body. This supports the ergocalciferol [9]. Cholecalciferol and ergocal- standard practice of measuring 25(OH)D in ciferol are also available from fortified foods serum, and represents an integrated measure of (e.g., milk, cereal, some orange juice, and vitamin D derived from both UVB exposure and cheeses) and vitamin supplements. diet. As a side note, most assays that evaluate Relative to sun exposure, diet is a poor source 25(OH)D do not discriminate between the of vitamin D, providing only 40–400 IU per original forms of vitamin D (vitamin D3 or D2). food serving, whereas whole-body UVB Fig. 1 Chemical structures of the physiologically inactive (25[OH]D) (c); and the bioactive vitamin D3 metabolite vitamin D2 (a) and vitamin D3 (b); the main circulating 1,25-dihydroxyvitamin D (1,25[OH] VD) (d), or cal- vitamin D3 intermediate, 25-hydroxyvitamin D citriol if derived from vitamin D3 [5] Neurol Ther (2018) 7:59–85 61 Fig. 2 Sources and metabolism of vitamin D: The main 1,25(OH) VD has a half-life of several hours, while the sources of vitamin D are sunlight, diet, and supplemen- intermediate vitamin D form 25-hydroxyvitamin D tation. The primary forms of vitamin D are biologically [25(OH)D] has a relatively long half-life (20–60 days), inactive and need for their activation two hydroxylation and thus more accurately exemplifies the overall vitamin D steps in the liver and kidney. The hormonally active final stores in the body [7]. Reprinted from [7], with permission product is 1,25-dihydroxyvitamin D [1,25(OH) VDO]. from Elsevier However, the latter is usually a minor compo- was very common among children in industri- nent because natural sources of ergocalciferol alized cities, and observations were made that are scarce, and ergocalciferol is more rapidly sunlight exposure or cod liver oil may help to catabolized than cholecalciferol [7]. prevent this condition [10]. Other muscu- The active metabolite 1,25(OH) VD is loskeletal consequences of vitamin D deficiency released into the bloodstream and transported include secondary hyperparathyroidism, in the blood. It binds to the vitamin D binding increased bone turnover, bone loss, and risk of protein in blood and on the surface of target low-trauma fractures. Today, we understand tissues. 1,25(OH) VD mediates its biological that VDR is widely distributed throughout the human body and involved in many biological effects by binding to intracellular vitamin D receptor (VDR), which then recruits cofactors to functions. Vitamin D deficiency has been asso- form a transcriptional complex that binds to ciated with numerous diseases including can- vitamin D response elements [12]. This associ- cers, cardiovascular diseases, type 2 diabetes ation regulates the expression of at least 500 mellitus, infectious diseases, mental disorders, genes that drive a variety of physical functions and autoimmune disorders such as type 1 dia- [7]. The VDR is found in almost all human tis- betes mellitus, Crohn’s disease, and MS [10, 13]. sues, not just those participating in the classic These diseases are all linked to vitamin D levels actions of vitamin D, such as bone, gut, and that are sufficient to prevent rickets, but are still kidney. The non-classic actions of VDR can be suboptimal. Curiously, as rickets is no longer a allocated to three main categories: regulation of problem, one might assume that the vitamin D hormone secretion, regulation of immune deficiency problem is also no longer an issue. function, and regulation of cellular prolifera- However, now that we know that autoimmu- tion and differentiation [12]. nity may be related to low vitamin D levels, and Vitamin D deficiency has been classically that the incidence of autoimmune diseases has attributed to bone health. In the early 1900s, increased, we must consider if there is a higher rickets, a consequence of vitamin D deficiency, vitamin D threshold related to autoimmunity, 62 Neurol Ther (2018) 7:59–85 or if the environment changed since the • In macrophages and monocytes, 1,25(OH) VD positively impacts its own Industrial Revolution. effects by increasing the expression of VDR and the cytochrome P450 protein, CYP27B1. Roles of Vitamin D in Immunity • Certain Toll-like receptor (TLR)-mediated signals also can increase the expression of Since multiple sclerosis (MS) is considered an VDRs. autoimmune disease, it is of interest to review • The active form of vitamin D induces mono- briefly the potential effects of vitamin D related cyte proliferation and the expression of to immune function. The active form of vita- interleukin-1 (IL-1) and cathelicidin (an min D plays an essential role in lymphocyte antimicrobial peptide) by macrophages, con- activation and proliferation, T-helper cell dif- tributing to innate immune responses to ferentiation, tissue-specific lymphocyte hom- some bacteria. ing, the production of specific antibody • 1,25(OH) VD decreases DC maturation, isotypes, and regulation of the immune inhibiting upregulation of the expression of response [14]. Targeted immune cell types MHC class II, CD40, CD80, and CD86. In include macrophages, dendritic cells, and T and addition, it decreases IL-12 production by B cells. Mora and colleagues (Fig. 3)[14] sum- DCs while inducing the production of IL-10. marized the roles and effects of vitamin D on • In T cells, 1,25(OH) VD reduces the produc- these immune cell types [14]: tion of IL-2, IL-17, and interferon-c (IFNc) • Macrophages and dendritic cells (DCs) con- and attenuates the cytotoxic activity and stitutively express VDRs, whereas VDR proliferation of CD4? and CD8? T cells. expression in T cells is upregulated only • The active metabolite of vitamin D might after activation. also promote the development of forkhead Fig. 3 Potential mechanisms of vitamin D immunomod- vitamin D receptor (VDR), whereas VDR expression in T ulation: systemic 1,25(OH)2VD3 affects several immune- cells is only upregulated following activation. Reprinted by cell types, including macrophages, dendritic cells (DCs), T permission from Macmillan Publishers Ltd: [14] and B cells. Macrophages and DCs constantly express Neurol Ther (2018) 7:59–85 63 Table 1 Definition of vitamin D status [as measured by blood levels of 25(OH)D] and daily vitamin D intake recom- mended by the Institute of Medicine (IOM) and the Endocrine Society [4, 11, 13, 16] Institute of medicine Endocrine society Vitamin D status ‘‘Deficient’’ – B 20 ng/mL (B 50 nmol/L) ‘‘Insufficient’’ – 21–29 ng/mL (51–74 nmol/L) ‘‘Sufficient’’ 20 ng/mL (50 nmol/L) C 30 ng/mL (C 75 nmol/L) ‘‘Ideal’’ – 40–60 ng/mL (100–150 nmol/L) Considered ‘‘safe’’ – B 100 ng/mL (B 250 nmol/L) Daily vitamin D intake recommendations (upper limits) Infants 400 IU/day (1000–1500 IU/day) 400–1000 IU/day (2000 IU/day) Children 600 IU/day (2500–3000 IU/day) 600–1000 IU/day (4000 IU/day) Adults 600 IU/day (4000 IU/day), 800 IU/day for seniors 1500–2000 IU/day (10,000 IU/day) box protein 3 (FOXP3)? regulatory T (T ) absorption, bone mineral density, and osteo- Reg cells and IL-10-producing T regulatory type 1 malacia/rickets) aiming to prevent vitamin D (TR1) cells. deficiency in 97.5% of the general population. • 1,25(OH) VD blocks B cell proliferation, Based on the model applied, no evidence was plasma cell differentiation, and found that a serum 25(OH)D concentra- immunoglobulin production. tion[20 ng/mL (50 nmol/L) had beneficial Notable in the context of this review, many effects at a population level. Therefore, the IOM of the mechanisms of vitamin D on immune concluded that the daily requirements for vita- processes have similarities to mechanisms min D were adequate to reach the ‘‘sufficient’’ described for interferon-beta [15]. 25(OH)D level of 20 ng/mL (50 nmol/L), and that these levels were generally attained by most of the population [4, 16]. Definition of Vitamin D Deficiency Alternatively, the Endocrine Society con- and Targeted Levels of Vitamin D cluded that a level of 20 ng/mL (50 nmol/L) was not sufficient. The Endocrine Society based The clinical definition of vitamin D deficiency their recommendations on a medical model and what constitutes optimal levels has been taking into consideration available evidence on the subject of debate. Two organizations, the skeletal and extraskeletal effects of vitamin D, in Institute of Medicine (IOM) and the Endocrine addition to the few negative studies. Moreover, Society, have released separate recommenda- they took into consideration the low toxicity tions regarding vitamin D requirements potential of vitamin D supplementation. In [4, 11, 16]. Blood levels of 25(OH)D as suggested their view, serum 25(OH)D levels of C 30 ng/mL by the IOM and the Endocrine Society and the (C 75 nmol/L) are ‘‘sufficient’’ for children and recommended dietary allowances (RDAs) by adults, levels of 40–60 ng/mL (100–150 nmol/L) both organizations are provided in Table 1 are ‘‘ideal’’ (considering assay variability), and [4, 11, 16]. levels of up to 100 ng/mL (250 nmol/L) could be The foundational basis for the recommen- considered ‘‘safe’’ [11, 13]. dations by these two organizations are funda- The Endocrine Society advocates for screen- mentally different. The IOM guidelines based ing and corrective action for individuals at risk their recommendation on a population model of vitamin D deficiency. Such individuals and focused on bone health (calcium 64 Neurol Ther (2018) 7:59–85 include African American and Hispanic chil- Vitamin D Safety Risks and Vitamin D Intoxication dren and adults; pregnant and lactating women; older adults with a history of falls or nontraumatic fractures; obese children and 1,25(OH) VD stimulates intestinal calcium adults (BMI[30 kg/m ); and patients with absorption [18]. Without vitamin D, only musculoskeletal diseases, chronic kidney dis- 10–15% of dietary calcium and about 60% of ease, hepatic failure, malabsorption syndromes, phosphorus are absorbed. Vitamin D sufficiency and some lymphomas [11]. Furthermore, the enhances absorption of calcium by 30–40% and group recommends supplementation at sug- phosphorus by 80% [11, 19, 20]. Vitamin D gested daily intake and tolerable-upper-limit intoxication is characterized by hypercalcemia, levels, depending on age and clinical circum- hypercalciuria, and hyperphosphatemia and in stances (Table 1)[4, 11, 13, 16]. the long term, can lead to soft tissue and vas- cular calcification and nephrolithiasis [13]. After review of available literature, the Endo- Supplemental Vitamin D crine Practice Guidelines Committee concluded that vitamin D toxicity is a rare event caused by The recommended dietary allowance (RDA) for inadvertent or intentional ingestion of exces- vitamin D and the tolerable-upper-limit levels sively high amounts of vitamin D [11]. Con- vary with age and under certain circumstances cerns were expressed for people with 25(OH)D such as those involving pregnancy, obesity, or levels of 150 ng/mL (375 nmol/L) or higher, comorbidities. A daily dose of 600–800 IU when daily doses of vitamin D exceed 10,000 IU should satisfy the requirements for optimal or when high intake of vitamin D is combined bone health [16], but a higher intake with high intake of calcium. A dose-ranging (1000–2000 IU) is needed to achieve and main- study reported that 10,000 IU/day of vitamin tain 25(OH)D levels[30 ng/mL (75 nmol/L) D3 for 5 months in healthy men did not alter [11]. Vitamin D supplements can be adminis- their serum calcium or their urinary calcium tered daily, weekly, monthly, or every 4 months excretion, which is the most sensitive indicator to reach an adequate serum 25(OH)D concen- for potential vitamin D intoxication [21]. tration. For cases of extreme vitamin D defi- However, there is a paucity of evidence sup- ciency, a bolus application of vitamin D has porting the use of higher levels of vitamin D been proposed, but a steady-state serum over a prolonged time [11]. 25(OH)D concentration is more likely to be Safety findings in three studies conducted in maintained by more frequent, lower doses of patients with MS using doses of vitamin D vitamin D [13]. Vitamin D3 (cholecalciferol) is above 10,000 IU/day are noteworthy. One widely preferred over vitamin D2 (ergocalcif- open-label trial of vitamin D in patients with erol), as it has proven to be the more potent MS evaluated the safety of a dose-escalation form of vitamin D in all primate species, protocol from 4000 to 40,000 IU/day (mean of including humans [17]. Vitamin D supplemen- 14,000 IU/day). Concomitantly, patients tation at doses of 1500–2000 IU/day for adults received 1200 mg of calcium per day vs. a con- as suggested by the Endocrine Society appears to trol group (allowed up to 4000 IU/day of vita- be well tolerated, with relatively minor con- min D and supplemental calcium if desired) cerns about toxicity for most patients [11]. over 1 year [22]. All calcium-related measures Caution should be exercised in patients with within and between groups were normal. impairment of renal function, cardiovascular Despite a mean peak 25(OH)D level of 165 ng/ diseases, chronic granuloma-forming disorders mL (413 nmol/L), no significant adverse events (sarcoidosis or tuberculosis), or chronic fungal occurred. The safety results were in line with a infections. Some patients with lymphoma have previously conducted, smaller study in 12 activated macrophages that produce patients with MS also using doses of up to 1,25(OH) VD in an unregulated fashion. 40,000 IU [23]. In the third study, 15 patients with relapsing–remitting MS (RRMS) were Neurol Ther (2018) 7:59–85 65 supplemented with 20,000 IU/day of vitamin questions such as Does vitamin D prevent MS? D3 for 12 weeks [24]. The median vitamin D How does vitamin D impact MS activity? and Can level increased from 50 nmol/L (range: vitamin D supplementation favorably alter the 31–175 nmol/L) at week 0–380 nmol/L (range: course of MS? Observational study data does 151–535 nmol/L) at week 12 (P\0.001). All suggest that adequate vitamin D levels may patients completed the observation period reduce the risk of MS and affect the course of without side effects, hypercalcemia, or hyper- the disease. However, study limitations restrict calciuria [24]. the extent to which inverse associations can be There are cases in the literature in which attributed to vitamin D, and additional studies exceptionally high doses (considerably above are needed to further understand the nature of the daily upper limit of 10,000 IU) led to vita- this association [2]. min D toxicity: • Bell and coworkers described a 67-year-old Epidemiologic Study Data woman with vitamin D intoxication. Because of a compounding error by the Epidemiologic studies substantiate that the pharmacy, the woman had taken prevalence of MS is greater at higher latitudes 600,000 IU (rather than the intended and tends to peak in areas with the lowest 600 IU) of cholecalciferol daily for more exposure to ultraviolet light [27–32]. Addition- than 3 years, leading to reversible hypercal- ally, to some degree, diets rich in vitamin cemia and partially reversible renal impair- D-containing oily fish may offset this risk ment [25]. [27, 28]. In ‘‘historical’’ cohorts, the risk of MS • Fragoso and colleagues reported consider- decreased among people who migrate from able vitamin D toxicity in 21 MS patients higher to lower latitudes [33]. However, this who were exposed to levels ranging from latitudinal finding has appeared to decline in 8000 IU/day to extremely high, supra-phys- recent decades and may be linked to an iological doses of 150,000 IU/day (average increased trend towards avoiding sun exposure 87,000 IU) [26]. or staying indoors for longer portions of the In order to assess the correlation between day, even in warmer climates [7, 34]. vitamin D and MS, a literature search of large, An Australian case–control study examined prospective, observational studies, epidemio- whether leisure sun exposure, combined with logical studies, and studies using new approa- 25(OH)D status impacts the risk of a first ches such as Mendelian randomization was demyelinating event and whether this was conducted. related to a latitude gradient [35]. Indepen- dently, higher levels of sun exposure (past, Compliance and Ethics Guidelines recent, and cumulative), higher actinic skin damage and higher 25(OH)D levels were asso- This article is based on previously conducted ciated with significantly reduced risks of a studies, and as such, does not involve any new demyelinating event. The investigators calcu- studies of human or animal subjects performed lated that the differences in leisure sun expo- by any of the authors. sure, serum 25(OH)D level, and skin type would additively account for a 32.4% increase in the incidence of first demyelinating events from the VITAMIN D LEVELS AND MS low to high latitude regions in Australia [35]. SUSCEPTIBILITY The independent association of sun exposure and MS risk suggests that UV light itself may Since vitamin D was proposed as an important influence MS risk. Partially supporting this is factor in MS development in the 1970s, research that showed that experimental numerous experimental and epidemiologic autoimmune encephalitis (EAE) could be pre- studies have been conducted to answer key vented in mice through whole-body irradiation 66 Neurol Ther (2018) 7:59–85 with UV light [36]. However, this research did sample from the pregnancy with the affected not discriminate between vitamin D-related and child, were matched with 326 controls. Vitamin nonrelated effects of UV light. The research did D levels were low in both groups, but lower in note that in the Northern Hemisphere, signifi- the mothers of MS patients than in controls cantly more people with MS are born in May [34.6 nmol/L (13.9 ng/mL) vs. 37.5 nmol/L (9.1%), when there is less sunlight during (15.0 ng/mL); P = 0.006]. Moreover, MS risk was pregnancy than in November (8.5%), when 90% higher in the offspring of vitamin D-defi- there is an increased amount of sunlight [37]. cient mothers [25(OH)D\30 nmol/L (12.0 ng/ Some argue that this is an artifact of more births mL)] compared with offspring of mothers who during certain months [38] though others dis- were not vitamin D deficient [relative risk, 1.90; agree [39]. 