The relapsing-remitting multiple sclerosis (RRMS) is the most common type of MS with prevalence rate 20-60 patients/100.000 individuals in Egypt. Poor postural control and cognitive dysfunctions are well-established complications of RRMS without potent remedy yet. The latest evidence highlighted the potential and independent immune-modulating effects of vitamin D3 and ultraviolet radiation in the management of RRMS.

To investigate the efficacy of broadband ultraviolet B radiation (UVBR) versus moderate loading dose of vitamin D3 supplementation in improving postural control and cognitive functions.

Pretest-posttest randomized controlled study.

Multiple sclerosis outpatient unit of Kasr Al-Ainy Hospital.

Forty-seven patients with RRMS were recruited from both genders, yet only 40 completed the study.

Patients were randomized into two groups: UVBR group involved 24 patients, received sessions for 4 weeks and vitamin D3 group involved 23 patients, took vitamin D3 supplementation (50 000 IU/week) for 12 weeks.

Overall balance system index (OSI) and symbol digit modalities test (SDMT).

Highly significant decrease (P < 0.001) of the OSI in both groups post-treatment, indicating improved postural control. Moreover, highly significant improvement in the SDMT scores was noted, indicating information processing speed enhancement. Nonetheless, no statistically significant (P ≥ 0.05) differences were evident between the two groups post-treatment in all tested measures.

Both therapeutic programs were statistically equal in improving postural control and cognitive functions. However, clinically, UVBR therapy was more convenient owing to its shorter treatment time and higher percentage of change for all tested measures.

Vitamin D and its main active metabolite 1,25-dihydroxyvitamin D serve a crucial role in maintenance of a healthy calcium metabolism, yet have additional roles in immune and central nervous system cell homeostasis. Serum levels of 25-hydroxyvitamin D are a biomarker of future disease activity in patients with early relapsing-remitting multiple sclerosis (RRMS), and vitamin D supplementation in patients with low circulating 25-dihydroxyvitamin D levels has been anticipated as a potential efficacious treatment strategy. The results of the first large randomized clinical trials (RCTs), the SOLAR and CHOLINE studies, have now been published. The SOLAR study compared 14,000 IU of vitamin D3 (cholecalciferol) per day with placebo for 48 weeks in 232 randomized patients, whereas CHOLINE compared vitamin D3 100,000 IU every other week with placebo for 96 weeks in 129 randomized patients. All patients in both studies also used interferon-β-1a. None of the studies met their primary endpoints, which were no evidence of disease activity (NEDA-3) at 48 weeks in SOLAR and annualized relapse rate at 96 weeks in CHOLINE. Both studies did, however, suggest modest effects on secondary endpoints. Thus, vitamin D reduced the number of new or enlarging lesions and new T2 lesions in SOLAR, and the annualized relapse rate and number of new T1 lesions, volume of hypointense T1 lesions, and disability progression in the 90 patients who completed 96 weeks' follow-up in CHOLINE. We conclude that none of the RCTs on vitamin supplementation in MS have met their primary clinical endpoint in the intention to treat cohorts. This contrasts the observation studies, where each 25 nmol/l increase in 25-hydroxyvitamin D levels were associated with 14-34% reduced relapse risk and 15-50% reduced risk of new lesions on magnetic resonnance imaging. This discrepancy may have several explanations, including confounding and reverse causality in the observational studies. The power calculations of the RCTs have been based on the observational studies, and the RCTs may have been underpowered to detect less prominent yet important effects of vitamin D supplementation. Although the effect of vitamin D supplementation is uncertain and less pronounced than suggested by observational studies, current evidence still support that people with MS should avoid vitamin D insufficiency, and preferentially aim for vitamin D levels around 100 nmol/L or somewhat higher.

The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS.

The aim of this study is to determine and critically evaluate the plausible relationships of vitamin D with extra-skeletal tissues in humans. Severe vitamin D deficiency results in rickets in children and osteomalacia in adults; these beneficial effects in the musculoskeletal system and certain physiological functions are well understood. Nevertheless, mounting reports support additional beneficial effects of vitamin D, outside the musculoskeletal system. This review explores the recent advances in knowledge about the non-skeletal effects of vitamin D. Peer-reviewed papers were extracted from research databases using key words, to assess correlations between vitamin D and extra-skeletal diseases and conditions. As per the guidelines of the Preferred Reporting Items for Systematic Reviews (PRISMA); general interpretations of results are included; taking into consideration the broader evidence and implications. This review summarizes current knowledge of the effects of vitamin D status on extra-skeletal tissues with special attention given to relationships between vitamin D status and various diseases commonly affecting adults; the effects of intervention with vitamin D and exposure to sunlight. Evidence suggests that vitamin D facilitates the regulation of blood pressure; and cardiac; endothelial; and smooth muscle cell functions; playing an important role in cardiovascular protection. In addition; 1,25(OH)₂D improves immunity; subdues inflammation; and reduces the incidence and severity of common cancers; autoimmune diseases and infectious diseases. Almost all adequately powered; epidemiological and biological studies that use; adequate doses of vitamin D supplementation in D-deficient populations have reported favorable outcomes. These studies have concluded that optimizing 25(OH)D status improves the functionality of bodily systems; reduces comorbidities; improves the quality of life; and increases survival. Although accumulating evidence supports biological associations of vitamin D sufficiency with improved physical and mental functions; no definitive evidence exists from well-designed; statistically powered; randomized controlled clinical trials. Nevertheless, most studies point to significant protective effects of vitamin D in humans when the minimum 25(OH)D serum level exceeds 30ng/mL and is maintained throughout the year.

