cholecalciferol and Multiple-Sclerosis

Environmental triggers often work via signal transduction cascades that modulate the epigenome and transcriptome of cell types involved in the disease process. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system being characterized by a combination of recurring inflammation, demyelination and progressive loss of axons. The mechanisms of MS onset are not fully understood and genetic variants may explain only some 20% of the disease susceptibility. From the environmental factors being involved in disease development low vitamin D levels have been shown to significantly contribute to MS susceptibility. The pro-hormone vitamin D

Topics: Cholecalciferol; Gene Expression Regulation; Humans; Multiple Sclerosis; Signal Transduction; Vitamin D; Vitamins

This review is an update of a previously published review, "Vitamin D for the management of multiple sclerosis" (published in the Cochrane Library; 2010, Issue 12). Multiple sclerosis (MS) is characterised by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system (CNS), which can result in varying levels of disability. Some studies have provided evidence showing an association of MS with low levels of vitamin D and benefit derived from its supplementation.. To evaluate the benefit and safety of vitamin D supplementation for reducing disease activity in people with MS.. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Specialized Register up to 2 October 2017 through contact with the Information Specialist with search terms relevant to this review. We included references identified from comprehensive electronic database searches and from handsearches of relevant journals and abstract books from conferences.. We included randomised controlled trials (RCTs) and quasi-RCTs that compared vitamin D versus placebo, routine care, or low doses of vitamin D in patients with MS. Vitamin D was administered as monotherapy or in combination with calcium. Concomitant interventions were allowed if they were used equally in all trial intervention groups.. Two review authors independently extracted data and assessed the methodological quality of studies, while another review author sorted any disagreements. We expressed treatment effects as mean differences (MDs) for continuous outcomes (Expanded Disability Status Scale and number of magnetic resonance imaging (MRI) gadolinium-enhancing T1 lesions), as standardised MDs for health-related quality of life, as rate differences for annualised relapse rates, and as risk differences (RDs) for serious adverse events and minor adverse events, together with 95% confidence intervals (CIs).. We identified 12 RCTs enrolling 933 participants with MS; 464 were randomised to the vitamin D group, and 469 to the comparator group. Eleven trials tested vitamin D₃, and one trial tested vitamin D₂. Vitamin D₃ had no effect on the annualised relapse rate at 52 weeks' follow-up (rate difference -0.05, 95% CI -0.17 to 0.07; I² = 38%; five trials; 417 participants; very low-quality evidence according to the GRADE instrument); on the Expanded Disability Status Scale at 52 weeks' follow-up (MD -0.25, 95% CI -0.61 to 0.10; I² = 35%; five trials; 221 participants; very low-quality evidence according to GRADE); and on MRI gadolinium-enhancing T1 lesions at 52 weeks' follow-up (MD 0.02, 95% CI -0.45 to 0.48; I² = 12%; two trials; 256 participants; very low-quality evidence according to GRADE). Vitamin D₃ did not increase the risk of serious adverse effects within a range of 26 to 52 weeks' follow-up (RD 0.01, 95% CI -0.03 to 0.04; I² = 35%; eight trials; 621 participants; low-quality evidence according to GRADE) or minor adverse effects within a range of 26 to 96 weeks' follow-up (RD 0.02, 95% CI -0.02 to 0.06; I² = 20%; eight trials; 701 participants; low-quality evidence according to GRADE). Three studies reported health-related quality of life (HRQOL) using different HRQOL scales. One study reported that vitamin D improved ratings on the psychological and social components of the HRQOL scale but had no effects on the physical components. The other two studies found no effect of vitamin D on HRQOL. Two studies reported fatigue using different scales. One study (158 participants) reported that vitamin D₃ reduced fatigue compared with placebo at 26 weeks' follow-up. The other study (71 participants) found no effect on fatigue at 96 weeks' follow-up. Seven studies reported on cytokine levels, four on T-lymphocyte proliferation, and one on matrix metalloproteinase levels, with no consistent pattern of change in these immunological outcomes. The randomised trials included in this review provided no data on time to first treated relapse, number of participants requiring hospitalisation owing to progression of the disease, proportion of participants who remained relapse-free, cognitive function, or psychological symptoms.. To date, very low-quality evidence suggests no benefit of vitamin D for patient-important outcomes among people with MS. Vitamin D appears to have no effect on recurrence of relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions. Effects on health-related quality of life and fatigue are unclear. Vitamin D₃ at the doses and treatment durations used in the included trials appears to be safe, although available data are limited. Seven ongoing studies will likely provide further evidence that can be included in a future update of this review.