95% confidence interval (CI), 1.20–3.01; P = 0.006] [3]. These data suggest that insuffi- cient vitamin D levels during pregnancy may Dietary Intake of Vitamin D and MS Risk increase the risk of MS [3]. The association between neonatal 25(OH)D Using data from two large cohorts of the Nurses’ status and risk of MS was examined in a large Health Study involving more than 187,000 population-based case–control study using data women (including 300 who developed MS dur- from the nationwide Danish MS Registry and ing the study), Munger and colleagues evalu- the Danish Newborn Screening Biobank (DNSB) ated the association between calculated vitamin [41]. Data from 521 patients with MS and 972 D intake from diet or supplements and the risk controls were investigated. The analysis by of developing MS [40]. Women who had a quintiles revealed individuals with the highest higher intake of dietary vitamin D (approxi- risk of MS were in the lowest quintile group of mately 700 IU/day) had a 33% lower incidence 25(OH)D (\20.7 nmol/L), and individuals the of MS compared with those with lower intake. lowest risk were in the highest quintile group In addition, women who used vitamin D sup- (C 48.9 nmol/L); with an odds ratio for highest plements (C 400 IU/day) had a 41% reduced risk vs. lowest group of 0.53 (95% CI 0.36–0.78). of developing MS compared to non-users. Hav- Children born with 25(OH)D levels\30 nmol/L ing higher levels of 25(OH)D (irrespective of seemed to be at an especially high risk of dietary vitamin D intake) also seems to predict a developing MS. The additional benefits of lower risk of MS onset. Using a longitudinal higher levels of 25(OH)D were less pronounced study design, Munger and colleagues evaluated [41]. serum vitamin D levels derived from blood samples of seven million US military personnel. Studies Utilizing Mendelian Those with 25(OH)D levels greater than Randomization to Measure MS Risk 100 nmol/L (40 ng/mL) had a 62% lower chance of subsequently developing MS [1]. Data on vitamin D and risk of MS have been largely based on observational studies that Vitamin D Levels During Pregnancy measure an inverse association. However, MS is and MS Risk in Offspring identified as the primary cause of low 25(OH)D) and thus cannot be excluded with these meth- The Finnish Maternity Cohort is a comprehen- ods. Mendelian randomization (MR) analyses sive registry, established in 1983, that includes use genetic associations to test the effects of more than 800,000 women and more than biomarkers, such as 25(OH)D, on the risk of 1.5 million serum samples. This cohort also disease, because inherited alleles are not affec- served as a basis for examining the association ted by most confounding variables or disease of vitamin D levels during pregnancy and MS status [42, 43]. Thus, the possibility of con- risk [3]. One hundred ninety-three patients with founding or reverse causation can largely be a diagnosis of MS, whose mothers were captured excluded. Three recent publications made use of in the registry and had an available serum Neurol Ther (2018) 7:59–85 67 this epidemiological approach. Mokry and col- range of 25(OH)D levels at birth was narrow and leagues applied genome-wide data on genetic mostly low (mean = 29.7 nmol/L, median = variants that predicted blood 25(OH)D levels 25.6, interquartile range = 17.0–38.4 nmol/L) from the Canadian Multicentre Osteoporosis [47]. Study to participants in the International MS Optic neuritis (ON) is a common first symp- Genetics Consortium study [42]. They found tom of MS. Pihl-Jensen and coworkers con- that a genetically determined decrease in blood ducted a cross-sectional study to assess whether 25(OH)D level predicted increased MS suscep- 25(OH)D levels can predict later development tibility. An increase of 25(OH)D levels by 50% of MS in acute ON by evaluating the differences decreased the odds of getting MS by approxi- in mean serum 25(OH)D levels between subjects mately 50% [42, 44]. Similar findings were seen with ON (n = 164) and those with MS (n = 948) from MR analyses using data from two popula- [48]. Deseasonalized serum 25(OH)D levels of tions, a US administrative claim database and the ON onset group were used for statistical two population-based case–control studies from analyses. The majority (56.1%) of the patients Sweden [45]. The third publication, from the had 25(OH)D levels below 50 nmol/L (mean Network of Pediatric Multiple Sclerosis Centers, 47.64 ± 21.48 nmol/L). There were no signifi- again investigated the US and Swedish datasets cant differences in 25(OH)D levels between ON [43]. Genetic risk scores were used to estimate subjects who developed MS and those who did the causal association between low 25(OH)D not develop MS during the median follow-up levels and pediatric-onset MS. This data also time of 741 days (P = 0.279), indicating no sta- supports independent and causal effects of tistically significant effect on the hazard of MS decreased 25(OH)D levels on susceptibility to development. However, significant associations pediatric-onset MS [43]. were found between 25(OH)D levels and ele- vated IgG index levels or CSF pleocytosis, both markers of inflammatory activity or risk of MS. Studies Contradicting the Association The interpretation of the latter finding was dif- of Vitamin D Levels with MS Risk ficult due to the risk of reverse causation. Although the role of using 25(OH)D levels as a Ueda and colleagues investigated the link predictor for the development of MS after acute between vitamin D status at birth and risk of ON could not be demonstrated, the study data adult-onset MS in a population-based, multi- do suggest that there may be a link between center, case–control study in Sweden [46]. The development of MS after acute ON. They also authors analyzed stored neonatal dried blood provide a rationale for additional research for a samples of 459 MS subjects and 663 controls possible role of vitamin D in the early stages of (matched on sex, age, and residential area). MS [48]. There was no association between neonatal serum 25(OH)D quintiles and risk of MS as Levels of Dietary Vitamin D Intake adults. When the findings were adjusted for and Risk of MS–Implications for Public confounding factors in early life (e.g., month of Health birth, latitude of birth, and breastfeeding), in adult life (e.g., sun exposure, intake of vitamin D-rich dairy products, fatty fish consumption, Whether a daily dose of vitamin D or a gesta- smoking, and body mass index at 20 years of tional dose of vitamin D per day ‘‘keeps the MS age), ancestry, MS heredity, and socioeconomic doctor away’’ is not yet proven [49]. Addition- group, results were not considerably affected ally, it is not known what level of serum [46]. Whether the study provided conclusive 25(OH)D would prevent MS in a large majority results was the subject of debate for two primary of individuals. Most studies in this review reasons: (1) blood samples at birth were not well reported 25(OH)D levels below 50 nmol/L preserved and may have been affected by sub- (20 ng/mL) in a significant proportion of their stantial degradation of 25(OH)D; and (2) the investigated populations, which is below the 68 Neurol Ther (2018) 7:59–85 healthy minimum level. Indicating that estab- decrease in relapse risk. Similar findings were lishing a target in the general population gen- seen in a prospective cohort study from Tas- eral population, pregnant women, and their mania, Australia, in a group of 145 adults with offspring to achieve the minimum levels of RRMS, in which 25(OH)D levels were measured 25(OH)D may be considered an important goal twice a year for a period of 3 years [52]. For each for health (i.e., 50 nmol/L (20 ng/mL), accord- 10 nmol/L increase in serum vitamin D level, ing to IOM [4, 15] or 75 nmol/L (30 ng/mL), there was an associated 12% lower risk of MS according to the Endocrine Society) [11, 13]. relapse. Adjustment for potential confounders, such as timing of the blood testing, did not affect the results. Most of the participants in EFFECTS OF VITAMIN D STATUS this study (82%) were receiving immunomod- AND MS DISEASE ACTIVITY ulatory therapy. The authors concluded that raising 25(OH)D levels by 50 nmol/L could Understanding how existing vitamin D levels decrease the hazard of a relapse by up to 50% and vitamin D exposure affect clinical relapses (Fig. 4)[52]. and MS lesion activity is critically important to The EPIC natural history study was a 5-year this review. As such, the findings from larger cohort study conducted at the University of studies investigating these effects are summa- California, San Francisco which sought to rized below. determine the associations between serum or plasma vitamin D levels and MRI activity in a group of 469 white, mostly non-Hispanic Impact of Vitamin D Levels on Disease patients with MS or clinically isolated syndrome Activity in RRMS: Observational Studies (CIS) [53]. Sixty-four percent received disease- modifying therapy within the previous In a prospective longitudinal study from the 12 months. Vitamin D levels increased signifi- Netherlands, 25(OH)D was measured every cantly during the study, especially for those 8 weeks for a mean of 1.7 years in 73 patients patients using supplements. Only 9% of with RRMS [50]. Fifty-eight patients experi- patients were taking vitamin D supplements at enced a total of 139 exacerbations during the baseline, but 43% were taking them by year 5. study period. Relapse risk was significantly Patients who reported using vitamin D supple- reduced in those with medium [50–100 nmol/L ments had an 8.7 ng/mL (21.75 nmo/L) higher (20–40 ng/mL)] and high [[100 nmol/L vitamin D level, on average, compared with ([40 ng/mL)] serum vitamin D levels (vs.\50 mol/L or 20 ng/mL) compared to those with low levels [50]. For each doubling of serum vitamin D concentration from baseline of 10, 20, 30, MS relapse risk decreased by 27%. Although this suggests a beneficial effect of vitamin D on MS, it must be noted that there is also a possibility that conditions associated with MS relapse had an effect on serum vitamin D levels [50]. Incident rate ratios (RR) for relapse in rela- tion to serum vitamin D levels were measured in a retrospective study of 110 patients with pedi- atric-onset MS [51]. After adjusting for several Fig. 4 Association of vitamin D and relapse risk in MS. factors (age, gender, race, ethnicity, disease The graph shows risk of relapse according to 25(OH)D duration, and treatment), the authors found levels, adjusted for age and month of serum measurement. Size of points is proportional to the inverse of the variance that every 10 ng/mL (25 nmol/L) increase in (larger bubbles represent greater precision). Reprinted with 25(OH)D level was associated with a 34% permission from Wiley Company [52] Neurol Ther (2018) 7:59–85 69 those who did not. Additionally, lower vitamin that brain volume is thought to reflect neu- D levels were strongly associated with develop- rodegeneration better than classical MRI ment of new T2 lesions and with contrast-en- parameters such as T2 lesion load and hancing lesions on brain MRI. Each additional Gd?-enhancing lesions [54]. Each 25-nmol/L 10 ng/mL (25 nmol/L) increment of 25(OH)D increase in 25(OH)D level was associated with was associated with a 15% lower risk of new T2 7.8-mL higher gray matter volume (P = 0.025). lesions and a 32% lower risk of enhancing Higher levels of 25(OH)D also were associated lesions (Fig. 5)[53]. Higher vitamin D levels with the composite endpoint of C 3 new brain were associated with a lower (but not statisti- T2 lesions or C 1 relapse within 1 year cally significantly) risk of MS relapses. Findings (P = 0.096). Despite the limitations of the small from this study also showed strong ‘‘within- sample size, these findings suggest that higher person’’ effects of vitamin D levels in individual vitamin D levels in CIS may slow neurodegen- patients with MS. The authors concluded that eration [54]. ‘‘individuals with CIS/RRMS with higher vita- Lower vitamin D levels also correlate with min D levels are at much lower risk of the sub- other surrogates of MS disease activity, includ- sequent development of new lesions and of ing lower odds of remaining relapse free in MS gadolinium (Gd?)-enhancing lesions on brain [55], greater disability and disease severity in MS MRI, even after accounting for potential con- [53, 55–57], conversion from CIS to clinically founding factors’’ [53]. definite MS (CDMS) [58], and poorer nonverbal More recently, Mowry and colleagues exam- long-term memory performance [59]. These ined the association of vitamin D levels with data were largely generated by observational brain volume measures and new lesions in studies that restrict the extent to which inverse patients with CIS (N = 65) [54]. The scientific associations can be attributed specifically to rationale for these data are based on the concept vitamin D. Properly designed and conducted Fig. 5 Magnetic resonance imaging outcomes associated (25 nmol/L) higher 25-hydroxyvitamin D level was asso- with quintiles of vitamin D in the EPIC study. EPIC is a ciated with a 15% lower risk of a new T2 lesion (incidence 5-year longitudinal MS cohort study at the University of rate ratio [IRR],0.85; 95% confidence interval [CI], California at San Francisco, USA. Participants (N = 469) 0.76–0.95; P = 0.004) and a 32% lower risk of a had clinical evaluations, brain MRI, and blood draws gadolinium-enhancing lesion (IRR, 0.68; 95% CI, annually. MRI outcomes were associated with quintiles of 0.53–0.87; P ? 0.002). Reprinted with permission from vitamin D. In multivariate analyses, each 10 ng/mL Wiley Company [53] 70 Neurol Ther (2018) 7:59–85 clinical trials are needed to further define the of long-term 25(OH)D status. To minimize the nature of this association. possibility that lower 25(OH)D levels were a consequence, rather than the cause, of MS severity, the cumulative average 25(OH)D levels Impact of Vitamin D Levels on Disease at 12 months were related to the outcomes Activity Based on Post-Hoc Analyses between 12 and 60 months or between 24 and from BENEFIT and BEYOND 60 months (thereby allowing inserting a 1-year lag between 25[OH]D measurements and the To our knowledge, no large randomized, dou- assessment of MS activity or progression) [60]. ble-blind, controlled, prospectively phase 3 tri- Three sets of analyses were performed: (1) con- als have been conducted to study the impact of tinuous 50-nmol/L (20-ng/mL) increments to vitamin D levels on MS activity as a primary determine the overall linear trend; (2) quintiles endpoint. However, in two phase 3 studies, the to explore the dose response; and (3) categorical BENEFIT study [60], and the BEYOND study [61] analysis using C 50 nmol/L versus\50 nmol/L post hoc analyses were conducted to investigate (20 ng/mL) [60]. this potential link. Findings indicated that patient characteris- The BENEFIT (Betaseron in Newly Emerging tics affected vitamin D levels. Those with higher Multiple Sclerosis for Initial Treatment) study (seasonally adjusted) 25(OH)D levels tended to was a randomized trial originally designed to be younger and to have a lower body mass evaluate the impact of early versus delayed index (BMI), a lower number of T2 lesions, and IFNB-1b treatment in patients with CIS [62–64]. a higher brain volume at the CIS stage, but Patients with a first event suggestive of MS and a otherwise were similar to patients with lower minimum of two clinically silent lesions on MRI levels of 25(OH)D [60]. were randomly assigned to receive interferon Over the 5-year follow-up period, 81.3% (377 beta-1b (IFNB-1b) 250 lg(n = 292; early treat- patients) converted to MS according to the ment) or placebo (n = 176; delayed treatment) McDonald 2001 criteria that include MRI subcutaneously every other day for 2 years or lesions [65] and 46.6% (216 patients) converted until diagnosis of CDMS, in which case they to CDMS based on exacerbations or progression could switch to IFNB-1b therapy. All patients alone. The hazard of conversion decreased with were then eligible to enter a prospective follow- increasing serum 25(OH)D and mean serum up phase with open-label IFNB-1b for up to 25(OH)D levels at 12 months predicted subse- 5 years after randomization. Patients and study quent conversions to McDonald MS (P = 0.02) personnel remained unaware of initial treat- and CDMS (P = 0.05) [60]. ment allocation throughout the study up to An increasing serum 25(OH)D level was year 5. During the observation period, regular associated with a decreasing rate of new active study visits were scheduled to collect clinical lesions on MRI; this effect was particularly and MRI data, with visits at baseline and strong in patients with both 6- and 12-month months 3, 6, 9, 12, 18, 24, 36, 48, and 60 [64]. A serum 25(OH)D measurements. A 50 nmol/L post hoc analyses aimed to determine whether (20 ng/mL) increment in average serum vitamin D status [serum 25(OH)D levels] would 25(OH)D levels within the first 12 months pre- predict disease activity and prognosis up to dicted a 57% lower rate of new active lesions 5 years after the first attack in early-disease CIS (RR, 95% CI: 0.43 (0.26–0.70), P\0.001) and a patients [60]. Serum samples were collected at 57% lower relapse rate (RR (95% CI): 0.43 baseline, 6, 12, and 24 months and levels of (0.20–0.92, P = 0.03). In evaluating the poten- 25(OH)D were measured (by ELISA). Of the 468 tial progression of MS on MRI, higher levels of patients included in BENEFIT, 465 patients had serum 25(OH)D were associated with less T2 at least one 25(OH)D measurement, 417 had lesion volume accumulation over time. For a two or more, 396 had three or more, and 303 50 nmol/L increase in serum 25(OH)D, the rel- had all four measurements. 25(OH)D levels ative decrease in T2 lesion volume was 20% per were seasonally adjusted to obtain an estimate year (P\0.001). Restricting results to patients Neurol Ther (2018) 7:59–85 71 with both 6-month and 12-month serum 25(OH)D levels\50 nmol/L (P = 0.005). 25(OH)D measures, tended to strengthen results Although a 50 nmol/L increase in 25(OH)D [60]. levels did not reach significance for a reduction The dichotomous analysis of serum 25(OH)D in the average expanded disability status scale levels (\50 vs. C 50 nmol/L) is shown in Fig. 6 (EDSS) score (P = 0.11), patients with serum [60]. For instance, the percentage loss of brain 25(OH)D levels C 50 nmol/L had a significantly volume over time was lower in patients with lower annualized change in EDSS score com- 25(OH)D levels C 50 nmol/L at the 12-month pared with those patients with serum 25(OH)D time point compared with those with serum levels\50 nmol/L (P = 0.004) while on IFN-b- Fig. 6 Multiple sclerosis outcomes according to dichoto- new active lesions on brain MRI (b); the percentage mous serum 25(OH)D levels. Analyses are based on change in T2 lesion volume from year 1 to year 5 on brain patients with averaged 6- and 12-month measurements of MRI (c); and the percentage change in brain volume from 25(OH)D. Group comparisons are adjusted for age, sex, year 1 to year 5 (d). The error bars indicate the standard treatment, time of follow-up, and T2 lesion score at error of the mean (SEM). Reproduced with permission baseline. The graphs show the probability of conversion to from [60]. Copyright2014 American Medical Associa- CDMS after 12 months (a); the cumulative number of tion. All rights reserved 72 Neurol Ther (2018) 7:59–85 Table 2 Comparison of clinical and MRI outcomes in patients with Reproduced with permission from [60]. Copyright2014 American plasma 25(OH)D levels\ 50 nmol/L versus C 50 nmol/L in all Medical Association. All rights reserved patients and those with early or delayed start of interferon beta-1b. All patients Early treatment Delayed treatment Probability of conversion CDMS up to 0.65 (0.42–0.99), 0.48 (0.28–0.83), 1.22 (0.59–2.5), year 5, RR (95% CI) P = 0.05 P = 0.008 P = 0.6 Cumulative number of new lesions up to 0.73 (0.60–0.90), 0.70 (0.55–0.90), 0.71 (0.52–0.97), year 5, RR (95% CI) P = 0.002 P = 0.005 P = 0.03 Percent change in T2 volume from year - 8.99 (- 15.1 - 11.0 (- 19.0 - 8.84 (- 17.14 to 1–5, % (95% CI) to - 2.5), P = 0.008 to - 2.2), P = 0.02 0.29), P = 0.06 Percent change in brain volume from year 0.34 (0.10–0.57), 0.43 (0.14–0.72), 0.17 (- 0.24 to 0.58), 1–5, % (95% CI) P = 0.005 P = 0.004 P = 0.4 All data were adjusted for age, sex, treatment, time of follow-up, and T2 lesion score at baseline CDMS Clinically definite multiple sclerosis, RR rate ratio Includes new T2 lesions, new Gd ? -enhancing lesions, and enlarging T2 lesions 1b. Across all analyses, associations were gen- were more pronounced for patients in the early erally stronger for MRI than for clinical out- treatment group than for those in the delayed comes. Nevertheless, ‘‘the latter were still treatment group (Table 2 [60] and Fig. 7 [66]), remarkable considering the overall low rate of although a test for interaction between relapses (0.2 per year) and small EDSS score 25(OH)D levels and treatment assignment was change (median change, 0.0) in BENEFIT’’ [60]. significant only for the time to CDMS (P = 0.04) Strengths of the BENEFIT study included (1) [62]. These results suggest that early treatment its longitudinal design, (2) the exclusive with IFNB-1b may have an additive effect along recruitment of patients at the CIS stage, (3) the with 25(OH)D to reduce disease severity and use of repeated serum 25(OH)D measurements, progression in both clinical and imaging (4) the large number of patients, (5) standard- outcomes. ized treatment (e.g., early vs. late IFNB-1b), and To explore the mechanistic rationale for the (6) rigorous clinical and MRI assessment of all potential additive effects of 25(OH)D levels and patients during a 5-year period. Limitations of early IFNB-1b treatment, Munger and col- the study included (1) the fact that most leagues conducted a global gene expression patients were eventually treated with IFNB-1b analysis in which expression profiles were and some crossed over during the 2 years of the measured at various time points among partic- study, and (2) while a clear dose response was ipants in the BENEFIT clinical trial [67]. The observed for the most sensitive MRI outcomes, relationship between genes or gene sets the effects did not reach a plateau level, and, expressed in association with 25(OH)D and therefore, serum 25(OH)D levels greater than those associated with MS activity was exam- the median 69 nmol/L could have had a greater ined. The numbers of Gd?