The most recent findings linking exposure to sun and vitamin D insufficiency to multiple sclerosis (MS) are reviewed. Due to insufficient sunshine and changing lifestyles, hypovitaminosis D is widespread in temperate countries. Numerous epidemiological studies have strongly suggested that sunshine and vitamin D insufficiency contributes to MS risk in these countries. Moreover, several large genetic studies in MS patients have recently stated unequivocally that diverse abnormalities involving vitamin D metabolism are related to the risk of the disease. The important implications of such results are discussed here. Then, the interactions of hypovitaminosis D with the other genetic and environmental protective and risk factors, such as the allele HLA DRB1*1501, Epstein-Barr virus infection, obesity, smoking and sexual hormones, are summarized. Vitamin D insufficiency and sufficiency could be a risk and a protective factor, respectively, among many other factors possibly continuously modulating the global MS risk from the mother's pregnancy to the triggering of MS in adulthood. However, many interactions between these different factors occur more particularly between conception and the end of adolescence, which corresponds to the period of maturation of the immune system and thymus and may be related to the dysimmune nature of the disease. The main mechanisms of action of vitamin D in MS appear to be immunomodulatory, involving the various categories of T and B lymphocytes in the general immune system, but neuroprotector and neurotrophic mechanisms could also be exerted at the central nervous system level. Furthermore, several controlled immunological studies performed in MS patients have recently confirmed that vitamin D supplementation has multiple beneficial immunomodulatory effects. However, there is still an enduring absence of major conclusive randomized clinical trials testing vitamin D supplementation in MS patients because of the quasi-insurmountable practical difficulties that exist nowadays in conducting and completing over several years such studies involving the use of a vitamin. Nevertheless, it should be noted that similar robust statistical models used in five different association studies have already predicted a favorable vitamin D effect reducing relapses by 50-70%. If there is now little doubt that vitamin D exerts a beneficial action on the inflammatory component of MS, the results are as yet much less clear for the progressive degenerative component. Lastly, until more information becomes available, vitamin D supplementation of MS patients, using a moderate physiological dose essentially correcting their vitamin insufficiency, is recommended.

Genome-wide association studies have identified a linkage disequilibrium (LD) block on chromosome 12 associated with multiple sclerosis (MS), type 1 diabetes and other autoimmune diseases. This block contains CYP27B1, which catalyzes the conversion of 25 vitamin D3 (VitD3) to 1,25VitD3. Fine-mapping analysis has failed to identify which of the 17 genes in this block is most associated with MS. We have previously used a functional approach to identify the causal gene. We showed that the expression of several genes in this block in whole blood is highly associated with the MS risk allele, but not CYP27B1. Here, we show that CYP27B1 is predominantly expressed in dendritic cells (DCs). Its expression in these cells is necessary for their response to VitD, which is known to upregulate pathways involved in generating a tolerogenic DC phenotype. Here, we utilize a differentiation protocol to generate inflammatory (DC1) and tolerogenic (DC2) DCs, and show that for the MS risk allele CYP27B1 is underexpressed in DCs, especially DC2s. Of the other Chr12 LD block genes expressed in these cells, only METT21B expression was as affected by the genotype. Another gene associated with autoimmune diseases, CYP24A1, catabolizes 1,25 VitD3, and is predominantly expressed in DCs, but equally between DC1s and DC2s. Overall, these data are consistent with the hypothesis that reduced VitD pathway gene upregulation in DC2s of carriers of the risk haplotype of CYP27B1 contributes to autoimmune diseases. These data support therapeutic approaches aimed at targeting VitD effects on DCs.

The extraskeletal effects of vitamin D have attracted considerable interest. Vitamin D deficiency appears to be related to the development of diabetes mellitus type 2 and the metabolic syndrome. Vitamin D may affect glucose homeostasis, vitamin D levels having been found to be inversely related to glycosylated hemoglobin levels in gestational diabetes mellitus. In addition, vitamin D appears to protect from the development of gestational diabetes mellitus. The aim was to study levels of 25-hydroxy vitamin D3 [25(OH)D3] and the relationship between 25(OH)D3 levels and glycemic control in patients with diabetes mellitus type 2.

Glycosylated hemoglobin (HbA1c) and 25(OH)D3 levels were measured in a group of 120 diabetes mellitus type 2 patients. The same measurements were performed in a group of 120 control subjects of the same age and sex. 25(OH)D3 was measured by radioimmunoassay and glycosylated hemoglobin (HbA1c) was measured by high-performance liquid chromatography.

25(OH)D3 levels were lower in the diabetes mellitus type 2 patients than in the control group, being 19.26 ± 0.95 ng/ml and 25.49 ± 1.02 ng/ml, in the patient and control groups, respectively (p < 0.001, Student's t-test). 25(OH)D3 levels were found to be inversely associated with HbA1c levels in the diabetic patients (p = 0.008, r (2) = 0.058, linear regression). 25(OH)D3 levels were found to be inversely associated with HbA1c when the patient and control groups were analysed together (p < 0.001, r (2) = 0.086).

Vitamin D levels appeared to be lower in diabetes mellitus type 2 patients than in the control group, vitamin D levels being related to glycemic control in diabetes mellitus type 2. These findings may have therapeutic implications as cautious vitamin D supplementation may improve glycemic control in diabetes mellitus type 2.

The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.