Topics: Cholecalciferol; Ergocalciferols; Fatigue; Humans; Multiple Sclerosis; Quality of Life; Randomized Controlled Trials as Topic; Vitamins

Sex-steroids, corticosteroids and vitamin D3-derived molecules have all been subject to experimental studies and clinical trials in a plethora of autoimmune diseases. These molecules are all derived from cholesterol metabolites and are ligands for nuclear receptors. Ligation of these receptors results in direct regulation of multiple gene transcription involved in general homeostatic and adaptation networks, including the immune system. Indeed, the distinct ligands affect the function of both myeloid and lymphoid cells, eventually resulting in a less pro-inflammatory immune response which is considered beneficial in autoimmune diseases. Next to the immune system, also the central nervous system is prone to regulation by these nuclear receptor ligands. Understanding of the intricate interactions between sex-steroids, corticosteroids and vitamin D3 metabolites, on the one hand, and the immune and central nervous system, on the other hand, may reveal novel approaches to utilize these nuclear receptor ligands to full extent as putative treatments in multiple sclerosis, the prototypic immune-driven disease of the central nervous system.

Topics: Adrenal Cortex Hormones; Animals; Central Nervous System; Cholecalciferol; Gonadal Steroid Hormones; Humans; Ligands; Metabolic Networks and Pathways; Multiple Sclerosis; Receptors, Cytoplasmic and Nuclear

Multiple sclerosis (MS) is a disease with multiple etiologies. The most recent theory of the vascular etiology of MS, Chronic Cerebrospinal Venous Insufficiency (CCSVI), suggests that cerebral venous obstruction could lead to cerebral venous reflux, promoting local inflammatory processes. This review article offers strong evidence that the route of the observed narrowing of cerebral veins arises from autonomic nervous system dysfunction, particularly cardiovascular autonomic dysfunction. The dysfunction of this system has two major effects: 1) the reduction of mean arterial blood pressure, which has the potential to reduce the cerebral perfusion pressure and the transmural pressure, and 2) the failure of cerebral autoregulation to maintain constant cerebral blood flow in the face of fluctuations in cerebral perfusion pressure. Alterations in cerebral autoregulation could in turn raise the critical closure pressure, indicated to be the cerebral perfusion pressure at which the transmural pressure will be sub-sufficient to overcome the active tension imparted by the smooth muscle layer of the vessel. These two effects of autonomic nervous system dysfunction (reduction in arterial blood pressure and alterations in cerebral autoregulation), when combined with inflammation-induced high levels of nitric oxide in the brain, will lower transmural pressure sufficiently to the point where the threshold for critical closure pressure is reached, leading to venous closure. In addition, cerebral vessels fail to overcome the closure as a result of low central venous pressure, which is also regulated by autonomic nervous system function. Furthermore, through their neuroregulatory effects, infectious agents such as the Epstein-Barr virus and vitamin D(3) are able to alter the functions of the autonomic nervous system, influencing the rate of CCSVI occurrence. The absence of CCSVI specificity for MS, observed in recent clinical studies, may stem from a high prevalence of autonomic nervous system dysfunction in control groups which were recruited to these studies. Future studies should investigate CCSVI in relation to cardiovascular autonomic function.

Topics: Autonomic Nervous System Diseases; Cerebral Veins; Cholecalciferol; Herpesvirus 4, Human; Humans; Multiple Sclerosis; Spinal Cord; Venous Insufficiency

Vitamin D, is a secosteroid which, in its active form 1,25-(OH)2-Vitamin D3, has hormone activities. Most cells and tissues in the human body have vitamin D receptors that stimulate the nuclear transcription of various genes to alter cellular function. Vitamin D, appears to have an effect on numerous disease states and disorders, including osteoporosis, chronic musculoskeletal pain, diabetes (types 1 and 2), multiple sclerosis, cardiovascular disease, and cancers of the breast, prostate, and colon. According to many researchers there is currently a worldwide vitamin D deficiency in various populations, including infants, pregnant and lactating women, and the elderly. The prevalence of vitamin D, insufficiency in the general German population is high. Vitamin D in the food supply is limited and most often inadequate to prevent deficiencies. Supplemental vitamin D is likely necessary to avoid deficiency, especially in winter months. The estimated cost saving effect of improving vitamin D status in Germany might be up to 37.5 billion euros annually.