-enhancing lesions effect. According to the authors, a low 25(OH)D served as a marker of disease activity. A level early in the disease course is a strong risk 50 nmol/L increase in serum 25(OH) levels factor for long-term MS activity and progression reduced the Gd? lesion count by 55%. Adjust- in patients with early MS who were treated with ing for gender, age, treatment, and treat- IFNB-1b [60]. ment - 25(OH)D interaction did not alter the The BENEFIT cohort had an early treatment significance of the findings. Gene expression in group and a delayed treatment group. The whole blood was studied in 295 individuals, associations of 25(OH)D levels and MS activity evaluating approximately 19,000 genes. Neurol Ther (2018) 7:59–85 73 Fig. 7 Data from the Vitamin D analysis of the BENEFIT versus C 50 nmol/L in all patients and those with early trial. Comparison of probability of conversion to CDMS or delayed start of interferon beta-1b. Reproduced with in patients with plasma 25(OH)D\50 nmol/L permission from [66] Reduced Gd? lesion count was significantly course and disease progression as characterized associated with increased expression of by MRI and clinical endpoints [58]. Eligible 25(OH)D-related genes, an effect that was patients for the vitamin D analyses included independent of IFNB-1b treatment. This effect 1482 participants randomized to receive 250, or was also noticed when looking at single genes 500 lg of IFNB-1b with at least two measure- that were associated with regulation of ments of 25(OH)D obtained 6 months apart. 25(OH)D levels. The authors hypothesized that Serum 25(OH)D measurements were performed there was an additive effect of 25(OH)D and at baseline, 6, and 12 months. IFNB-1bin reducing Gd? lesion counts [67]. In longitudinal analyses, 25(OH)D was The second data set from randomized, dou- inversely correlated with the cumulative num- ble-blind, phase 3 trials in MS was derived from ber of active lesions between baseline and the the BEYOND (Betaseron Efficacy Yielding last MRI (average follow-up time, 2 years). A Outcomes of a New Dose) study [61]. Compared 50-nmol/L higher level of serum 25(OH)D was with the BENEFIT study, the BEYOND study associated with a 31% lower rate of new lesions included patients with established MS (vs. [relative rate (RR), 0.69; 95% CI, 0.55–0.86; patients with CIS) and was shorter in duration P = 0.001]. This inverse association was also (2 vs. 5 years). It also included considerably strong and significant in analyses restricted to more patients (1482 vs. 465) and was conducted patients with 25(OH)D levels[50 nmol/L (RR, in different geographical regions (North Amer- 0.62; 95% CI, 0.46–0.84; P = 0.002) and was ica, Western and Eastern Europe, Southern consistent in each of the four geographic Hemisphere vs. Europe and Canada). regions (Fig. 8)[61]. The lowest rate of new BEYOND was a large, phase 3, prospective, lesions was observed among patients with multicenter, blinded, randomized clinical trial. 25(OH)D levels[100 nmol/L (RR, 0.53; 95% CI, Patients were monitored for at least 2 years. 0.37–0.78; P = 0.002). No significant associa- Clinical visits were scheduled every 3 months, tions were found between 25(OH)D levels and and an MRI was performed at baseline and change in brain volume, relapse rates, or EDSS annually thereafter. A post hoc analysis assessed scores [61]. Strengths of this study include the 25(OH)D levels and the subsequent MS disease large number of participants, the regionally 74 Neurol Ther (2018) 7:59–85 Effects of Disease-Modifying Therapies on Vitamin D Levels in MS Patients MS disease activity may be additively affected by vitamin D and IFNB-1b [60]. This hypothesis is supported by investigations from the same researchers suggesting that processes regulated and triggered by 25(OH)D may be additively enhanced by IFNB-1b [67], and independently by observations from Stewart and colleagues from the Menzies Research Institute in Tasma- nia [68]. In an observational cohort study, conducted in 178 patients with MS, vitamin D levels were measured every 6 months over an average of 2.2 years. Patients who took an Fig. 8 The relative rate of cumulative new active lesions interferon had significantly higher 25(OH)D (NALs) vs. average of baseline, 6-month, and 12-month 25[OH]D levels stratified by geographic region. The solid levels than those who did not (P\0.001). Each lines and shaded regions represent the relative rate ratios of 10-nmol/L increase in serum vitamin D was cumulative NALs for changes in 25(OH)D relative to the associated with a 10% lower relapse rate. Inter- median level and the corresponding 95% CIs, respectively. estingly, interferon treatment was protective Analyses were adjusted for age, sex, randomization status, only against relapse among persons with higher baseline EDSS score, and disease duration. Models assume vitamin D levels. Among those with insufficient a linear association between the logarithm of the rate of vitamin D, there was an increased risk of relapse cumulative NALs and serum 25(OH)D. Analyses using despite interferon treatment. The investigators cubic splines revealed no significant deviation from hypothesized that treatment with IFNB may linearity. (To convert 25[OH]D values to ng/mL, divide increase serum vitamin D levels through by 2.496). Reproduced with permission from [61]. enhanced responsiveness to sun exposure and Copyright2015 American Medical Association. All recommended that persons being treated with rights reserved IFNB should have vitamin D status monitored and maintained in the sufficiency range [68]. diverse population with varying baseline char- Also, noteworthy from these data, this group acteristics, and the repeated measurements of did not find similar associations for glatiramer 25(OH)D, which helped characterize patients’ acetate (GA) therapy and vitamin D. long-term vitamin D status. The relatively short The notion of complementary or even syn- follow-up is the most important limitation of ergistic effects of IFNB and vitamin D is further this study. This limited follow-up may explain supported by observations from Rotstein and the lack of association between serum 25(OH)D coworkers based on the CLIMB (Comprehensive levels and measures of brain atrophy or clinical Longitudinal Investigation of MS at Brigham endpoints, both of which were modified by and Women’s Hospital) cohort [69]. The CLIMB 25(OH)D in the longer BENEFIT study [60, 61]. cohort is a prospective cohort study that began Regarding targeted vitamin D levels, the authors enrolling patients in 2000. The objective of the stated: ‘‘Our observation of the lowest level of study was to determine whether 25(OH)D levels MS activity among patients with serum predicted new disease activity in MS patients 25(OH)D levels above 100.0 nmol/L [40 ng/mL] treated with IFN-b (n = 96) or GA (n = 151). is consistent with the results of a previous Separately, due to different selection criteria, a investigation in the US [50], and suggests that similar analysis was conducted for patients the 25(OH)D levels in most patients with MS treated with fingolimod (FTY, n = 77). Serum who are not receiving supplemental vitamin D 25(OH)D concentration was adjusted for sea- may be suboptimal’’ [53]. son, and patients were divided into subgroups by 25(OH)D tertile. The primary study endpoint Neurol Ther (2018) 7:59–85 75 was ‘time to first inflammatory event’, defined disease activity after initiation of IFNB. With as a combination of either first relapse or first clinical measures, neither the occurrence of Gd? lesion, using a Cox model adjusted for age, relapses nor EDSS progression was associated sex, and disease duration. The results demon- with 25(OH)D levels during both study phases. strated higher 25(OH)D levels associated with a Strengths of the study were the prospective longer time to the combined first event in the design and the frequent MRI and 25(OH)D IFNB subgroup [hazard ratio (HR) = 0.58; assessments during the observation period. IFNB P = 0.012], but not in GA-treated partici- Limitations were the relatively short time on IFNB pants (HR = 0.89; P = 0.50). For Gd? IFNB and the small number of participants, as GA GA lesions alone, there was a significant association well as the minimal 4 nmol/L increase in serum observed in GA and IFNB subgroups, although vitamin D levels following vitamin D supple- the effect was more pronounced with IFNB mentation. In the discussion of the study (HR = 0.57; P = 0.039 vs. HR = 0.41; results, the authors expressed their surprise GA GA IFNB P = 0.022). No significant associations were about the lack of an association between IFNB found for relapses. There were some sampling 25(OH)D levels and MRI after initiation of IFNB, difficulties in this cohort and, therefore, the ‘‘as there is no evidence suggesting that the results need to be interpreted with certain cau- immunomodulatory effects of vitamin D are tion. For FTY, due to the mandated first-dose counteracted by IFNB or vice versa. A reasonable observation, samples were available for all explanation is that IFNB reduced radiologic patients. Higher 25(OH)D was associated with a disease activity, leaving relatively little left to be longer time to the first event (HR = 0.48; reduced’’ by vitamin D [70]. FTY P = 0.016) and with relapses (HR = 0.50; FTY FTY P = 0.046), but not with Gd? lesions [69]. FTY THE ROLE OF SUPPLEMENTAL The large, prospective cohort and the prolonged follow-up times were strengths of this study, as VITAMIN D IN MS well as the availability of two 25(OH)D mea- surements for the majority of patients. How- When reviewing available data discussing the ever, more regular 25(OH)D measurements effects of vitamin D and MS, of key interest is whether vitamin D supplementation can would have been ideal and offered greater insights into study conclusions [69]. favorably alter the course of MS. Unfortunately, current evidence does not offer consensus to answer this question. Studies with vitamin D Studies Contradicting the Association alone or with vitamin D as an add-on to a dis- of Vitamin D Levels with Disease Activity ease-modifying therapy are conflicting [22, 71–81]. Although these studies are gener- Contradictory to the aforementioned informa- ally small, largely uncontrolled, and used tion are findings reported by researchers from highly variable doses of vitamin D, it can be Norway [70]. In this small prospective cohort noted that there are initial promising data study, 88 patients with RRMS were followed arguing for vitamin D supplementation in with regular MRI and 25(OH)D measurements patients with MS [22, 75–81]. Furthermore, during 6 months before and up to 18 months recent investigations with immunological after initiation of IFNB. During the pre–IFNB response markers suggest that vitamin D sup- treatment phase, higher levels of 25(OH)D were plementation in patients with MS exhibits associated with reduced MRI activity; each in vivo pleiotropic immunomodulatory effects 10-nmol/L increase in 25(OH)D was associated in MS [82], and lacking evidence of a treatment with 12.7% (P = 0.037) lower odds for new T1 effect does not necessarily demonstrate proof of Gd ? lesions, 11.7% (P = 0.044) lower odds for no effect. new T2 lesions, and 14.1% (P = 0.024) lower odds for combined unique activity. However, there was no association between 25(OH)D and 76 Neurol Ther (2018) 7:59–85 Studies Supporting the Benefit group, but these differences also did not reach of Supplemental Vitamin D significance (P = 0.322). While there was no significant difference in annual relapse rate demonstrated between groups, there was a Researchers from Finland conducted a 1-year, tendency toward reduced disability accumula- randomized, double-blind, placebo-controlled tion as measured by EDSS (P = 0.071) and trial with vitamin D3 as an add-on treatment to toward improved timed tandem walk IFNB-1b in patients with MS. Thirty-four (P = 0.076). There were no significant differ- patients were randomly assigned to the treat- ences in adverse events between the groups. The ment group (vitamin D, 20,000 IU/week vita- authors concluded that larger randomized, min D3 (cholecalciferol), and IFNB-1b) and 32 controlled trials with more than 1 year of fol- to the control group (placebo and IFNB-1b) [75]. low-up are warranted to confirm the promising The primary outcome measure was an MRI T2 MRI results and to fully address clinical out- burden of disease (BOD), which tended to comes [75]. increase more in the placebo group (median A study by Burton and colleagues introduced change of 287 mm ) than in the vitamin D earlier in this manuscript in the context of the group (median change of 83 mm ); however, safety profile of higher doses of vitamin D sup- the difference was not statistically significant plementation also offers insight into the role of (P = 0.105) (Fig. 9)[75]. Results for other MRI vitamin D supplementation and the disease outcomes were mixed. The number of T1 Gd? course of MS [22]. In this open-label, controlled lesions decreased in both groups (P = 0.002), trial, patients were randomized to a vitamin D but the change was significantly higher in the treatment group (n = 25, escalation protocol vitamin D group (P = 0.04). New/enlarging T2 4000–40,000 IU/day, mean 14,000 IU/day) or to lesions at the 12-month point trended higher in a control group (n = 24, received vitamin D3 the placebo group, but the differences were not 4000 IU/day if desired). Despite the high doses statistically significant (P = 0.286). The per- of vitamin D, no significant adverse events centage of patients with MRI activity (12-month occurred during the 52-week study period. The time point) trended lower in the vitamin D annualized relapse rate during the trial year was lower in the treatment group than in the con- trol group (0.26 vs. 0.45; P = 0.09), and more patients in the treatment group remained relapse free. Additionally, the treated patients reported a persistent reduction in T-cell prolif- eration compared with controls, and treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell pro- liferation compared to controls. Study limita- tions included the use of supplementation or other agents in the control group, the small sample-size, and thus the limited power [22]. The Danish Multiple Sclerosis Center prospectively gathered data in a cohort of 170 Fig. 9 Change in MRI T2 burden of disease (BOD) from natalizumab-treated patients during winter baseline to month 12 in the vitamin D-treated and 2009–2010 (baseline) with follow-up during the placebo-treated patients. Data are mean ± standard error subsequent winter [78]. Patients with insuffi- of 34 patients in the vitamin D group and 32 patients in cient serum 25(OH)D levels (selected cut-off the placebo group at baseline and 32 in the vitamin D 50 nmol/L) at baseline were advised to take group and 30 in the placebo group at 12 months. The Vitamin D supplements according to Danish P value for the difference between vitamin D and placebo recommendations: 2000 IU for patients with is 0.105 (trend). Reproduced from [75], with permission levels between 25 and 50 nmol/L, 3000 IU for from BMJ Publishing Group Ltd Neurol Ther (2018) 7:59–85 77 those with levels between 25 and 12.5 nmol/L a quarter of the patients not returning to the and 4000 IU for those with levels below month 3 visit. The authors also described not 12.5 nmol/L. 134 patients were included in the allowing true control for other sources of vita- clinical data set. Of the 134 patients, 43 had min D as other possible confounders, such as taken vitamin D supplements due to vitamin D sun exposure and dietary vitamin D [79]. insufficiency (mean 25(OH)D levels: 34 nmol/L). Only available in abstract format are the Their levels increased significantly by results of two studies which evaluated the ben- 32.6 nmol/L (95% CI: 24.4–40.8 nmol/L, efits and risks associated with high-dose vitamin P\0.0001) from baseline to follow-up. More- D supplementation in patients treated with over, a significant inverse relationship with the IFNB-1a. Although both failed to demonstrate annualized relapse rate (ARR) was found: for an effect on clinical parameters, their MRI each nmol/l increase in 25(OH)D, a 0.014 (95% results demonstrated positive results. • SOLAR is a randomized, double-blind, pla- CI - 0.026 to - 0.003) decrease in ARR was observed (P = 0.02). Overall, the data suggest cebo-controlled, multicenter, phase 2 study. Two hundred and twenty-nine patients with that correcting vitamin D insufficiency by the means of vitamin D supplements in patients a 25(OH)D serum level below 150 nmol/L with MS may be beneficial [78]. were randomly assigned to cholecalciferol at Darwish and colleagues looked into the a dose of 14,000 IU per day or placebo [80]. cognitive effects of vitamin D supplementation All patients received subcutaneous IFNB-1a. of patients with MS on IFNB [79]. At baseline, After recruitment delays, the study design patients were stratified into a vitamin D-defi- was adjusted and the percentage of patients cient group (25(OH)D levels\25 ng/mL or with ‘‘disease activity free’’ status (defined as 62.5 nmol/L, N = 39) and a vitamin D-sufficient no relapses, no EDSS progression, and no new Gd? or T2 MRI lesions) at week 48 were group (25(OH)D levels[35 ng/mL or 87.5 nmol/L). ‘‘Deficient’’ patients received introduced as a new primary endpoint. This endpoint was not met (37.2% for cholecal- 10,000 IU vitamin D3 daily for 3 months and reported a significant increase of 25(OH)D levels ciferol group vs. 35.3% for placebo group, to 49.0 ± 14.6 ng/mL (122.5 ± 36.5 nmol/L). P = 0.912). Likewise, no differences between Additionally, after 3 months these ‘‘deficient’’ groups for other clinical parameters such as patients scored better on the Brief Visuospatial ARR or EDSS were found. However, results Memory test delayed recall (BVMT-DR, regarding the MRI parameters were promis- P = 0.02) and the montreal cognitive assess- ing with a significant 32% reduction in the ment (MoCA, P = 0.006), but not on the symbol number of new, combined, unique active digit modalities test (SDMT) and Stroop. The lesions in the cholecalciferol group (P = 0.005). Furthermore, there was a trend authors concluded that the lack of significant change on the SDMR and Stroop testing was due toward more cholecalciferol recipients being to the short disease duration and the propensity free from new T1 hypointense lesions, which for study participants to perform within normal became significant in those aged 18–- ranges for these tests. 30 years. The short duration of the trial Alternatively, ‘‘sufficient’’ patients continued (48 weeks) and the relatively small sample their usual treatment that may have included size (229 patients) may have led to the lack vitamin D3 supplementation at various dosages. of significance of the clinical outcomes. For These patients reported 25(OH)D levels at comparisons, most randomized trials of new 64.2 ± 18.7 ng/mL (160.5 ± 46.8 nmol/L) at MS drugs recruited over 800 patients to be study end. Sufficient 25(OH)D levels predicted able to demonstrate a significant effect vs. placebo. Despite the large sizes, some were better cognitive performance on the BVMT-DR at baseline and 3 months after adjusting for all not able to show a significant effect on measured confounding variables. Study limita- disability progression (e.g. CONFIRM study tions included a small study population [83] TRANSFORMS [84]). Additionally, these (N = 88), short study duration (3 months), and data are not placebo-controlled, but rather 78 Neurol Ther (2018) 7:59–85 an active comparator. Also, the power anal- participants were asked to respond to a health- ysis is not designed to assess a minor effect related quality-of-life (HRQoL) questionnaire. and would require[10,000 patients. Bivariate and multivariate analyses were used • Likewise, the second study was a random- for comparisons, including multiple linear ized, placebo-controlled, phase 2 study [81]. regression modeling. Nearly two thirds of One hundred and twenty-nine patients respondents (64.6%) lived in the Northern (N = 129) were randomly assigned to receive Hemisphere, mostly in developed countries. 100,000 IU of cholecalciferol twice monthly Most (82.3%) were female, with a median age of (equivalent to a daily dose of 7143 IU) in 45 years (interquartile range [IQR]: 38–53 years) addition to IFNB-1a over a 24-month period. and a median time since diagnosis of 6 years Again, significant effects in favor of vitamin (IQR: 3–12 years), with the majority (61.6%) D supplementation were found for selected having RRMS. More than 80% of the patients MRI parameters such as new or enlarged indicated that they took vitamin D supple- weighted T1 and T2 lesion, but no effect was ments, mostly between 2000 and 5000 IU daily found for clinical parameters [81]. (Table 3)[77], and 67% reported intentional sun A preliminary study from Iran conducted by exposure to raise vitamin D levels. Etemadifar and colleagues assessed the safety Unadjusted regression modeling incorporat- and efficacy of high-dose vitamin D supple- ing deliberate sun exposure, latitude, and vita- mentation during pregnancy in women with min D supplementation showed strong MS [76]. Fifteen pregnant women with con- associations between sun exposure and HRQoL. firmed MS and with serum 25(OH)D However, the effect disappeared when control- levels\50 nmol/L (20 ng/mL) were randomly ling for age, disability, physical activity, and fish allocated to received 50,000 IU/week (daily dose consumption. In contrast, the associations of 7143 IU) vitamin D3 or routine care from 12 between supplementation of vitamin D and to 16 weeks of gestation until delivery. 25(OH)D HRQoL were maintained when adjusting for levels increased significantly and no significant these variables, with a dose–response effect. The adverse events occurred. The women in the beneficial effect of vitamin D supplementation vitamin D group had significantly fewer relapses on HRQoL was considered to be of ‘‘clinically during pregnancy (0 vs. 5; P\0.05), a tendency significant magnitude’’ [77]. Lower annualized for fewer relapses up to 6 months after preg- relapse rates were significantly associated with nancy (0 vs. 4; statistically nonsignificant), and taking vitamin D supplementation vs. not tak- a more stable EDSS than those without supple- ing supplements. The dose taken seemed to be mentation. The authors advocated for adding of less importance. No effect on disability was high-dose vitamin D3 supplementation during found for either supplementation or deliberate pregnancy to the routine care of women with sun exposure, but an increase of latitude by 1 MS. Study limitations included a small sample (farther from the equator) predicted increased size, and conclusions are limited by the loss to odds of moderate or high disability [77]. follow-up of 37 out of 52 of the original baseline cohort [76]. Table 3 Self-reported average daily dose of supplemental The role of vitamin D supplementation in vitamin D in an Internet survey among 2301 patients with patients with MS was also evaluated by Jelinek MS. Originally published on BioMed Central, an open and colleagues, with the authors taking a very access journal, in [77] different epidemiological approach [77]. This was an internet survey among 2301 patients Vitamin D dose N Percentage with MS who self-reported data on geographical [5000 IU 447 20.4 location, intentional sun exposure for health, 2001–5000 IU 734 33.5 supplementation with vitamin D, and other lifestyle variables, as well as self-reported doc- 1–2000 IU 613 28.0 tor-diagnosed relapse rates and disability (Pa- None 399 18.2 tient Determined Disease Steps). Survey Neurol Ther (2018) 7:59–85 79 The large data set may compensate for some data in favor of the low-dose group. In addition, of the limitations of this study design. Vitamin this study compared low-dose and high-dose D supplementation (along with all other mea- vitamin D administration and did not utilize a sures) was self-reported and not validated with concurrent control group of subjects that did blood tests. No validated tool exists for quanti- not receive any supplemental vitamin D. fying variables like deliberate sun exposure; in Finally, even though vitamin D2 seems to be a this study, the question required simply a yes/ less potent form of vitamin D than vitamin D3 no answer [78]. Furthermore, there might be a in all primate species [17], the 1000-IU/day selection bias in terms of the patients included, regimen for the low-dose group is above what as respondents to such Internet surveys are the IOM recommends in terms of daily intake patients who are typically very ‘‘engaged’’ with [4] and both groups may have benefited from their situation and disease. vitamin D supplementation. In a 96-week, randomized, controlled trial designed to evaluate the effects of supplemen- Studies Contradicting the Benefit tation with 20,000 IU/week of vitamin D (aver- of Supplemental Vitamin D aged to approximately 2800 IU/day) on bone mineral density in 35 MS patients, Kampman A study by Stein and colleagues is widely dis- and colleagues found that consumption of cussed among those not supporting vitamin D vitamin D did not result in beneficial effects on supplementation [72]. In this 6-month, double- the measured MS-related outcomes, which blind, placebo-controlled, randomized trial, included annualized relapse rates. However, the patients were allocated to either high or low study was not powered to address clinical out- dose of vitamin D2. The high-dose regimen was comes [73]. The authors suggested that the low 6000 IU twice daily, the low-dose regimen annualized relapse rate seen at baseline could 1000 IU daily. Twenty-three patients were have contributed to the absence of significant included (11 in the treatment arm, 12 in the effects in this study. Study limitations included control group). There were no significant dif- a small sample size (N = 68), which may be ferences between the groups on the two primary inadequate for assessing effects on clinical out- endpoints—cumulative number of new Gd? comes [73]. lesions and change in the total volume of T2 Furthermore, two studies from Iran did not lesions—nor were there differences on clinical find a beneficial effect of vitamin D supple- outcome measures, such as number of relapses mentation on clinical or MRI outcome measures and effect on EDSS [72]. Neurology, in which the in patients with RRMS. Shaygannejad and col- manuscript was published, ranked the study as leagues studied 50 patients in a 12-month, providing class I evidence, but this rating is randomized, double-blind, placebo-controlled, arguable. Although the study was double-blind, phase 2 clinical trial [74]. The 25 patients in the placebo-controlled, and randomized, the sam- treatment group received 4000 IU/day of vita- ple size was very small (N = 23). Moreover, there min D for the first 2 weeks and were thereafter were withdrawals (two in the low-dose group, escalated to 8000 IU/day in addition to their one in the high-dose group), and one patient disease-modifying agent. The control group from the low-dose group was partially excluded (n = 25) was treated with placebo combined from MRI analyses due to brain surgery. with disease-modifying therapy. In a separate Although the authors stated that the two groups study, Mosayebi and colleagues evaluated the were well matched, one patient (in the high- effects of vitamin D3 supplementation at a dose dose group) had 38 Gd? lesions at baseline, of 300,000 IU/month vs. placebo in a random- while all other patients had between two and ized, prospective study with 62 patients [71]. five Gd? lesions at baseline. The low-dose group Over the 6-month observation period, no dif- was, on average, 10.5 years older than the high- ferences between groups on either EDSS or Gd? dose group; importantly, the number of exac- lesion count were observed, but immune-in- erbations in MS declines over time, biasing the hibitory transforming growth factor beta and 80 Neurol Ther (2018) 7:59–85 interleukin 10 were significantly higher in the ongoing, and results are expected in 2018 or 2019. vitamin D-supplemented group compared with placebo [71]. • The Vitamin D to Ameliorate Multiple Sclerosis (VIDAMS) study (NCT01490502) Several of the studies above were included in a meta-analysis conducted by James and col- [88, 90] is a randomized, controlled, phase leagues evaluating the effect of vitamin D-re- 3 study that aims to include 172 patients in lated intervention trials on MS relapses [85]. the US. After a run-in phase of 1 month on The five studies [22, 72–75] included 129 GA, patients will be assigned to low-dose patients with high-dose vitamin D supplemen- (600 IU/day) vs. high-dose (5000 IU/day) tations and 125 controls. Administered doses of vitamin D3 as an add-on therapy to GA. This academic study is currently recruiting vitamin D supplementations, study designs, patient populations, outcome parameters, and patients and will terminate in 2018 [86, 88]. Clinical and MRI parameters will also be observation period were considerably variable among the assessed studies. Given these differ- evaluated. ences, the numerous limitations of each of these studies and the mixed reported study SUMMARY AND CONCLUSIONS results, it is not surprising that the meta-analy- sis did not find a significant association between Evidence available to date suggests that the vitamin D treatment and the relative risk of level of serum vitamin D affects the risk of relapse in MS [85]. In the view of the authors, developing MS and also modifies disease ‘‘further larger and more prolonged studies…are activity in MS patients. Until several years ago, merited’’ to better understand the role of vita- evidence that higher levels of vitamin D are min D supplementation in MS [85]. associated with favorable effects on MS risk and a reduction in MS activity was supported Ongoing Studies Evaluating the Role largely by observational studies. Limitations of of Supplemental Vitamin D in MS these studies restricted confidence in a specific effect of vitamin D in MS. Newer data with A search of recently initiated and ongoing Mendelian randomization analyses suggest clinical studies evaluating the role of supple- there is a causal relationship between low mental vitamin D in MS revealed the following: vitamin D level and the risk of MS. Further- • The Efficacy of Vitamin D Supplementation more, post hoc evaluations from the phase 3 in Multiple Sclerosis (EVIDIMS) study BENEFIT and BEYOND studies substantiate (NCT01440062) [86, 87] is a German multi- findings of observational trials. Across all trials, center, stratified, randomized, controlled, associations between 25(OH) levels and MS double-blind, clinical phase 2 study. Eighty and its activity are generally stronger for MRI patients with CIS or MS whose disease than for clinical outcomes, which may be due courses were stable while taking IFNB-1b to the higher sensitivity of MRI compared to were randomized to receive either high-dose typical clinical parameters. Low or even insuf- (on average, 10,200 IU/day) or low-dose (on ficient 25(OH)D levels were common in many average 200 IU/day) vitamin D3 for earlier cohorts. Patients in more recent studies 18 months as a supplement. The primary have higher baseline vitamin D levels, poten- outcome measure is the number of new T2 tially changing the immunopathology of MS lesions. Secondary endpoints include addi- and altering responses to some therapeutic tional MRI and optical coherence tomogra- drugs. phy (OCT) parameters, clinical parameters, In aggregate, studies suggest that vitamin D as well as cognition, fatigue, depression, and supplementation may be beneficial for patients quality of life. Safety and tolerability of high- with MS and others. However, the study limi- dose vitamin D supplementation are addi- tations identified in this review recognize the tional outcome measures. This study is need for larger controlled clinical trials to Neurol Ther (2018) 7:59–85 81 establish vitamin D supplementation as the Disclosures. Martina B Sintzel, PhD has standard of care for MS patients. Though there received consultancy fees from Bayer and Fre- is increasing evidence indicating that lower senius. Mark Rametta, D.O is employed by vitamin D levels are associated with increased Bayer. Anthony T. Reder, MD has received risk of MS and greater clinical and brain MRI unrestricted grant and clinical trials support activity in established MS, the impact of vita- from Bayer, Biogen, Novartis, Serono, and Teva. min D supplementation on MS activity remains Compliance with Ethics Guidelines. This inadequately investigated. There is no consen- article is based on previously conducted studies, sus on ‘‘sufficient’’ vitamin D levels. In the view and as such, and does not involve any new of IOM, 25(OH)D levels greater than 50 nmol/L studies of human or animal subjects performed (20 ng/mL) are sufficient. The Endocrine Society by any of the authors. argues for 75 nmol/L (30 ng/mL) or higher, based on a medical model which takes into Data Availability. Data sharing is not account skeletal and non-skeletal health. applicable to this article as no datasets were Numerous studies suggest that serum 25(OH)D generated or analyzed during the current study. levels of approximately 100 nmol/L (40 ng/mL) are the lower limit for controlling MRI and Open Access. This article is distributed clinical activity in patients with MS. More under the terms of the Creative Commons research is needed to establish the recom- Attribution-NonCommercial 4.0 International mended levels of vitamin D supplementation License (http://creativecommons.org/licenses/ necessary to reduce the risk for MS and MS by-nc/4.0/), which permits any noncommer- clinical activity. cial use, distribution, and reproduction in any In conclusion, based on the data reviewed, medium, provided you give appropriate credit identification and correction of vitamin D to the original author(s) and the source, provide insufficiency with supplementation at recom- a link to the Creative Commons license, and mended doses is a sensible clinical indicate if changes were made. action/course/target/objective and one that provides a favorable risk–benefit profile for vitamin D for most patients with MS. REFERENCES 1. Munger K, Levin L, Hollis B, Howard N, Ascherio A. ACKNOWLEDGEMENTS Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. 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Vitamin D and Multiple Sclerosis: A Comprehensive Review