Topics: Aged; Aging; Cholecalciferol; Diabetes Mellitus; Female; Germany; Humans; Infant; Male; Multiple Sclerosis; Neoplasms; Nutritional Status; Pregnancy; Receptors, Calcitriol; Vitamin D Deficiency; Vitamins

This collective review focuses on three major factors that influence the incidences of multiple sclerosis (MS) to include ultraviolet radiation (UVR), vitamin D3 supplementation, and vitamin D receptor gene (VDRG) polymorphisms. In general, the rate of MS increases with latitude. Individuals tend to carry their original risk with them if they migrate to a different latitude after adolescence. It is important to emphasize that UVR increases the synthesis of vitamin D3, which has a known immune suppressant action via the VDRG. Clinical studies have pointed out that vitamin D deficiency may exacerbate the development of MS. Because vitamin D3 is an inhibitor of MS, providing supplemental D3 for individuals at risk for MS should be mandatory. There is unanimous agreement that exposure to UVR and vitamin D3 supplementation can reduce the incidence of MS. Although there is debate regarding the association of MS with the use of silver mercury fillings, there is general agreement throughout the world that there is a need for dental-patient informed-consent brochures for all dentists who use dental restoration materials. For the dentists who remove silver mercury amalgam from their patients, there is a uniform international agreement that all dental offices should use reliable debris collection devices that prevent pollution of our environment.

Topics: Cholecalciferol; Dental Amalgam; Humans; Multiple Sclerosis; Polymorphism, Genetic; Receptors, Calcitriol; Ultraviolet Rays

Multiple sclerosis (MS) is a major inflammatory and demyelinating disease of the central nervous system and has an increasing prevalence in populations residing at higher latitudes. This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of vitamin D in the MS population. The vitamin D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as apoptosis and immune regulation in immune cells such as T helper cells and dendritic cells. Evidence from experimental autoimmune encephalomyelitis and prospective studies on MS suggests an important role of vitamin D as a modifiable environmental factor in MS. These provide guidance for future studies with regard to the potential role of vitamin D in the prevention and/or treatment of MS. Here, we first review the metabolism and immune functions of vitamin D. Then, we describe the current thinking on the etiology of vitamin D in MS and the accumulating evidence pointing to a link between vitamin D and MS. Further, we describe how genetic susceptibility interacts with environmental risk factors at the population level, MS-associated risk factors, and genetic studies related to the vitamin D receptor. This review also discusses the therapeutic potential of vitamin D for treating MS.

Topics: Animals; Cholecalciferol; Encephalomyelitis, Autoimmune, Experimental; Humans; Multiple Sclerosis; Polymorphism, Genetic; Receptors, Calcitriol; Vitamin D-Binding Protein

Recently, it has been clearly demonstrated that exogenous 1,25-dihydroxyvitamin D3, the hormonal form of vitamin D3, can completely prevent experimental autoimmune encephalomyelitis (EAE), a widely accepted mouse model of human multiple sclerosis (MS). This finding has focused attention on the possible relationship of this disease to vitamin D. Although genetic traits certainly contribute to MS susceptibility, an environmental factor is also clearly involved. It is our hypothesis that one crucial environmental factor is the degree of sunlight exposure catalyzing the production of vitamin D3 in skin, and, further, that the hormonal form of vitamin D3 is a selective immune system regulator inhibiting this autoimmune disease. Thus, under low-sunlight conditions, insufficient vitamin D3 is produced, limiting production of 1,25-dihydroxyvitamin D3, providing a risk for MS. Although the evidence that vitamin D3 is a protective environmental factor against MS is circumstantial, it is compelling. This theory can explain the striking geographic distribution of MS, which is nearly zero in equatorial regions and increases dramatically with latitude in both hemispheres. It can also explain two peculiar geographic anomalies, one in Switzerland with high MS rates at low altitudes and low MS rates at high altitudes, and one in Norway with a high MS prevalence inland and a lower MS prevalence along the coast. Ultraviolet (UV) light intensity is higher at high altitudes, resulting in a greater vitamin D3 synthetic rate, thereby accounting for low MS rates at higher altitudes. On the Norwegian coast, fish is consumed at high rates and fish oils are rich in vitamin D3. Further, experimental work on EAE provides strong support for the importance of vitamin D3 in reducing the risk and susceptibility for MS. If this hypothesis is correct, then 1,25-dihydroxyvitamin D3 or its analogs may have great therapeutic potential in patients with MS. More importantly, current research together with data from migration studies opens the possibility that MS may be preventable in genetically susceptible individuals with early intervention strategies that provide adequate levels of hormonally active 1,25-dihydroxyvitamin D3 or its analogs.

Topics: Animals; Brain; Calcitriol; Cholecalciferol; Diet; Humans; Mice; Multiple Sclerosis; Sunlight; Ultraviolet Rays

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 D. To investigate the efficacy of broadband ultraviolet B radiation (UVBR) versus moderate loading dose of vitamin D. 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.. 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.