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Neurol Ther (2018) 7:59–85 https://doi.org/10.1007/s40120-017-0086-4 REVIEW Vitamin D and Multiple Sclerosis: A Comprehensive Review . . Martina B. Sintzel Mark Rametta Anthony T. Reder Received: October 10, 2017 / Published online: December 14, 2017 The Author(s) 2017. This article is an open access publication limitations identified in this review recognize ABSTRACT the need for larger controlled clinical trials to establish vitamin D supplementation as the Numerous observational studies have suggested standard of care for MS patients. Though there that there is a correlation between the level of is increasing evidence indicating that lower serum vitamin D and MS risk and disease vitamin D levels are associated with increased activity. To explore this hypothesis, a literature risk of MS and with greater clinical and brain search of large, prospective, observation studies, MRI activity in established MS, the impact of epidemiological studies, and studies using new vitamin D supplementation on MS activity approaches such as Mendelian randomization remains inadequately investigated. was conducted. Available data and ongoing research included in this review suggest that the level of serum vitamin D affects the risk of Keywords: Autoimmune disease; Health developing MS and also modifies disease activ- outcomes; Mendelian randomization; Multiple ity in MS patients. Newer Mendelian random- sclerosis; Optic neuritis; Pregnancy; Relapsing- ization analyses suggest there is a causal remitting MS (RRMS); Supplementation; relationship between low vitamin D level and Vitamin D the risk of MS. Post-hoc evaluations from two phase 3 studies, BENEFIT and BEYOND, support the findings of observational trials. Study INTRODUCTION Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/ Knowledge of the widespread effects of vitamin F5FCF060794BDA24. D on skeletal and non-skeletal functions, including immune functions, has developed M. B. Sintzel considerably over the past 3 decades. Higher Medical Communication Services, Erlenbach, levels of vitamin D are associated with reduced Zurich, Switzerland risk for developing multiple sclerosis (MS), and M. Rametta with reduced clinical activity in established MS, Bayer HealthCare Pharmaceuticals, Whippany, NJ, including decreased risk of relapse and reduc- USA tion in disease activity on brain MRI [1, 2]. A. T. Reder (&) Vitamin D supplementation may diminish the Department of Neurology, University of Chicago, risk of MS in the general population, as well as Chicago, IL, USA in children of mothers supplemented before e-mail: areder@neurology.bsd.uchicago.edu 60 Neurol Ther (2018) 7:59–85 and during pregnancy [3]. In the information exposure for 20 min for a light-skinned person that follows, we will summarize the available during the summer months will produce data on vitamin D, with a focus on vitamin D’s upwards of 10,000 IU of vitamin D [7, 10]. effects on the risk of onset of MS and on the However, UVB exposure and vitamin D pro- disease course of MS. duction through the skin may be reduced with increased skin pigmentation, age, use of sun- screen, and environmental factors such as win- Sources, Metabolism, and Biological ter season, high latitude, pollution, cloud cover, Functions of Vitamin D and ozone levels [7]. For instance, sun exposure during most of the winter at latitudes Vitamin D is a lipid-soluble vitamin, but acts above * 33 North (e.g., Atlanta, GA, USA; like a hormone. Unlike a vitamin, which is an Casablanca, Morocco) and below * 33 degrees essential organic compound that cannot be South (e.g., Santiago, Chile; New South Wales, synthesized by the body and must be ingested, Australia; Southern Cape of Africa) provides vitamin D can be synthesized [4]. The active minimal, if any, vitamin D production [11]. form of vitamin D, 1,25-dihydroxyvitamin D Both forms of vitamin D, cholecalciferol, and (1,25[OH] VD), also known as calcitriol (Fig. 1) ergocalciferol are biologically inactive and [5] has chemical similarities to typical hor- undergo an enzymatic transformation in the mones such as testosterone, estrogen, and cor- liver to 25(OH)D (calcidiol). Stimulated by tisol [6]. The main sources of vitamin D are parathyroid hormone, 25(OH)D goes through a sunlight, diet, and supplementation (Fig. 2)[7]. second hydroxylation in the kidney or other UVB in the 290–315-nm range photolyses tissues to 1,25(OH) VD (also known as calcitriol 7-dehydrocholesterol in the skin to form pre- if derived from vitamin D3), which is the active vitamin D3, which then isomerizes to vitamin metabolite (Figs. 1 and 2)[5, 7]. 1,25(OH) VD D3 or cholecalciferol [8]. Foods rich in vitamin has a half-life of several hours, while 25(OH)D D include fatty fish (e.g., salmon, mackerel), cod has a relatively long half-life (20–60 days), and liver oil, egg yolk, and shiitake mushrooms. The thus more accurately exemplifies the overall plant form of vitamin D is called vitamin D2 or vitamin D stores in the body. This supports the ergocalciferol [9]. Cholecalciferol and ergocal- standard practice of measuring 25(OH)D in ciferol are also available from fortified foods serum, and represents an integrated measure of (e.g., milk, cereal, some orange juice, and vitamin D derived from both UVB exposure and cheeses) and vitamin supplements. diet. As a side note, most assays that evaluate Relative to sun exposure, diet is a poor source 25(OH)D do not discriminate between the of vitamin D, providing only 40–400 IU per original forms of vitamin D (vitamin D3 or D2). food serving, whereas whole-body UVB Fig. 1 Chemical structures of the physiologically inactive (25[OH]D) (c); and the bioactive vitamin D3 metabolite vitamin D2 (a) and vitamin D3 (b); the main circulating 1,25-dihydroxyvitamin D (1,25[OH] VD) (d), or cal- vitamin D3 intermediate, 25-hydroxyvitamin D citriol if derived from vitamin D3 [5] Neurol Ther (2018) 7:59–85 61 Fig. 2 Sources and metabolism of vitamin D: The main 1,25(OH) VD has a half-life of several hours, while the sources of vitamin D are sunlight, diet, and supplemen- intermediate vitamin D form 25-hydroxyvitamin D tation. The primary forms of vitamin D are biologically [25(OH)D] has a relatively long half-life (20–60 days), inactive and need for their activation two hydroxylation and thus more accurately exemplifies the overall vitamin D steps in the liver and kidney. The hormonally active final stores in the body [7]. Reprinted from [7], with permission product is 1,25-dihydroxyvitamin D [1,25(OH) VDO]. from Elsevier However, the latter is usually a minor compo- was very common among children in industri- nent because natural sources of ergocalciferol alized cities, and observations were made that are scarce, and ergocalciferol is more rapidly sunlight exposure or cod liver oil may help to catabolized than cholecalciferol [7]. prevent this condition [10]. Other muscu- The active metabolite 1,25(OH) VD is loskeletal consequences of vitamin D deficiency released into the bloodstream and transported include secondary hyperparathyroidism, in the blood. It binds to the vitamin D binding increased bone turnover, bone loss, and risk of protein in blood and on the surface of target low-trauma fractures. Today, we understand tissues. 1,25(OH) VD mediates its biological that VDR is widely distributed throughout the human body and involved in many biological effects by binding to intracellular vitamin D receptor (VDR), which then recruits cofactors to functions. Vitamin D deficiency has been asso- form a transcriptional complex that binds to ciated with numerous diseases including can- vitamin D response elements [12]. This associ- cers, cardiovascular diseases, type 2 diabetes ation regulates the expression of at least 500 mellitus, infectious diseases, mental disorders, genes that drive a variety of physical functions and autoimmune disorders such as type 1 dia- [7]. The VDR is found in almost all human tis- betes mellitus, Crohn’s disease, and MS [10, 13]. sues, not just those participating in the classic These diseases are all linked to vitamin D levels actions of vitamin D, such as bone, gut, and that are sufficient to prevent rickets, but are still kidney. The non-classic actions of VDR can be suboptimal. Curiously, as rickets is no longer a allocated to three main categories: regulation of problem, one might assume that the vitamin D hormone secretion, regulation of immune deficiency problem is also no longer an issue. function, and regulation of cellular prolifera- However, now that we know that autoimmu- tion and differentiation [12]. nity may be related to low vitamin D levels, and Vitamin D deficiency has been classically that the incidence of autoimmune diseases has attributed to bone health. In the early 1900s, increased, we must consider if there is a higher rickets, a consequence of vitamin D deficiency, vitamin D threshold related to autoimmunity, 62 Neurol Ther (2018) 7:59–85 or if the environment changed since the • In macrophages and monocytes, 1,25(OH) VD positively impacts its own Industrial Revolution. effects by increasing the expression of VDR and the cytochrome P450 protein, CYP27B1. Roles of Vitamin D in Immunity • Certain Toll-like receptor (TLR)-mediated signals also can increase the expression of Since multiple sclerosis (MS) is considered an VDRs. autoimmune disease, it is of interest to review • The active form of vitamin D induces mono- briefly the potential effects of vitamin D related cyte proliferation and the expression of to immune function. The active form of vita- interleukin-1 (IL-1) and cathelicidin (an min D plays an essential role in lymphocyte antimicrobial peptide) by macrophages, con- activation and proliferation, T-helper cell dif- tributing to innate immune responses to ferentiation, tissue-specific lymphocyte hom- some bacteria. ing, the production of specific antibody • 1,25(OH) VD decreases DC maturation, isotypes, and regulation of the immune inhibiting upregulation of the expression of response [14]. Targeted immune cell types MHC class II, CD40, CD80, and CD86. In include macrophages, dendritic cells, and T and addition, it decreases IL-12 production by B cells. Mora and colleagues (Fig. 3)[14] sum- DCs while inducing the production of IL-10. marized the roles and effects of vitamin D on • In T cells, 1,25(OH) VD reduces the produc- these immune cell types [14]: tion of IL-2, IL-17, and interferon-c (IFNc) • Macrophages and dendritic cells (DCs) con- and attenuates the cytotoxic activity and stitutively express VDRs, whereas VDR proliferation of CD4? and CD8? T cells. expression in T cells is upregulated only • The active metabolite of vitamin D might after activation. also promote the development of forkhead Fig. 3 Potential mechanisms of vitamin D immunomod- vitamin D receptor (VDR), whereas VDR expression in T ulation: systemic 1,25(OH)2VD3 affects several immune- cells is only upregulated following activation. Reprinted by cell types, including macrophages, dendritic cells (DCs), T permission from Macmillan Publishers Ltd: [14] and B cells. Macrophages and DCs constantly express Neurol Ther (2018) 7:59–85 63 Table 1 Definition of vitamin D status [as measured by blood levels of 25(OH)D] and daily vitamin D intake recom- mended by the Institute of Medicine (IOM) and the Endocrine Society [4, 11, 13, 16] Institute of medicine Endocrine society Vitamin D status ‘‘Deficient’’ – B 20 ng/mL (B 50 nmol/L) ‘‘Insufficient’’ – 21–29 ng/mL (51–74 nmol/L) ‘‘Sufficient’’ 20 ng/mL (50 nmol/L) C 30 ng/mL (C 75 nmol/L) ‘‘Ideal’’ – 40–60 ng/mL (100–150 nmol/L) Considered ‘‘safe’’ – B 100 ng/mL (B 250 nmol/L) Daily vitamin D intake recommendations (upper limits) Infants 400 IU/day (1000–1500 IU/day) 400–1000 IU/day (2000 IU/day) Children 600 IU/day (2500–3000 IU/day) 600–1000 IU/day (4000 IU/day) Adults 600 IU/day (4000 IU/day), 800 IU/day for seniors 1500–2000 IU/day (10,000 IU/day) box protein 3 (FOXP3)? regulatory T (T ) absorption, bone mineral density, and osteo- Reg cells and IL-10-producing T regulatory type 1 malacia/rickets) aiming to prevent vitamin D (TR1) cells. deficiency in 97.5% of the general population. • 1,25(OH) VD blocks B cell proliferation, Based on the model applied, no evidence was plasma cell differentiation, and found that a serum 25(OH)D concentra- immunoglobulin production. tion[20 ng/mL (50 nmol/L) had beneficial Notable in the context of this review, many effects at a population level. Therefore, the IOM of the mechanisms of vitamin D on immune concluded that the daily requirements for vita- processes have similarities to mechanisms min D were adequate to reach the ‘‘sufficient’’ described for interferon-beta [15]. 25(OH)D level of 20 ng/mL (50 nmol/L), and that these levels were generally attained by most of the population [4, 16]. Definition of Vitamin D Deficiency Alternatively, the Endocrine Society con- and Targeted Levels of Vitamin D cluded that a level of 20 ng/mL (50 nmol/L) was not sufficient. The Endocrine Society based The clinical definition of vitamin D deficiency their recommendations on a medical model and what constitutes optimal levels has been taking into consideration available evidence on the subject of debate. Two organizations, the skeletal and extraskeletal effects of vitamin D, in Institute of Medicine (IOM) and the Endocrine addition to the few negative studies. Moreover, Society, have released separate recommenda- they took into consideration the low toxicity tions regarding vitamin D requirements potential of vitamin D supplementation. In [4, 11, 16]. Blood levels of 25(OH)D as suggested their view, serum 25(OH)D levels of C 30 ng/mL by the IOM and the Endocrine Society and the (C 75 nmol/L) are ‘‘sufficient’’ for children and recommended dietary allowances (RDAs) by adults, levels of 40–60 ng/mL (100–150 nmol/L) both organizations are provided in Table 1 are ‘‘ideal’’ (considering assay variability), and [4, 11, 16]. levels of up to 100 ng/mL (250 nmol/L) could be The foundational basis for the recommen- considered ‘‘safe’’ [11, 13]. dations by these two organizations are funda- The Endocrine Society advocates for screen- mentally different. The IOM guidelines based ing and corrective action for individuals at risk their recommendation on a population model of vitamin D deficiency. Such individuals and focused on bone health (calcium 64 Neurol Ther (2018) 7:59–85 include African American and Hispanic chil- Vitamin D Safety Risks and Vitamin D Intoxication dren and adults; pregnant and lactating women; older adults with a history of falls or nontraumatic fractures; obese children and 1,25(OH) VD stimulates intestinal calcium adults (BMI[30 kg/m ); and patients with absorption [18]. Without vitamin D, only musculoskeletal diseases, chronic kidney dis- 10–15% of dietary calcium and about 60% of ease, hepatic failure, malabsorption syndromes, phosphorus are absorbed. Vitamin D sufficiency and some lymphomas [11]. Furthermore, the enhances absorption of calcium by 30–40% and group recommends supplementation at sug- phosphorus by 80% [11, 19, 20]. Vitamin D gested daily intake and tolerable-upper-limit intoxication is characterized by hypercalcemia, levels, depending on age and clinical circum- hypercalciuria, and hyperphosphatemia and in stances (Table 1)[4, 11, 13, 16]. the long term, can lead to soft tissue and vas- cular calcification and nephrolithiasis [13]. After review of available literature, the Endo- Supplemental Vitamin D crine Practice Guidelines Committee concluded that vitamin D toxicity is a rare event caused by The recommended dietary allowance (RDA) for inadvertent or intentional ingestion of exces- vitamin D and the tolerable-upper-limit levels sively high amounts of vitamin D [11]. Con- vary with age and under certain circumstances cerns were expressed for people with 25(OH)D such as those involving pregnancy, obesity, or levels of 150 ng/mL (375 nmol/L) or higher, comorbidities. A daily dose of 600–800 IU when daily doses of vitamin D exceed 10,000 IU should satisfy the requirements for optimal or when high intake of vitamin D is combined bone health [16], but a higher intake with high intake of calcium. A dose-ranging (1000–2000 IU) is needed to achieve and main- study reported that 10,000 IU/day of vitamin tain 25(OH)D levels[30 ng/mL (75 nmol/L) D3 for 5 months in healthy men did not alter [11]. Vitamin D supplements can be adminis- their serum calcium or their urinary calcium tered daily, weekly, monthly, or every 4 months excretion, which is the most sensitive indicator to reach an adequate serum 25(OH)D concen- for potential vitamin D intoxication [21]. tration. For cases of extreme vitamin D defi- However, there is a paucity of evidence sup- ciency, a bolus application of vitamin D has porting the use of higher levels of vitamin D been proposed, but a steady-state serum over a prolonged time [11]. 25(OH)D concentration is more likely to be Safety findings in three studies conducted in maintained by more frequent, lower doses of patients with MS using doses of vitamin D vitamin D [13]. Vitamin D3 (cholecalciferol) is above 10,000 IU/day are noteworthy. One widely preferred over vitamin D2 (ergocalcif- open-label trial of vitamin D in patients with erol), as it has proven to be the more potent MS evaluated the safety of a dose-escalation form of vitamin D in all primate species, protocol from 4000 to 40,000 IU/day (mean of including humans [17]. Vitamin D supplemen- 14,000 IU/day). Concomitantly, patients tation at doses of 1500–2000 IU/day for adults received 1200 mg of calcium per day vs. a con- as suggested by the Endocrine Society appears to trol group (allowed up to 4000 IU/day of vita- be well tolerated, with relatively minor con- min D and supplemental calcium if desired) cerns about toxicity for most patients [11]. over 1 year [22]. All calcium-related measures Caution should be exercised in patients with within and between groups were normal. impairment of renal function, cardiovascular Despite a mean peak 25(OH)D level of 165 ng/ diseases, chronic granuloma-forming disorders mL (413 nmol/L), no significant adverse events (sarcoidosis or tuberculosis), or chronic fungal occurred. The safety results were in line with a infections. Some patients with lymphoma have previously conducted, smaller study in 12 activated macrophages that produce patients with MS also using doses of up to 1,25(OH) VD in an unregulated fashion. 40,000 IU [23]. In the third study, 15 patients with relapsing–remitting MS (RRMS) were Neurol Ther (2018) 7:59–85 65 supplemented with 20,000 IU/day of vitamin questions such as Does vitamin D prevent MS? D3 for 12 weeks [24]. The median vitamin D How does vitamin D impact MS activity? and Can level increased from 50 nmol/L (range: vitamin D supplementation favorably alter the 31–175 nmol/L) at week 0–380 nmol/L (range: course of MS? Observational study data does 151–535 nmol/L) at week 12 (P\0.001). All suggest that adequate vitamin D levels may patients completed the observation period reduce the risk of MS and affect the course of without side effects, hypercalcemia, or hyper- the disease. However, study limitations restrict calciuria [24]. the extent to which inverse associations can be There are cases in the literature in which attributed to vitamin D, and additional studies exceptionally high doses (considerably above are needed to further understand the nature of the daily upper limit of 10,000 IU) led to vita- this association [2]. min D toxicity: • Bell and coworkers described a 67-year-old Epidemiologic Study Data woman with vitamin D intoxication. Because of a compounding error by the Epidemiologic studies substantiate that the pharmacy, the woman had taken prevalence of MS is greater at higher latitudes 600,000 IU (rather than the intended and tends to peak in areas with the lowest 600 IU) of cholecalciferol daily for more exposure to ultraviolet light [27–32]. Addition- than 3 years, leading to reversible hypercal- ally, to some degree, diets rich in vitamin cemia and partially reversible renal impair- D-containing oily fish may offset this risk ment [25]. [27, 28]. In ‘‘historical’’ cohorts, the risk of MS • Fragoso and colleagues reported consider- decreased among people who migrate from able vitamin D toxicity in 21 MS patients higher to lower latitudes [33]. However, this who were exposed to levels ranging from latitudinal finding has appeared to decline in 8000 IU/day to extremely high, supra-phys- recent decades and may be linked to an iological doses of 150,000 IU/day (average increased trend towards avoiding sun exposure 87,000 IU) [26]. or staying indoors for longer portions of the In order to assess the correlation between day, even in warmer climates [7, 34]. vitamin D and MS, a literature search of large, An Australian case–control study examined prospective, observational studies, epidemio- whether leisure sun exposure, combined with logical studies, and studies using new approa- 25(OH)D status impacts the risk of a first ches such as Mendelian randomization was demyelinating event and whether this was conducted. related to a latitude gradient [35]. Indepen- dently, higher levels of sun exposure (past, Compliance and Ethics Guidelines recent, and cumulative), higher actinic skin damage and higher 25(OH)D levels were asso- This article is based on previously conducted ciated with significantly reduced risks of a studies, and as such, does not involve any new demyelinating event. The investigators calcu- studies of human or animal subjects performed lated that the differences in leisure sun expo- by any of the authors. sure, serum 25(OH)D level, and skin type would additively account for a 32.4% increase in the incidence of first demyelinating events from the VITAMIN D LEVELS AND MS low to high latitude regions in Australia [35]. SUSCEPTIBILITY The independent association of sun exposure and MS risk suggests that UV light itself may Since vitamin D was proposed as an important influence MS risk. Partially supporting this is factor in MS development in the 1970s, research that showed that experimental numerous experimental and epidemiologic autoimmune encephalitis (EAE) could be pre- studies have been conducted to answer key vented in mice through whole-body irradiation 66 Neurol Ther (2018) 7:59–85 with UV light [36]. However, this research did sample from the pregnancy with the affected not discriminate between vitamin D-related and child, were matched with 326 controls. Vitamin nonrelated effects of UV light. The research did D levels were low in both groups, but lower in note that in the Northern Hemisphere, signifi- the mothers of MS patients than in controls cantly more people with MS are born in May [34.6 nmol/L (13.9 ng/mL) vs. 37.5 nmol/L (9.1%), when there is less sunlight during (15.0 ng/mL); P = 0.006]. Moreover, MS risk was pregnancy than in November (8.5%), when 90% higher in the offspring of vitamin D-defi- there is an increased amount of sunlight [37]. cient mothers [25(OH)D\30 nmol/L (12.0 ng/ Some argue that this is an artifact of more births mL)] compared with offspring of mothers who during certain months [38] though others dis- were not vitamin D deficient [relative risk, 1.90; agree [39]. 