Topics: Cholecalciferol; Cognition; Female; Humans; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Research Design; Ultraviolet Rays

B-cells contribute to MS pathogenesis. The association of circulating B-cell phenotypes with combined unique active lesions (CUA) on MRI at 48 weeks follow-up was investigated in 50 interferon beta-treated MS patients. Transitional B-cell proportions were lower in participants with CUA at week 0 and 48 [p = 0.004, p = 0.002]. A decrease in circulating anti-EBNA-1 IgG levels between week 0 and 48 associated with absence of CUA [p = 0.047], but not with B-cell profiles. In a multi-factor model for CUA-risk, transitional B-cell proportions contributed independent from NK/T-cell ratio, change in anti-EBNA-1 IgG, and vitamin D supplementation. Transitional B-cells may predict treatment response in MS.

Topics: Cholecalciferol; Humans; Immunologic Factors; Interferon-beta; Magnetic Resonance Imaging; Multiple Sclerosis; Precursor Cells, B-Lymphoid

Combined omega-3 fatty acid and vitamin D supplementation may improve multiple sclerosis (MS) by correcting metabolic abnormalities and attenuating oxidative stress and inflammation.. This study aimed to determine the effects of ω-3 fatty acid and vitamin D cosupplementation on the disability score and metabolic status of patients with MS.. This was a randomized, placebo-controlled clinical trial with Expanded Disability Status Scale (EDSS) score and inflammation as primary outcomes and oxidative stress biomarkers and metabolic profile as secondary outcomes. Patients, aged 18-55 y, were matched for disease EDSS scores, gender, medications, BMI, and age (n = 53) and randomly received a combined 2 × 1000 mg/d ω-3 fatty acid and 50,000 IU/biweekly cholecalciferol supplement or placebo for 12 wk. The placebos were matched in colour, shape, size, packaging, smell, and taste with supplements. Fasting blood samples were collected at baseline and end of intervention to measure different outcomes. Multiple linear regression models were used to assess treatment effects on outcomes adjusting for confounding variables.. Patients taking ω-3 fatty acid plus vitamin D supplements showed a significant improvement in EDSS (β -0.18; 95% CI: -0.33, -0.04; P = 0.01), compared with placebo. Serum high-sensitivity C-reactive protein (β -1.70 mg/L; 95% CI: -2.49, -0.90 mg/L; P < 0.001), plasma total antioxidant capacity (β +55.4 mmol/L; 95% CI: 9.2, 101.6 mmol/L; P = 0.02), total glutathione (β +51.14 µmol/L; 95% CI: 14.42, 87.87 µmol/L; P = 0.007), and malondialdehyde concentrations (β -0.86 µmol/L; 95% CI: -1.10, -0.63 µmol/L; P < 0.001) were significantly improved in the supplemented group compared with the placebo group. In addition, ω-3 fatty acid and vitamin D cosupplementation resulted in a significant reduction in serum insulin, insulin resistance, and total/HDL-cholesterol, and a significant increase in insulin sensitivity and serum HDL-cholesterol concentrations.. Overall, taking ω-3 fatty acid and vitamin D supplements for 12 wk by patients with MS had beneficial effects on EDSS and metabolic status. This trial was registered at the Iranian website (www.irct.ir) for registration of clinical trials as IRCT2017090133941N20.

Topics: Adult; Analgesics; Antioxidants; C-Reactive Protein; Cholecalciferol; Cholesterol; Cholesterol, HDL; Dietary Fats; Dietary Supplements; Disability Evaluation; Disabled Persons; Fatty Acids, Omega-3; Female; Glutathione; Humans; Inflammation; Insulin; Insulin Resistance; Malondialdehyde; Multiple Sclerosis; Oxidative Stress; Vitamins

Multiple Sclerosis is associated with deficient serum 25 hydroxyvitamin D (25 (OH)D) level and cognitive impairment. The aim of this study is to evaluate cognitive performance in MS patients with deficient 25 (OH)D (<25 ng/ml) compared to patients with sufficient levels (>35 ng/ml), then to evaluate the change in cognitive performance after 3 months of vitamin D3 oral replacement. Eighty-eight MS patients with relapsing remitting and clinically isolated type of MS, older than 18 years treated with interferon beta were enrolled. Cognitive testing was performed at baseline and at 3 months using the Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities (SDMT) and Brief Visuospatial Memory Test (BVMT-R). Serum 25 (OH)D was measured at baseline and at the end of the study. Vitamin D3 replacement improved the MS patients' cognitive performance after 3 months on the MoCA and BVMT-Delayed Recall (DR). Sufficient serum 25 (OH)D level predicted better cognitive performance on the BVMT-DR at baseline (β: 1.74, p: <0.008) and 3 months (β: 1.93, p: <0.01) after adjusting for all measured confounding variables. Vitamin D

Topics: Adult; Calcifediol; Cholecalciferol; Cognition; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Multivariate Analysis; Neuropsychological Tests; Prospective Studies; Quality of Life; Vitamin D Deficiency; Vitamins; Young Adult