95% confidence interval (CI), 1.20–3.01; P = 0.006] [3]. These data suggest that insuffi- cient vitamin D levels during pregnancy may Dietary Intake of Vitamin D and MS Risk increase the risk of MS [3]. The association between neonatal 25(OH)D Using data from two large cohorts of the Nurses’ status and risk of MS was examined in a large Health Study involving more than 187,000 population-based case–control study using data women (including 300 who developed MS dur- from the nationwide Danish MS Registry and ing the study), Munger and colleagues evalu- the Danish Newborn Screening Biobank (DNSB) ated the association between calculated vitamin [41]. Data from 521 patients with MS and 972 D intake from diet or supplements and the risk controls were investigated. The analysis by of developing MS [40]. Women who had a quintiles revealed individuals with the highest higher intake of dietary vitamin D (approxi- risk of MS were in the lowest quintile group of mately 700 IU/day) had a 33% lower incidence 25(OH)D (\20.7 nmol/L), and individuals the of MS compared with those with lower intake. lowest risk were in the highest quintile group In addition, women who used vitamin D sup- (C 48.9 nmol/L); with an odds ratio for highest plements (C 400 IU/day) had a 41% reduced risk vs. lowest group of 0.53 (95% CI 0.36–0.78). of developing MS compared to non-users. Hav- Children born with 25(OH)D levels\30 nmol/L ing higher levels of 25(OH)D (irrespective of seemed to be at an especially high risk of dietary vitamin D intake) also seems to predict a developing MS. The additional benefits of lower risk of MS onset. Using a longitudinal higher levels of 25(OH)D were less pronounced study design, Munger and colleagues evaluated [41]. serum vitamin D levels derived from blood samples of seven million US military personnel. Studies Utilizing Mendelian Those with 25(OH)D levels greater than Randomization to Measure MS Risk 100 nmol/L (40 ng/mL) had a 62% lower chance of subsequently developing MS [1]. Data on vitamin D and risk of MS have been largely based on observational studies that Vitamin D Levels During Pregnancy measure an inverse association. However, MS is and MS Risk in Offspring identified as the primary cause of low 25(OH)D) and thus cannot be excluded with these meth- The Finnish Maternity Cohort is a comprehen- ods. Mendelian randomization (MR) analyses sive registry, established in 1983, that includes use genetic associations to test the effects of more than 800,000 women and more than biomarkers, such as 25(OH)D, on the risk of 1.5 million serum samples. This cohort also disease, because inherited alleles are not affec- served as a basis for examining the association ted by most confounding variables or disease of vitamin D levels during pregnancy and MS status [42, 43]. Thus, the possibility of con- risk [3]. One hundred ninety-three patients with founding or reverse causation can largely be a diagnosis of MS, whose mothers were captured excluded. Three recent publications made use of in the registry and had an available serum Neurol Ther (2018) 7:59–85 67 this epidemiological approach. Mokry and col- range of 25(OH)D levels at birth was narrow and leagues applied genome-wide data on genetic mostly low (mean = 29.7 nmol/L, median = variants that predicted blood 25(OH)D levels 25.6, interquartile range = 17.0–38.4 nmol/L) from the Canadian Multicentre Osteoporosis [47]. Study to participants in the International MS Optic neuritis (ON) is a common first symp- Genetics Consortium study [42]. They found tom of MS. Pihl-Jensen and coworkers con- that a genetically determined decrease in blood ducted a cross-sectional study to assess whether 25(OH)D level predicted increased MS suscep- 25(OH)D levels can predict later development tibility. An increase of 25(OH)D levels by 50% of MS in acute ON by evaluating the differences decreased the odds of getting MS by approxi- in mean serum 25(OH)D levels between subjects mately 50% [42, 44]. Similar findings were seen with ON (n = 164) and those with MS (n = 948) from MR analyses using data from two popula- [48]. Deseasonalized serum 25(OH)D levels of tions, a US administrative claim database and the ON onset group were used for statistical two population-based case–control studies from analyses. The majority (56.1%) of the patients Sweden [45]. The third publication, from the had 25(OH)D levels below 50 nmol/L (mean Network of Pediatric Multiple Sclerosis Centers, 47.64 ± 21.48 nmol/L). There were no signifi- again investigated the US and Swedish datasets cant differences in 25(OH)D levels between ON [43]. Genetic risk scores were used to estimate subjects who developed MS and those who did the causal association between low 25(OH)D not develop MS during the median follow-up levels and pediatric-onset MS. This data also time of 741 days (P = 0.279), indicating no sta- supports independent and causal effects of tistically significant effect on the hazard of MS decreased 25(OH)D levels on susceptibility to development. However, significant associations pediatric-onset MS [43]. were found between 25(OH)D levels and ele- vated IgG index levels or CSF pleocytosis, both markers of inflammatory activity or risk of MS. Studies Contradicting the Association The interpretation of the latter finding was dif- of Vitamin D Levels with MS Risk ficult due to the risk of reverse causation. Although the role of using 25(OH)D levels as a Ueda and colleagues investigated the link predictor for the development of MS after acute between vitamin D status at birth and risk of ON could not be demonstrated, the study data adult-onset MS in a population-based, multi- do suggest that there may be a link between center, case–control study in Sweden [46]. The development of MS after acute ON. They also authors analyzed stored neonatal dried blood provide a rationale for additional research for a samples of 459 MS subjects and 663 controls possible role of vitamin D in the early stages of (matched on sex, age, and residential area). MS [48]. There was no association between neonatal serum 25(OH)D quintiles and risk of MS as Levels of Dietary Vitamin D Intake adults. When the findings were adjusted for and Risk of MS–Implications for Public confounding factors in early life (e.g., month of Health birth, latitude of birth, and breastfeeding), in adult life (e.g., sun exposure, intake of vitamin D-rich dairy products, fatty fish consumption, Whether a daily dose of vitamin D or a gesta- smoking, and body mass index at 20 years of tional dose of vitamin D per day ‘‘keeps the MS age), ancestry, MS heredity, and socioeconomic doctor away’’ is not yet proven [49]. Addition- group, results were not considerably affected ally, it is not known what level of serum [46]. Whether the study provided conclusive 25(OH)D would prevent MS in a large majority results was the subject of debate for two primary of individuals. Most studies in this review reasons: (1) blood samples at birth were not well reported 25(OH)D levels below 50 nmol/L preserved and may have been affected by sub- (20 ng/mL) in a significant proportion of their stantial degradation of 25(OH)D; and (2) the investigated populations, which is below the 68 Neurol Ther (2018) 7:59–85 healthy minimum level. Indicating that estab- decrease in relapse risk. Similar findings were lishing a target in the general population gen- seen in a prospective cohort study from Tas- eral population, pregnant women, and their mania, Australia, in a group of 145 adults with offspring to achieve the minimum levels of RRMS, in which 25(OH)D levels were measured 25(OH)D may be considered an important goal twice a year for a period of 3 years [52]. For each for health (i.e., 50 nmol/L (20 ng/mL), accord- 10 nmol/L increase in serum vitamin D level, ing to IOM [4, 15] or 75 nmol/L (30 ng/mL), there was an associated 12% lower risk of MS according to the Endocrine Society) [11, 13]. relapse. Adjustment for potential confounders, such as timing of the blood testing, did not affect the results. Most of the participants in EFFECTS OF VITAMIN D STATUS this study (82%) were receiving immunomod- AND MS DISEASE ACTIVITY ulatory therapy. The authors concluded that raising 25(OH)D levels by 50 nmol/L could Understanding how existing vitamin D levels decrease the hazard of a relapse by up to 50% and vitamin D exposure affect clinical relapses (Fig. 4)[52]. and MS lesion activity is critically important to The EPIC natural history study was a 5-year this review. As such, the findings from larger cohort study conducted at the University of studies investigating these effects are summa- California, San Francisco which sought to rized below. determine the associations between serum or plasma vitamin D levels and MRI activity in a group of 469 white, mostly non-Hispanic Impact of Vitamin D Levels on Disease patients with MS or clinically isolated syndrome Activity in RRMS: Observational Studies (CIS) [53]. Sixty-four percent received disease- modifying therapy within the previous In a prospective longitudinal study from the 12 months. Vitamin D levels increased signifi- Netherlands, 25(OH)D was measured every cantly during the study, especially for those 8 weeks for a mean of 1.7 years in 73 patients patients using supplements. Only 9% of with RRMS [50]. Fifty-eight patients experi- patients were taking vitamin D supplements at enced a total of 139 exacerbations during the baseline, but 43% were taking them by year 5. study period. Relapse risk was significantly Patients who reported using vitamin D supple- reduced in those with medium [50–100 nmol/L ments had an 8.7 ng/mL (21.75 nmo/L) higher (20–40 ng/mL)] and high [[100 nmol/L vitamin D level, on average, compared with ([40 ng/mL)] serum vitamin D levels (vs.\50 mol/L or 20 ng/mL) compared to those with low levels [50]. For each doubling of serum vitamin D concentration from baseline of 10, 20, 30, MS relapse risk decreased by 27%. Although this suggests a beneficial effect of vitamin D on MS, it must be noted that there is also a possibility that conditions associated with MS relapse had an effect on serum vitamin D levels [50]. Incident rate ratios (RR) for relapse in rela- tion to serum vitamin D levels were measured in a retrospective study of 110 patients with pedi- atric-onset MS [51]. After adjusting for several Fig. 4 Association of vitamin D and relapse risk in MS. factors (age, gender, race, ethnicity, disease The graph shows risk of relapse according to 25(OH)D duration, and treatment), the authors found levels, adjusted for age and month of serum measurement. Size of points is proportional to the inverse of the variance that every 10 ng/mL (25 nmol/L) increase in (larger bubbles represent greater precision). Reprinted with 25(OH)D level was associated with a 34% permission from Wiley Company [52] Neurol Ther (2018) 7:59–85 69 those who did not. Additionally, lower vitamin that brain volume is thought to reflect neu- D levels were strongly associated with develop- rodegeneration better than classical MRI ment of new T2 lesions and with contrast-en- parameters such as T2 lesion load and hancing lesions on brain MRI. Each additional Gd?-enhancing lesions [54]. Each 25-nmol/L 10 ng/mL (25 nmol/L) increment of 25(OH)D increase in 25(OH)D level was associated with was associated with a 15% lower risk of new T2 7.8-mL higher gray matter volume (P = 0.025). lesions and a 32% lower risk of enhancing Higher levels of 25(OH)D also were associated lesions (Fig. 5)[53]. Higher vitamin D levels with the composite endpoint of C 3 new brain were associated with a lower (but not statisti- T2 lesions or C 1 relapse within 1 year cally significantly) risk of MS relapses. Findings (P = 0.096). Despite the limitations of the small from this study also showed strong ‘‘within- sample size, these findings suggest that higher person’’ effects of vitamin D levels in individual vitamin D levels in CIS may slow neurodegen- patients with MS. The authors concluded that eration [54]. ‘‘individuals with CIS/RRMS with higher vita- Lower vitamin D levels also correlate with min D levels are at much lower risk of the sub- other surrogates of MS disease activity, includ- sequent development of new lesions and of ing lower odds of remaining relapse free in MS gadolinium (Gd?)-enhancing lesions on brain [55], greater disability and disease severity in MS MRI, even after accounting for potential con- [53, 55–57], conversion from CIS to clinically founding factors’’ [53]. definite MS (CDMS) [58], and poorer nonverbal More recently, Mowry and colleagues exam- long-term memory performance [59]. These ined the association of vitamin D levels with data were largely generated by observational brain volume measures and new lesions in studies that restrict the extent to which inverse patients with CIS (N = 65) [54]. The scientific associations can be attributed specifically to rationale for these data are based on the concept vitamin D. Properly designed and conducted Fig. 5 Magnetic resonance imaging outcomes associated (25 nmol/L) higher 25-hydroxyvitamin D level was asso- with quintiles of vitamin D in the EPIC study. EPIC is a ciated with a 15% lower risk of a new T2 lesion (incidence 5-year longitudinal MS cohort study at the University of rate ratio [IRR],0.85; 95% confidence interval [CI], California at San Francisco, USA. Participants (N = 469) 0.76–0.95; P = 0.004) and a 32% lower risk of a had clinical evaluations, brain MRI, and blood draws gadolinium-enhancing lesion (IRR, 0.68; 95% CI, annually. MRI outcomes were associated with quintiles of 0.53–0.87; P ? 0.002). Reprinted with permission from vitamin D. In multivariate analyses, each 10 ng/mL Wiley Company [53] 70 Neurol Ther (2018) 7:59–85 clinical trials are needed to further define the of long-term 25(OH)D status. To minimize the nature of this association. possibility that lower 25(OH)D levels were a consequence, rather than the cause, of MS severity, the cumulative average 25(OH)D levels Impact of Vitamin D Levels on Disease at 12 months were related to the outcomes Activity Based on Post-Hoc Analyses between 12 and 60 months or between 24 and from BENEFIT and BEYOND 60 months (thereby allowing inserting a 1-year lag between 25[OH]D measurements and the To our knowledge, no large randomized, dou- assessment of MS activity or progression) [60]. ble-blind, controlled, prospectively phase 3 tri- Three sets of analyses were performed: (1) con- als have been conducted to study the impact of tinuous 50-nmol/L (20-ng/mL) increments to vitamin D levels on MS activity as a primary determine the overall linear trend; (2) quintiles endpoint. However, in two phase 3 studies, the to explore the dose response; and (3) categorical BENEFIT study [60], and the BEYOND study [61] analysis using C 50 nmol/L versus\50 nmol/L post hoc analyses were conducted to investigate (20 ng/mL) [60]. this potential link. Findings indicated that patient characteris- The BENEFIT (Betaseron in Newly Emerging tics affected vitamin D levels. Those with higher Multiple Sclerosis for Initial Treatment) study (seasonally adjusted) 25(OH)D levels tended to was a randomized trial originally designed to be younger and to have a lower body mass evaluate the impact of early versus delayed index (BMI), a lower number of T2 lesions, and IFNB-1b treatment in patients with CIS [62–64]. a higher brain volume at the CIS stage, but Patients with a first event suggestive of MS and a otherwise were similar to patients with lower minimum of two clinically silent lesions on MRI levels of 25(OH)D [60]. were randomly assigned to receive interferon Over the 5-year follow-up period, 81.3% (377 beta-1b (IFNB-1b) 250 lg(n = 292; early treat- patients) converted to MS according to the ment) or placebo (n = 176; delayed treatment) McDonald 2001 criteria that include MRI subcutaneously every other day for 2 years or lesions [65] and 46.6% (216 patients) converted until diagnosis of CDMS, in which case they to CDMS based on exacerbations or progression could switch to IFNB-1b therapy. All patients alone. The hazard of conversion decreased with were then eligible to enter a prospective follow- increasing serum 25(OH)D and mean serum up phase with open-label IFNB-1b for up to 25(OH)D levels at 12 months predicted subse- 5 years after randomization. Patients and study quent conversions to McDonald MS (P = 0.02) personnel remained unaware of initial treat- and CDMS (P = 0.05) [60]. ment allocation throughout the study up to An increasing serum 25(OH)D level was year 5. During the observation period, regular associated with a decreasing rate of new active study visits were scheduled to collect clinical lesions on MRI; this effect was particularly and MRI data, with visits at baseline and strong in patients with both 6- and 12-month months 3, 6, 9, 12, 18, 24, 36, 48, and 60 [64]. A serum 25(OH)D measurements. A 50 nmol/L post hoc analyses aimed to determine whether (20 ng/mL) increment in average serum vitamin D status [serum 25(OH)D levels] would 25(OH)D levels within the first 12 months pre- predict disease activity and prognosis up to dicted a 57% lower rate of new active lesions 5 years after the first attack in early-disease CIS (RR, 95% CI: 0.43 (0.26–0.70), P\0.001) and a patients [60]. Serum samples were collected at 57% lower relapse rate (RR (95% CI): 0.43 baseline, 6, 12, and 24 months and levels of (0.20–0.92, P = 0.03). In evaluating the poten- 25(OH)D were measured (by ELISA). Of the 468 tial progression of MS on MRI, higher levels of patients included in BENEFIT, 465 patients had serum 25(OH)D were associated with less T2 at least one 25(OH)D measurement, 417 had lesion volume accumulation over time. For a two or more, 396 had three or more, and 303 50 nmol/L increase in serum 25(OH)D, the rel- had all four measurements. 25(OH)D levels ative decrease in T2 lesion volume was 20% per were seasonally adjusted to obtain an estimate year (P\0.001). Restricting results to patients Neurol Ther (2018) 7:59–85 71 with both 6-month and 12-month serum 25(OH)D levels\50 nmol/L (P = 0.005). 25(OH)D measures, tended to strengthen results Although a 50 nmol/L increase in 25(OH)D [60]. levels did not reach significance for a reduction The dichotomous analysis of serum 25(OH)D in the average expanded disability status scale levels (\50 vs. C 50 nmol/L) is shown in Fig. 6 (EDSS) score (P = 0.11), patients with serum [60]. For instance, the percentage loss of brain 25(OH)D levels C 50 nmol/L had a significantly volume over time was lower in patients with lower annualized change in EDSS score com- 25(OH)D levels C 50 nmol/L at the 12-month pared with those patients with serum 25(OH)D time point compared with those with serum levels\50 nmol/L (P = 0.004) while on IFN-b- Fig. 6 Multiple sclerosis outcomes according to dichoto- new active lesions on brain MRI (b); the percentage mous serum 25(OH)D levels. Analyses are based on change in T2 lesion volume from year 1 to year 5 on brain patients with averaged 6- and 12-month measurements of MRI (c); and the percentage change in brain volume from 25(OH)D. Group comparisons are adjusted for age, sex, year 1 to year 5 (d). The error bars indicate the standard treatment, time of follow-up, and T2 lesion score at error of the mean (SEM). Reproduced with permission baseline. The graphs show the probability of conversion to from [60]. Copyright2014 American Medical Associa- CDMS after 12 months (a); the cumulative number of tion. All rights reserved 72 Neurol Ther (2018) 7:59–85 Table 2 Comparison of clinical and MRI outcomes in patients with Reproduced with permission from [60]. Copyright2014 American plasma 25(OH)D levels\ 50 nmol/L versus C 50 nmol/L in all Medical Association. All rights reserved patients and those with early or delayed start of interferon beta-1b. All patients Early treatment Delayed treatment Probability of conversion CDMS up to 0.65 (0.42–0.99), 0.48 (0.28–0.83), 1.22 (0.59–2.5), year 5, RR (95% CI) P = 0.05 P = 0.008 P = 0.6 Cumulative number of new lesions up to 0.73 (0.60–0.90), 0.70 (0.55–0.90), 0.71 (0.52–0.97), year 5, RR (95% CI) P = 0.002 P = 0.005 P = 0.03 Percent change in T2 volume from year - 8.99 (- 15.1 - 11.0 (- 19.0 - 8.84 (- 17.14 to 1–5, % (95% CI) to - 2.5), P = 0.008 to - 2.2), P = 0.02 0.29), P = 0.06 Percent change in brain volume from year 0.34 (0.10–0.57), 0.43 (0.14–0.72), 0.17 (- 0.24 to 0.58), 1–5, % (95% CI) P = 0.005 P = 0.004 P = 0.4 All data were adjusted for age, sex, treatment, time of follow-up, and T2 lesion score at baseline CDMS Clinically definite multiple sclerosis, RR rate ratio Includes new T2 lesions, new Gd ? -enhancing lesions, and enlarging T2 lesions 1b. Across all analyses, associations were gen- were more pronounced for patients in the early erally stronger for MRI than for clinical out- treatment group than for those in the delayed comes. Nevertheless, ‘‘the latter were still treatment group (Table 2 [60] and Fig. 7 [66]), remarkable considering the overall low rate of although a test for interaction between relapses (0.2 per year) and small EDSS score 25(OH)D levels and treatment assignment was change (median change, 0.0) in BENEFIT’’ [60]. significant only for the time to CDMS (P = 0.04) Strengths of the BENEFIT study included (1) [62]. These results suggest that early treatment its longitudinal design, (2) the exclusive with IFNB-1b may have an additive effect along recruitment of patients at the CIS stage, (3) the with 25(OH)D to reduce disease severity and use of repeated serum 25(OH)D measurements, progression in both clinical and imaging (4) the large number of patients, (5) standard- outcomes. ized treatment (e.g., early vs. late IFNB-1b), and To explore the mechanistic rationale for the (6) rigorous clinical and MRI assessment of all potential additive effects of 25(OH)D levels and patients during a 5-year period. Limitations of early IFNB-1b treatment, Munger and col- the study included (1) the fact that most leagues conducted a global gene expression patients were eventually treated with IFNB-1b analysis in which expression profiles were and some crossed over during the 2 years of the measured at various time points among partic- study, and (2) while a clear dose response was ipants in the BENEFIT clinical trial [67]. The observed for the most sensitive MRI outcomes, relationship between genes or gene sets the effects did not reach a plateau level, and, expressed in association with 25(OH)D and therefore, serum 25(OH)D levels greater than those associated with MS activity was exam- the median 69 nmol/L could have had a greater ined. The numbers of Gd?-enhancing lesions effect. According to the authors, a low 25(OH)D served as a marker of disease activity. A level early in the disease course is a strong risk 50 nmol/L increase in serum 25(OH) levels factor for long-term MS activity and progression reduced the Gd? lesion count by 55%. Adjust- in patients with early MS who were treated with ing for gender, age, treatment, and treat- IFNB-1b [60]. ment - 25(OH)D interaction did not alter the The BENEFIT cohort had an early treatment significance of the findings. Gene expression in group and a delayed treatment group. The whole blood was studied in 295 individuals, associations of 25(OH)D levels and MS activity evaluating approximately 19,000 genes. Neurol Ther (2018) 7:59–85 73 Fig. 7 Data from the Vitamin D analysis of the BENEFIT versus C 50 nmol/L in all patients and those with early trial. Comparison of probability of conversion to CDMS or delayed start of interferon beta-1b. Reproduced with in patients with plasma 25(OH)D\50 nmol/L permission from [66] Reduced Gd? lesion count was significantly course and disease progression as characterized associated with increased expression of by MRI and clinical endpoints [58]. Eligible 25(OH)D-related genes, an effect that was patients for the vitamin D analyses included independent of IFNB-1b treatment. This effect 1482 participants randomized to receive 250, or was also noticed when looking at single genes 500 lg of IFNB-1b with at least two measure- that were associated with regulation of ments of 25(OH)D obtained 6 months apart. 25(OH)D levels. The authors hypothesized that Serum 25(OH)D measurements were performed there was an additive effect of 25(OH)D and at baseline, 6, and 12 months. IFNB-1bin reducing Gd? lesion counts [67]. In longitudinal analyses, 25(OH)D was The second data set from randomized, dou- inversely correlated with the cumulative num- ble-blind, phase 3 trials in MS was derived from ber of active lesions between baseline and the the BEYOND (Betaseron Efficacy Yielding last MRI (average follow-up time, 2 years). A Outcomes of a New Dose) study [61]. Compared 50-nmol/L higher level of serum 25(OH)D was with the BENEFIT study, the BEYOND study associated with a 31% lower rate of new lesions included patients with established MS (vs. [relative rate (RR), 0.69; 95% CI, 0.55–0.86; patients with CIS) and was shorter in duration P = 0.001]. This inverse association was also (2 vs. 5 years). It also included considerably strong and significant in analyses restricted to more patients (1482 vs. 465) and was conducted patients with 25(OH)D levels[50 nmol/L (RR, in different geographical regions (North Amer- 0.62; 95% CI, 0.46–0.84; P = 0.002) and was ica, Western and Eastern Europe, Southern consistent in each of the four geographic Hemisphere vs. Europe and Canada). regions (Fig. 8)[61]. The lowest rate of new BEYOND was a large, phase 3, prospective, lesions was observed among patients with multicenter, blinded, randomized clinical trial. 25(OH)D levels[100 nmol/L (RR, 0.53; 95% CI, Patients were monitored for at least 2 years. 0.37–0.78; P = 0.002). No significant associa- Clinical visits were scheduled every 3 months, tions were found between 25(OH)D levels and and an MRI was performed at baseline and change in brain volume, relapse rates, or EDSS annually thereafter. A post hoc analysis assessed scores [61]. Strengths of this study include the 25(OH)D levels and the subsequent MS disease large number of participants, the regionally 74 Neurol Ther (2018) 7:59–85 Effects of Disease-Modifying Therapies on Vitamin D Levels in MS Patients MS disease activity may be additively affected by vitamin D and IFNB-1b [60]. This hypothesis is supported by investigations from the same researchers suggesting that processes regulated and triggered by 25(OH)D may be additively enhanced by IFNB-1b [67], and independently by observations from Stewart and colleagues from the Menzies Research Institute in Tasma- nia [68]. In an observational cohort study, conducted in 178 patients with MS, vitamin D levels were measured every 6 months over an average of 2.2 years. Patients who took an Fig. 8 The relative rate of cumulative new active lesions interferon had significantly higher 25(OH)D (NALs) vs. average of baseline, 6-month, and 12-month 25[OH]D levels stratified by geographic region. The solid levels than those who did not (P\0.001). Each lines and shaded regions represent the relative rate ratios of 10-nmol/L increase in serum vitamin D was cumulative NALs for changes in 25(OH)D relative to the associated with a 10% lower relapse rate. Inter- median level and the corresponding 95% CIs, respectively. estingly, interferon treatment was protective Analyses were adjusted for age, sex, randomization status, only against relapse among persons with higher baseline EDSS score, and disease duration. Models assume vitamin D levels. Among those with insufficient a linear association between the logarithm of the rate of vitamin D, there was an increased risk of relapse cumulative NALs and serum 25(OH)D. Analyses using despite interferon treatment. The investigators cubic splines revealed no significant deviation from hypothesized that treatment with IFNB may linearity. (To convert 25[OH]D values to ng/mL, divide increase serum vitamin D levels through by 2.496). Reproduced with permission from [61]. enhanced responsiveness to sun exposure and Copyright2015 American Medical Association. All recommended that persons being treated with rights reserved IFNB should have vitamin D status monitored and maintained in the sufficiency range [68]. diverse population with varying baseline char- Also, noteworthy from these data, this group acteristics, and the repeated measurements of did not find similar associations for glatiramer 25(OH)D, which helped characterize patients’ acetate (GA) therapy and vitamin D. long-term vitamin D status. The relatively short The notion of complementary or even syn- follow-up is the most important limitation of ergistic effects of IFNB and vitamin D is further this study. This limited follow-up may explain supported by observations from Rotstein and the lack of association between serum 25(OH)D coworkers based on the CLIMB (Comprehensive levels and measures of brain atrophy or clinical Longitudinal Investigation of MS at Brigham endpoints, both of which were modified by and Women’s Hospital) cohort [69]. The CLIMB 25(OH)D in the longer BENEFIT study [60, 61]. cohort is a prospective cohort study that began Regarding targeted vitamin D levels, the authors enrolling patients in 2000. The objective of the stated: ‘‘Our observation of the lowest level of study was to determine whether 25(OH)D levels MS activity among patients with serum predicted new disease activity in MS patients 25(OH)D levels above 100.0 nmol/L [40 ng/mL] treated with IFN-b (n = 96) or GA (n = 151). is consistent with the results of a previous Separately, due to different selection criteria, a investigation in the US [50], and suggests that similar analysis was conducted for patients the 25(OH)D levels in most patients with MS treated with fingolimod (FTY, n = 77). Serum who are not receiving supplemental vitamin D 25(OH)D concentration was adjusted for sea- may be suboptimal’’ [53]. son, and patients were divided into subgroups by 25(OH)D tertile. The primary study endpoint Neurol Ther (2018) 7:59–85 75 was ‘time to first inflammatory event’, defined disease activity after initiation of IFNB. With as a combination of either first relapse or first clinical measures, neither the occurrence of Gd? lesion, using a Cox model adjusted for age, relapses nor EDSS progression was associated sex, and disease duration. The results demon- with 25(OH)D levels during both study phases. strated higher 25(OH)D levels associated with a Strengths of the study were the prospective longer time to the combined first event in the design and the frequent MRI and 25(OH)D IFNB subgroup [hazard ratio (HR) = 0.58; assessments during the observation period. IFNB P = 0.012], but not in GA-treated partici- Limitations were the relatively short time on IFNB pants (HR = 0.89; P = 0.50). For Gd? IFNB and the small number of participants, as GA GA lesions alone, there was a significant association well as the minimal 4 nmol/L increase in serum observed in GA and IFNB subgroups, although vitamin D levels following vitamin D supple- the effect was more pronounced with IFNB mentation. In the discussion of the study (HR = 0.57; P = 0.039 vs. HR = 0.41; results, the authors expressed their surprise GA GA IFNB P = 0.022). No significant associations were about the lack of an association between IFNB found for relapses. There were some sampling 25(OH)D levels and MRI after initiation of IFNB, difficulties in this cohort and, therefore, the ‘‘as there is no evidence suggesting that the results need to be interpreted with certain cau- immunomodulatory effects of vitamin D are tion. For FTY, due to the mandated first-dose counteracted by IFNB or vice versa. A reasonable observation, samples were available for all explanation is that IFNB reduced radiologic patients. Higher 25(OH)D was associated with a disease activity, leaving relatively little left to be longer time to the first event (HR = 0.48; reduced’’ by vitamin D [70]. FTY P = 0.016) and with relapses (HR = 0.50; FTY FTY P = 0.046), but not with Gd? lesions [69]. FTY THE ROLE OF SUPPLEMENTAL The large, prospective cohort and the prolonged follow-up times were strengths of this study, as VITAMIN D IN MS well as the availability of two 25(OH)D mea- surements for the majority of patients. How- When reviewing available data discussing the ever, more regular 25(OH)D measurements effects of vitamin D and MS, of key interest is whether vitamin D supplementation can would have been ideal and offered greater insights into study conclusions [69]. favorably alter the course of MS. Unfortunately, current evidence does not offer consensus to answer this question. Studies with vitamin D Studies Contradicting the Association alone or with vitamin D as an add-on to a dis- of Vitamin D Levels with Disease Activity ease-modifying therapy are conflicting [22, 71–81]. Although these studies are gener- Contradictory to the aforementioned informa- ally small, largely uncontrolled, and used tion are findings reported by researchers from highly variable doses of vitamin D, it can be Norway [70]. In this small prospective cohort noted that there are initial promising data study, 88 patients with RRMS were followed arguing for vitamin D supplementation in with regular MRI and 25(OH)D measurements patients with MS [22, 75–81]. Furthermore, during 6 months before and up to 18 months recent investigations with immunological after initiation of IFNB. During the pre–IFNB response markers suggest that vitamin D sup- treatment phase, higher levels of 25(OH)D were plementation in patients with MS exhibits associated with reduced MRI activity; each in vivo pleiotropic immunomodulatory effects 10-nmol/L increase in 25(OH)D was associated in MS [82], and lacking evidence of a treatment with 12.7% (P = 0.037) lower odds for new T1 effect does not necessarily demonstrate proof of Gd ? lesions, 11.7% (P = 0.044) lower odds for no effect. new T2 lesions, and 14.1% (P = 0.024) lower odds for combined unique activity. However, there was no association between 25(OH)D and 76 Neurol Ther (2018) 7:59–85 Studies Supporting the Benefit group, but these differences also did not reach of Supplemental Vitamin D significance (P = 0.322). While there was no significant difference in annual relapse rate demonstrated between groups, there was a Researchers from Finland conducted a 1-year, tendency toward reduced disability accumula- randomized, double-blind, placebo-controlled tion as measured by EDSS (P = 0.071) and trial with vitamin D3 as an add-on treatment to toward improved timed tandem walk IFNB-1b in patients with MS. Thirty-four (P = 0.076). There were no significant differ- patients were randomly assigned to the treat- ences in adverse events between the groups. The ment group (vitamin D, 20,000 IU/week vita- authors concluded that larger randomized, min D3 (cholecalciferol), and IFNB-1b) and 32 controlled trials with more than 1 year of fol- to the control group (placebo and IFNB-1b) [75]. low-up are warranted to confirm the promising The primary outcome measure was an MRI T2 MRI results and to fully address clinical out- burden of disease (BOD), which tended to comes [75]. increase more in the placebo group (median A study by Burton and colleagues introduced change of 287 mm ) than in the vitamin D earlier in this manuscript in the context of the group (median change of 83 mm ); however, safety profile of higher doses of vitamin D sup- the difference was not statistically significant plementation also offers insight into the role of (P = 0.105) (Fig. 9)[75]. Results for other MRI vitamin D supplementation and the disease outcomes were mixed. The number of T1 Gd? course of MS [22]. In this open-label, controlled lesions decreased in both groups (P = 0.002), trial, patients were randomized to a vitamin D but the change was significantly higher in the treatment group (n = 25, escalation protocol vitamin D group (P = 0.04). New/enlarging T2 4000–40,000 IU/day, mean 14,000 IU/day) or to lesions at the 12-month point trended higher in a control group (n = 24, received vitamin D3 the placebo group, but the differences were not 4000 IU/day if desired). Despite the high doses statistically significant (P = 0.286). The per- of vitamin D, no significant adverse events centage of patients with MRI activity (12-month occurred during the 52-week study period. The time point) trended lower in the vitamin D annualized relapse rate during the trial year was lower in the treatment group than in the con- trol group (0.26 vs. 0.45; P = 0.09), and more patients in the treatment group remained relapse free. Additionally, the treated patients reported a persistent reduction in T-cell prolif- eration compared with controls, and treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell pro- liferation compared to controls. Study limita- tions included the use of supplementation or other agents in the control group, the small sample-size, and thus the limited power [22]. The Danish Multiple Sclerosis Center prospectively gathered data in a cohort of 170 Fig. 9 Change in MRI T2 burden of disease (BOD) from natalizumab-treated patients during winter baseline to month 12 in the vitamin D-treated and 2009–2010 (baseline) with follow-up during the placebo-treated patients. Data are mean ± standard error subsequent winter [78]. Patients with insuffi- of 34 patients in the vitamin D group and 32 patients in cient serum 25(OH)D levels (selected cut-off the placebo group at baseline and 32 in the vitamin D 50 nmol/L) at baseline were advised to take group and 30 in the placebo group at 12 months. The Vitamin D supplements according to Danish P value for the difference between vitamin D and placebo recommendations: 2000 IU for patients with is 0.105 (trend). Reproduced from [75], with permission levels between 25 and 50 nmol/L, 3000 IU for from BMJ Publishing Group Ltd Neurol Ther (2018) 7:59–85 77 those with levels between 25 and 12.5 nmol/L a quarter of the patients not returning to the and 4000 IU for those with levels below month 3 visit. The authors also described not 12.5 nmol/L. 134 patients were included in the allowing true control for other sources of vita- clinical data set. Of the 134 patients, 43 had min D as other possible confounders, such as taken vitamin D supplements due to vitamin D sun exposure and dietary vitamin D [79]. insufficiency (mean 25(OH)D levels: 34 nmol/L). Only available in abstract format are the Their levels increased significantly by results of two studies which evaluated the ben- 32.6 nmol/L (95% CI: 24.4–40.8 nmol/L, efits and risks associated with high-dose vitamin P\0.0001) from baseline to follow-up. More- D supplementation in patients treated with over, a significant inverse relationship with the IFNB-1a. Although both failed to demonstrate annualized relapse rate (ARR) was found: for an effect on clinical parameters, their MRI each nmol/l increase in 25(OH)D, a 0.014 (95% results demonstrated positive results. • SOLAR is a randomized, double-blind, pla- CI - 0.026 to - 0.003) decrease in ARR was observed (P = 0.02). Overall, the data suggest cebo-controlled, multicenter, phase 2 study. Two hundred and twenty-nine patients with that correcting vitamin D insufficiency by the means of vitamin D supplements in patients a 25(OH)D serum level below 150 nmol/L with MS may be beneficial [78]. were randomly assigned to cholecalciferol at Darwish and colleagues looked into the a dose of 14,000 IU per day or placebo [80]. cognitive effects of vitamin D supplementation All patients received subcutaneous IFNB-1a. of patients with MS on IFNB [79]. At baseline, After recruitment delays, the study design patients were stratified into a vitamin D-defi- was adjusted and the percentage of patients cient group (25(OH)D levels\25 ng/mL or with ‘‘disease activity free’’ status (defined as 62.5 nmol/L, N = 39) and a vitamin D-sufficient no relapses, no EDSS progression, and no new Gd? or T2 MRI lesions) at week 48 were group (25(OH)D levels[35 ng/mL or 87.5 nmol/L). ‘‘Deficient’’ patients received introduced as a new primary endpoint. This endpoint was not met (37.2% for cholecal- 10,000 IU vitamin D3 daily for 3 months and reported a significant increase of 25(OH)D levels ciferol group vs. 35.3% for placebo group, to 49.0 ± 14.6 ng/mL (122.5 ± 36.5 nmol/L). P = 0.912). Likewise, no differences between Additionally, after 3 months these ‘‘deficient’’ groups for other clinical parameters such as patients scored better on the Brief Visuospatial ARR or EDSS were found. However, results Memory test delayed recall (BVMT-DR, regarding the MRI parameters were promis- P = 0.02) and the montreal cognitive assess- ing with a significant 32% reduction in the ment (MoCA, P = 0.006), but not on the symbol number of new, combined, unique active digit modalities test (SDMT) and Stroop. The lesions in the cholecalciferol group (P = 0.005). Furthermore, there was a trend authors concluded that the lack of significant change on the SDMR and Stroop testing was due toward more cholecalciferol recipients being to the short disease duration and the propensity free from new T1 hypointense lesions, which for study participants to perform within normal became significant in those aged 18–- ranges for these tests. 30 years. The short duration of the trial Alternatively, ‘‘sufficient’’ patients continued (48 weeks) and the relatively small sample their usual treatment that may have included size (229 patients) may have led to the lack vitamin D3 supplementation at various dosages. of significance of the clinical outcomes. For These patients reported 25(OH)D levels at comparisons, most randomized trials of new 64.2 ± 18.7 ng/mL (160.5 ± 46.8 nmol/L) at MS drugs recruited over 800 patients to be study end. Sufficient 25(OH)D levels predicted able to demonstrate a significant effect vs. placebo. Despite the large sizes, some were better cognitive performance on the BVMT-DR at baseline and 3 months after adjusting for all not able to show a significant effect on measured confounding variables. Study limita- disability progression (e.g. CONFIRM study tions included a small study population [83] TRANSFORMS [84]). Additionally, these (N = 88), short study duration (3 months), and data are not placebo-controlled, but rather 78 Neurol Ther (2018) 7:59–85 an active comparator. Also, the power anal- participants were asked to respond to a health- ysis is not designed to assess a minor effect related quality-of-life (HRQoL) questionnaire. and would require[10,000 patients. Bivariate and multivariate analyses were used • Likewise, the second study was a random- for comparisons, including multiple linear ized, placebo-controlled, phase 2 study [81]. regression modeling. Nearly two thirds of One hundred and twenty-nine patients respondents (64.6%) lived in the Northern (N = 129) were randomly assigned to receive Hemisphere, mostly in developed countries. 100,000 IU of cholecalciferol twice monthly Most (82.3%) were female, with a median age of (equivalent to a daily dose of 7143 IU) in 45 years (interquartile range [IQR]: 38–53 years) addition to IFNB-1a over a 24-month period. and a median time since diagnosis of 6 years Again, significant effects in favor of vitamin (IQR: 3–12 years), with the majority (61.6%) D supplementation were found for selected having RRMS. More than 80% of the patients MRI parameters such as new or enlarged indicated that they took vitamin D supple- weighted T1 and T2 lesion, but no effect was ments, mostly between 2000 and 5000 IU daily found for clinical parameters [81]. (Table 3)[77], and 67% reported intentional sun A preliminary study from Iran conducted by exposure to raise vitamin D levels. Etemadifar and colleagues assessed the safety Unadjusted regression modeling incorporat- and efficacy of high-dose vitamin D supple- ing deliberate sun exposure, latitude, and vita- mentation during pregnancy in women with min D supplementation showed strong MS [76]. Fifteen pregnant women with con- associations between sun exposure and HRQoL. firmed MS and with serum 25(OH)D However, the effect disappeared when control- levels\50 nmol/L (20 ng/mL) were randomly ling for age, disability, physical activity, and fish allocated to received 50,000 IU/week (daily dose consumption. In contrast, the associations of 7143 IU) vitamin D3 or routine care from 12 between supplementation of vitamin D and to 16 weeks of gestation until delivery. 25(OH)D HRQoL were maintained when adjusting for levels increased significantly and no significant these variables, with a dose–response effect. The adverse events occurred. The women in the beneficial effect of vitamin D supplementation vitamin D group had significantly fewer relapses on HRQoL was considered to be of ‘‘clinically during pregnancy (0 vs. 5; P\0.05), a tendency significant magnitude’’ [77]. Lower annualized for fewer relapses up to 6 months after preg- relapse rates were significantly associated with nancy (0 vs. 4; statistically nonsignificant), and taking vitamin D supplementation vs. not tak- a more stable EDSS than those without supple- ing supplements. The dose taken seemed to be mentation. The authors advocated for adding of less importance. No effect on disability was high-dose vitamin D3 supplementation during found for either supplementation or deliberate pregnancy to the routine care of women with sun exposure, but an increase of latitude by 1 MS. Study limitations included a small sample (farther from the equator) predicted increased size, and conclusions are limited by the loss to odds of moderate or high disability [77]. follow-up of 37 out of 52 of the original baseline cohort [76]. Table 3 Self-reported average daily dose of supplemental The role of vitamin D supplementation in vitamin D in an Internet survey among 2301 patients with patients with MS was also evaluated by Jelinek MS. Originally published on BioMed Central, an open and colleagues, with the authors taking a very access journal, in [77] different epidemiological approach [77]. This was an internet survey among 2301 patients Vitamin D dose N Percentage with MS who self-reported data on geographical [5000 IU 447 20.4 location, intentional sun exposure for health, 2001–5000 IU 734 33.5 supplementation with vitamin D, and other lifestyle variables, as well as self-reported doc- 1–2000 IU 613 28.0 tor-diagnosed relapse rates and disability (Pa- None 399 18.2 tient Determined Disease Steps). Survey Neurol Ther (2018) 7:59–85 79 The large data set may compensate for some data in favor of the low-dose group. In addition, of the limitations of this study design. Vitamin this study compared low-dose and high-dose D supplementation (along with all other mea- vitamin D administration and did not utilize a sures) was self-reported and not validated with concurrent control group of subjects that did blood tests. No validated tool exists for quanti- not receive any supplemental vitamin D. fying variables like deliberate sun exposure; in Finally, even though vitamin D2 seems to be a this study, the question required simply a yes/ less potent form of vitamin D than vitamin D3 no answer [78]. Furthermore, there might be a in all primate species [17], the 1000-IU/day selection bias in terms of the patients included, regimen for the low-dose group is above what as respondents to such Internet surveys are the IOM recommends in terms of daily intake patients who are typically very ‘‘engaged’’ with [4] and both groups may have benefited from their situation and disease. vitamin D supplementation. In a 96-week, randomized, controlled trial designed to evaluate the effects of supplemen- Studies Contradicting the Benefit tation with 20,000 IU/week of vitamin D (aver- of Supplemental Vitamin D aged to approximately 2800 IU/day) on bone mineral density in 35 MS patients, Kampman A study by Stein and colleagues is widely dis- and colleagues found that consumption of cussed among those not supporting vitamin D vitamin D did not result in beneficial effects on supplementation [72]. In this 6-month, double- the measured MS-related outcomes, which blind, placebo-controlled, randomized trial, included annualized relapse rates. However, the patients were allocated to either high or low study was not powered to address clinical out- dose of vitamin D2. The high-dose regimen was comes [73]. The authors suggested that the low 6000 IU twice daily, the low-dose regimen annualized relapse rate seen at baseline could 1000 IU daily. Twenty-three patients were have contributed to the absence of significant included (11 in the treatment arm, 12 in the effects in this study. Study limitations included control group). There were no significant dif- a small sample size (N = 68), which may be ferences between the groups on the two primary inadequate for assessing effects on clinical out- endpoints—cumulative number of new Gd? comes [73]. lesions and change in the total volume of T2 Furthermore, two studies from Iran did not lesions—nor were there differences on clinical find a beneficial effect of vitamin D supple- outcome measures, such as number of relapses mentation on clinical or MRI outcome measures and effect on EDSS [72]. Neurology, in which the in patients with RRMS. Shaygannejad and col- manuscript was published, ranked the study as leagues studied 50 patients in a 12-month, providing class I evidence, but this rating is randomized, double-blind, placebo-controlled, arguable. Although the study was double-blind, phase 2 clinical trial [74]. The 25 patients in the placebo-controlled, and randomized, the sam- treatment group received 4000 IU/day of vita- ple size was very small (N = 23). Moreover, there min D for the first 2 weeks and were thereafter were withdrawals (two in the low-dose group, escalated to 8000 IU/day in addition to their one in the high-dose group), and one patient disease-modifying agent. The control group from the low-dose group was partially excluded (n = 25) was treated with placebo combined from MRI analyses due to brain surgery. with disease-modifying therapy. In a separate Although the authors stated that the two groups study, Mosayebi and colleagues evaluated the were well matched, one patient (in the high- effects of vitamin D3 supplementation at a dose dose group) had 38 Gd? lesions at baseline, of 300,000 IU/month vs. placebo in a random- while all other patients had between two and ized, prospective study with 62 patients [71]. five Gd? lesions at baseline. The low-dose group Over the 6-month observation period, no dif- was, on average, 10.5 years older than the high- ferences between groups on either EDSS or Gd? dose group; importantly, the number of exac- lesion count were observed, but immune-in- erbations in MS declines over time, biasing the hibitory transforming growth factor beta and 80 Neurol Ther (2018) 7:59–85 interleukin 10 were significantly higher in the ongoing, and results are expected in 2018 or 2019. vitamin D-supplemented group compared with placebo [71]. • The Vitamin D to Ameliorate Multiple Sclerosis (VIDAMS) study (NCT01490502) Several of the studies above were included in a meta-analysis conducted by James and col- [88, 90] is a randomized, controlled, phase leagues evaluating the effect of vitamin D-re- 3 study that aims to include 172 patients in lated intervention trials on MS relapses [85]. the US. After a run-in phase of 1 month on The five studies [22, 72–75] included 129 GA, patients will be assigned to low-dose patients with high-dose vitamin D supplemen- (600 IU/day) vs. high-dose (5000 IU/day) tations and 125 controls. Administered doses of vitamin D3 as an add-on therapy to GA. This academic study is currently recruiting vitamin D supplementations, study designs, patient populations, outcome parameters, and patients and will terminate in 2018 [86, 88]. Clinical and MRI parameters will also be observation period were considerably variable among the assessed studies. Given these differ- evaluated. ences, the numerous limitations of each of these studies and the mixed reported study SUMMARY AND CONCLUSIONS results, it is not surprising that the meta-analy- sis did not find a significant association between Evidence available to date suggests that the vitamin D treatment and the relative risk of level of serum vitamin D affects the risk of relapse in MS [85]. In the view of the authors, developing MS and also modifies disease ‘‘further larger and more prolonged studies…are activity in MS patients. Until several years ago, merited’’ to better understand the role of vita- evidence that higher levels of vitamin D are min D supplementation in MS [85]. associated with favorable effects on MS risk and a reduction in MS activity was supported Ongoing Studies Evaluating the Role largely by observational studies. Limitations of of Supplemental Vitamin D in MS these studies restricted confidence in a specific effect of vitamin D in MS. Newer data with A search of recently initiated and ongoing Mendelian randomization analyses suggest clinical studies evaluating the role of supple- there is a causal relationship between low mental vitamin D in MS revealed the following: vitamin D level and the risk of MS. Further- • The Efficacy of Vitamin D Supplementation more, post hoc evaluations from the phase 3 in Multiple Sclerosis (EVIDIMS) study BENEFIT and BEYOND studies substantiate (NCT01440062) [86, 87] is a German multi- findings of observational trials. Across all trials, center, stratified, randomized, controlled, associations between 25(OH) levels and MS double-blind, clinical phase 2 study. Eighty and its activity are generally stronger for MRI patients with CIS or MS whose disease than for clinical outcomes, which may be due courses were stable while taking IFNB-1b to the higher sensitivity of MRI compared to were randomized to receive either high-dose typical clinical parameters. Low or even insuf- (on average, 10,200 IU/day) or low-dose (on ficient 25(OH)D levels were common in many average 200 IU/day) vitamin D3 for earlier cohorts. Patients in more recent studies 18 months as a supplement. The primary have higher baseline vitamin D levels, poten- outcome measure is the number of new T2 tially changing the immunopathology of MS lesions. Secondary endpoints include addi- and altering responses to some therapeutic tional MRI and optical coherence tomogra- drugs. phy (OCT) parameters, clinical parameters, In aggregate, studies suggest that vitamin D as well as cognition, fatigue, depression, and supplementation may be beneficial for patients quality of life. Safety and tolerability of high- with MS and others. However, the study limi- dose vitamin D supplementation are addi- tations identified in this review recognize the tional outcome measures. This study is need for larger controlled clinical trials to Neurol Ther (2018) 7:59–85 81 establish vitamin D supplementation as the Disclosures. Martina B Sintzel, PhD has standard of care for MS patients. Though there received consultancy fees from Bayer and Fre- is increasing evidence indicating that lower senius. Mark Rametta, D.O is employed by vitamin D levels are associated with increased Bayer. Anthony T. Reder, MD has received risk of MS and greater clinical and brain MRI unrestricted grant and clinical trials support activity in established MS, the impact of vita- from Bayer, Biogen, Novartis, Serono, and Teva. min D supplementation on MS activity remains Compliance with Ethics Guidelines. This inadequately investigated. There is no consen- article is based on previously conducted studies, sus on ‘‘sufficient’’ vitamin D levels. In the view and as such, and does not involve any new of IOM, 25(OH)D levels greater than 50 nmol/L studies of human or animal subjects performed (20 ng/mL) are sufficient. The Endocrine Society by any of the authors. argues for 75 nmol/L (30 ng/mL) or higher, based on a medical model which takes into Data Availability. Data sharing is not account skeletal and non-skeletal health. applicable to this article as no datasets were Numerous studies suggest that serum 25(OH)D generated or analyzed during the current study. levels of approximately 100 nmol/L (40 ng/mL) are the lower limit for controlling MRI and Open Access. This article is distributed clinical activity in patients with MS. More under the terms of the Creative Commons research is needed to establish the recom- Attribution-NonCommercial 4.0 International mended levels of vitamin D supplementation License (http://creativecommons.org/licenses/ necessary to reduce the risk for MS and MS by-nc/4.0/), which permits any noncommer- clinical activity. cial use, distribution, and reproduction in any In conclusion, based on the data reviewed, medium, provided you give appropriate credit identification and correction of vitamin D to the original author(s) and the source, provide insufficiency with supplementation at recom- a link to the Creative Commons license, and mended doses is a sensible clinical indicate if changes were made. action/course/target/objective and one that provides a favorable risk–benefit profile for vitamin D for most patients with MS. REFERENCES 1. Munger K, Levin L, Hollis B, Howard N, Ascherio A. ACKNOWLEDGEMENTS Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. 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Neurology and TherapySpringer Journals

Published: Dec 14, 2017

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