Our goal was to identify changes in the metabolome in multiple sclerosis (MS) and how vitamin D supplementation alters metabolic profiles in MS patients and healthy controls.. We applied global untargeted metabolomics to plasma from a cross-sectional cohort of age- and sex-matched MS patients and controls and a second longitudinal cohort of MS patients and healthy controls who received 5,000 IU cholecalciferol daily for 90 days. We applied partial least squares discriminant analysis, weighted correlation network analysis (WGCNA), and pathway analysis to the metabolomics data. Generalized estimating equations models were used to assess change in WGCNA-identified module scores or metabolite pathways with vitamin D supplementation.. Utilizing multiple analytical techniques, we identified metabolic alterations in oxidative stress (γ-glutamyl amino acid, glutathione) and xenobiotic metabolism (benzoate, caffeine) in MS patients compared with healthy controls in the first cohort. In the vitamin D supplementation cohort, we identified two sets of metabolites altered differentially between MS patients and healthy controls with vitamin D supplementation. The first included markers of oxidative stress and protein oxidation (P = 0.006), while the second contained lysolipids and fatty acids (P = 0.03).. Using metabolomics, we identified alterations in oxidative stress and xenobiotic metabolism in MS patients and subsequently demonstrated a reduction of oxidative stress markers with vitamin D supplementation in healthy controls but not in MS patients. We demonstrate the utility of metabolomics in identifying aberrant metabolic processes and in monitoring the ability of therapeutic interventions to correct these abnormalities.. ClinicalTrials.gov NCT01667796.. This study was supported by NIH grant K23 NS067055, grants from the Race to Erase MS, the National Multiple Sclerosis Society, the American Academy of Neurology, and North American Research Committee on Multiple Sclerosis.

Topics: Adult; Case-Control Studies; Cholecalciferol; Cross-Sectional Studies; Dietary Supplements; Female; Humans; Metabolome; Metabolomics; Middle Aged; Multiple Sclerosis; Oxidative Stress; Xenobiotics

Recently, the relationship between immunoreactivity to Epstein-Barr virus (EBV) and hypo-vitamin D in multiple sclerosis (MS) patients has been described. The aim of this study was to investigate whether vitamin D3 supplementation in MS patients could influence the immune response against latent EBV infection. Forty MS patients were recruited in this study. Twenty-seven patients were supplemented with 50,000 IU/week of vitamin D3 for 6 months and thirteen enrolled as controls. 25-Hydroxyvitamin D (25OHD) levels and IgG titers against EBNA1 and VCA were determined pre- and post-supplementation. All the patients were seropositive for EBV prior to vitamin D supplementation. In this cohort, 22.5% and 47.5% of the MS patients had deficient and insufficient levels of 25OHD, respectively. Our findings confirm that antibody titers against EBV in MS patients rise after the onset of the disease and indicate that vitamin D3 supplementation could limit augmentation of these titers in MS patients.

Topics: Adult; Antibodies, Viral; Antigens, Viral; Capsid Proteins; Cholecalciferol; Dietary Supplements; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Female; Herpesvirus 4, Human; Humans; Immunoglobulin G; Male; Multiple Sclerosis; Vitamin D

There is increasing evidence linking vitamin D deficiency to both susceptibility to, and severity of, multiple sclerosis (MS). Patients with the clinically isolated syndrome represent the initial presentation of a demyelinating disorder, and those with asymptomatic lesions on magnetic resonance imaging (MRI) are at risk of progression to clinically definite MS. The aims of this study are to examine the immunologic effects of vitamin D in both healthy individuals and in patients with clinically isolated syndrome, and in the latter group the effects on disease progression assessed by MRI and clinical measures.. This is a single-center double-blind randomized placebo-controlled clinical trial. The primary endpoint is the immunologic effects of two doses of vitamin D compared with placebo over 24 weeks in both healthy control participants and patients presenting with the clinically isolated syndrome. Healthy control participants (n = 39) and patients with clinically isolated syndrome (n = 45) will be randomized to one of three arms, namely 1) vitamin D 5,000 IU daily, 2) vitamin D 10,000 IU daily, or 3) placebo, and followed up for 24 weeks. In both patients and healthy control participants, the primary outcome will be immunologic measures of the frequency of CD4 T-cell subsets and cytokine responses in peripheral blood mononuclear cells, assessed at baseline, and after 16 and 24 weeks of treatment. Secondary endpoints, in the patients with clinically isolated syndrome, will be relapse activity, and the number of new T2 lesions and gadolinium-enhancing lesions assessed by MRI in the two vitamin D-treated groups compared with the placebo-treated group over the 24 weeks of the study.. EU Clinical Trials Register: EudraCT: 2012-000635-68. ClinicalTrials.gov identifier: NCT01728922.

Topics: Biomarkers; Brain; CD4 Lymphocyte Count; Cholecalciferol; Clinical Protocols; Cytokines; Demyelinating Diseases; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Humans; Ireland; Leukocytes, Mononuclear; Magnetic Resonance Imaging; Multiple Sclerosis; Research Design; Time Factors; Treatment Outcome; Vitamin D

Multiple sclerosis (MS) presents with optic neuritis (ON) in 20 % of cases and 50 % of ON patients develop MS within 15 years. In this study, we evaluated the preventive effects of vitamin D3 administration on the conversion of ON to MS (primary outcome) and on the MRI lesions (secondary outcome) of ON patients with low serum 25 (OH) D levels. Thirty ON patients (15 in each of 2 groups, aged 20-40 years) with serum 25 (OH) D levels of less than 30 ng/ml were enrolled in a double blind, randomized, parallel-group trial. The treatment group (cases) received 50,000 IU of vitamin D3 weekly for 12 months and the control group (controls) received a placebo weekly for 12 months. Finally, the subsequent relapse rate and changes in MRI plaques were compared between the two groups. Risk reduction was 68.4 % for the primary outcome in the treatment group (relative risk = 0.316, p = 0.007). After 12 months, patients in the treatment group had a significantly lower incidence rate of cortical, juxtacortical, corpus callosal, new T2, new gadolinium-enhancing lesions and black holes. The mean number of total plaques showed a marginally significant decrease in the group receiving vitamin D3 supplementation as compared with the placebo group (p = 0.092). Administration of vitamin D3 supplements to ON patients with low serum vitamin 25 (OH) D levels may delay the onset of a second clinical attack and the subsequent conversion to MS.

Topics: Adult; Cholecalciferol; Dietary Supplements; Disease Progression; Double-Blind Method; Female; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Optic Neuritis; Pilot Projects; Treatment Outcome; Young Adult

Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults. Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D, mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse. We here present the protocol of an interventional clinical phase II study to test the hypothesis, that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects.. The EVIDIMS trial is a German multi-center, stratified, randomized, controlled and double-blind clinical phase II pilot study. Eighty patients with the diagnosis of definite multiple sclerosis or clinically isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be randomized to additionally receive either high-dose (average daily dose 10.200 IU) or low-dose (average daily dose 200 IU) cholecalciferol for a total period of 18 months. The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla. Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration, clinical parameters for disease activity, as well as cognition, fatigue, depression, and quality of life. Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters.. In light of the discrepancy between existing epidemiological and preclinical data on the one hand and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients. The study design presented here fulfills the criteria of a high-quality clinical phase II trial in MS.. ClinicalTrials.gov Identifier: NCT01440062.

Topics: Brain; Cholecalciferol; Dietary Supplements; Double-Blind Method; Germany; Humans; Immunologic Factors; Interferon beta-1b; Interferon-beta; Magnetic Resonance Imaging; Multiple Sclerosis; Quality of Life; Research Design; Time Factors; Tomography, Optical Coherence; Treatment Outcome

High vitamin D levels may reduce the risk of relapses and disease progression in multiple sclerosis.. This 96-week randomised controlled trial was designed to assess the effect of vitamin D(3) supplementation on bone mineral density in persons with multiple sclerosis. Supplementation with 20,000 IU vitamin D(3) weekly raised median serum 25-hydroxy vitamin D (25[OH]D) to 121 nmol/L. The modified intention to treat analysis included 35 persons in the vitamin D(3) group and 33 in the placebo group. Participants were age 21 to 50 years and fully ambulatory (median Expanded Disability Status Scale (EDSS) 2.5). We studied the effect of supplementing vitamin D(3) on the exploratory outcomes annualised relapse rate (ARR), EDSS, multiple sclerosis functional composite (MSFC) components, grip strength, and fatigue.. After 96 weeks, there was no significant difference between groups in ARR (absolute difference 0.10, 95% CI -0.07 to 0.27; p = 0.25), EDSS (absolute difference -0.01, 95% CI -0.35 to 0.35; p = 0.97), MSFC components, grip strength, or fatigue.. Supplementation with 20,000 IU vitamin D(3) weekly did not result in beneficial effects on the measured multiple sclerosis-related outcomes. This study was not powered to address clinical outcomes, but none of the results were suggestive of an effect in this unselected population of fully ambulatory persons with multiple sclerosis.

Topics: Adult; Biomarkers; Bone Density; Chi-Square Distribution; Cholecalciferol; Dietary Supplements; Disability Evaluation; Disease Progression; Double-Blind Method; Fatigue; Female; Hand Strength; Humans; Linear Models; Male; Middle Aged; Multiple Sclerosis; Norway; Predictive Value of Tests; Recurrence; Time Factors; Treatment Outcome; Up-Regulation; Vitamin D; Young Adult

To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB) in patients with multiple sclerosis (MS).. 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests.. Median change in BOD was 287 mm(3) in the placebo group and 83 mm(3) in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19-82) nmol/l to 110 (range 67-163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate.. Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS.. EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Brain; Cholecalciferol; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Injections, Subcutaneous; Interferon beta-1b; Interferon-beta; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Neuroimaging; Parathyroid Hormone; Recurrence; Severity of Illness Index; Vitamin D; Vitamins; Walking

Multiple sclerosis (MS) is a possible cause of secondary osteoporosis. In this phase II trial we assessed whether a weekly dose of 20,000 IU vitamin D(3) prevents bone loss in ambulatory persons with MS age 18-50 years. ClinicalTrials.gov ID NCT00785473. All patients managed at the University Hospital of North Norway who fulfilled the main inclusion criteria were invited to participate in this double-blinded trial. Participants were randomised to receive 20,000 IU vitamin D(3) or placebo once a week and 500 mg calcium daily for 96 weeks. The primary outcome was the effect of the intervention on percentage change in bone mineral density (BMD) at the hip, the spine, and the ultradistal radius over the study period. Of 71 participants randomised, 68 completed. Mean serum 25-hydroxyvitamin D [25(OH)D] levels in the intervention group increased from 55 nmol/L at baseline to 123 nmol/L at week 96. After 96 weeks, percentage change in BMD did not differ between groups at any site. BMD decreased at the hip, by 1.4% in the placebo group (95% CI -2.3 to -0.4, SD 2.7, p = 0.006) and by 0.7% in the treatment group (-1.6 to 0.2, 2.7, p = 0.118), difference 0.7% (-1.9 to 0.7, p = 0.332). Findings were not altered by adjustment for sex or serum 25(OH)D. Supplementation with 20,000 IU vitamin D(3) a week did not prevent bone loss in this small population. Larger studies are warranted to assess the effect of vitamin D on bone health in persons with MS.

Topics: Adult; Bone Density Conservation Agents; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Osteoporosis; Placebos; Young Adult

Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of the central nervous system are damaged. The damage leads to demyelination and scarring as well as a broad spectrum of signs and symptoms. The epidemiological data suggest a possible influence of vitamin D as an immunomodulatory agent on multiple sclerosis susceptibility as well as on clinical course of the disease. We investigated the effects of short-term vitamin D3 therapy on Iranian patients with MS. In a prospective randomized controlled trial study, 62 MS patients received 300,000 IU/month vitamin D3 or placebo as intramuscular injection for 6 months. Our results showed no significant difference between the treatment and the control groups in the expanded disability status scale scores and number of gadolinium-enhancing lesions during the 6-month treatment period. After 6 months, the levels of cell proliferation in the vitamin D treatment group were significantly lower than the control group. Also, the levels of transforming growth factor-beta and interleukin-10 in the vitamin D treatment group were significantly higher than the control group. This result suggests that vitamin D therapy may help prevent the development of MS and could be a useful addition to the therapy.

Topics: Adolescent; Adult; Calcitriol; Cell Proliferation; Cholecalciferol; Double-Blind Method; Female; Humans; Injections, Intramuscular; Interferon-gamma; Interleukin-10; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Multiple Sclerosis; Phytohemagglutinins; T-Lymphocytes; Transforming Growth Factor beta; Treatment Outcome; Young Adult

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], is a potent modulator of immune cells in vitro.. Our objective was to determine whether the sun-dependent nutrient, cholecalciferol, can alter disease-associated cellular immune abnormalities in patients with multiple sclerosis (MS).. This was an open-label, 12-month, randomized controlled trial.. Patients with MS were recruited from the MS Clinic at St. Michael's Hospital, Toronto.. Forty-nine patients were matched (for age, sex, disease duration, disease-modifying drug, and disability) and enrolled (treated n = 25; control n = 24). Four patients were lost to follow-up (n = 2 from each group).. Treated patients received increasing doses of cholecalciferol (4,000-40,000 IU/d) plus calcium (1200 mg/d), followed by equilibration to a moderate, physiological intake (10,000 IU/d). Control patients did not receive supplements.. At enrollment and at 12 months, peripheral blood mononuclear cell (PBMC) proliferative responses to disease-associated, MS-relevant, and control antigens were measured, along with selected serum biochemical markers.. At 12 months, mean serum 25-hydroxyvitamin D [25(OH)D] concentrations were 83 ± 35 nmol/liter and 179 ± 76 nmol/liter in control and treated participants, respectively (paired t, P < 0.001). Serum 1,25(OH)(2)D did not differ between baseline and 1 yr. In treated patients, 12-month PBMC proliferative responses to neuron antigens myelin basic protein and exon-2 were suppressed (P = 0.002). In controls, there were no significant changes in disease-associated PBMC responsiveness. There were no significant differences between groups in levels of selected biomarkers.. MS-associated, abnormal T cell reactivities were suppressed in vivo by cholecalciferol at serum 25(OH)D concentrations higher than 100 nmol/liter.

Topics: Adult; Calcium; Cholecalciferol; Cytokines; Drug Administration Schedule; Female; Humans; Leukocytes, Mononuclear; Lost to Follow-Up; Male; Multiple Sclerosis; Treatment Outcome; Vitamin D; Vitamins

Multiple sclerosis is a common immune-mediated inflammatory and demyelinating disease. Lower cholecalciferol levels are an established environmental risk factor in multiple sclerosis. Although cholecalciferol supplementation in multiple sclerosis is widely accepted, optimal serum levels are still debated. Moreover, how cholecalciferol affects pathogenic disease mechanisms is still unclear. In the present study, we enrolled 65 relapsing-remitting multiple sclerosis patients who were double-blindly divided into two groups with low and high cholecalciferol supplementation, respectively. In addition to clinical and environmental parameters, we obtained peripheral blood mononuclear cells to analyze DNA, RNA, and miRNA molecules. Importantly, we investigated miRNA-155-5p, a previously published pro-inflammatory miRNA in multiple sclerosis known to be correlated to cholecalciferol levels. Our results show a decrease in miR-155-5p expression after cholecalciferol supplementation in both dosage groups, consistent with previous observations. Subsequent genotyping, gene expression, and eQTL analyses reveal correlations between miR-155-5p and the

Topics: Cholecalciferol; Dietary Supplements; Humans; Leukocytes, Mononuclear; MicroRNAs; Multiple Sclerosis; Up-Regulation

Topics: Cholecalciferol; Dietary Supplements; Humans; Intermediate Filaments; Multiple Sclerosis; Vitamin D

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). MS and its animal model called experimental autoimmune encephalomyelitis (EAE) immunopathogenesis involve a plethora of immune cells whose activation releases a variety of proinflammatory mediators and free radicals. Vitamin D3 (VitD) is endowed with immunomodulatory and antioxidant properties that we demonstrated to control EAE development. However, this protective effect triggered hypercalcemia. As such, we compared the therapeutic potential of VitD and paricalcitol (Pari), which is a non-hypercalcemic vitamin D analog, to control EAE. From the seventh day on after EAE induction, mice were injected with VitD or Pari every other day. VitD, but not Pari, displayed downmodulatory ability being able to reduce the recruitment of inflammatory cells, the mRNA expression of inflammatory parameters, and demyelination at the CNS. Lower production of proinflammatory cytokines by lymph node-derived cells and IL-17 by gut explants, and reduced intestinal inflammation were detected in the EAE/VitD group compared to the EAE untreated or Pari groups. Dendritic cells (DCs) differentiated in the presence of VitD developed a more tolerogenic phenotype than in the presence of Pari. These findings suggest that VitD, but not Pari, has the potential to be used as a preventive therapy to control MS severity.

Topics: Animals; Antioxidants; Bone Marrow Cells; Cholecalciferol; Cytokines; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Ergocalciferols; Female; Immunologic Factors; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Post-Exposure Prophylaxis; Severity of Illness Index; Signal Transduction; Treatment Outcome

Vitamin D has a steroid- and an anabolic-resembling chemical structure. Vitamin D is essential for many processes in the human body after hydroxylation.. To investigate the impact of 25-hydroxy-vitamin D plasma concentrations on the blood parameters number of erythrocytes, hematocrit, mean corpuscular hemoglobin and mean corpuscular volume.. Serial assessments were done in 290 patients with multiple sclerosis and repeated after a mean interval of 245 days. A recommendation for vitamin D supplementation was given in case of a concentration lower than 20 ng/mL combined with a prescription of a formulation containing vitamin D but not vitamin K.. There was a fall of vitamin D in 119 subjects and a rise in 164, while no change appeared in 7 participants. When vitamin D values went down between both assessments moments, the computed increase of mean corpuscular haemoglobin was significantly lower compared with the rise of mean corpuscular haemoglobin associated with a vitamin D elevation. When vitamin D declined, the computed fall of mean corpuscular volume fall was significantly lower compared with the decrease of mean corpuscular volume, when vitamin D rose. Positive correlations were found between differences of vitamin D and mean corpuscular haemoglobin, respectively mean corpuscular volume. Inverse relations appeared between disparities of vitamin D and erythrocytes, respectively haematocrit.. The elevation of vitamin D plasma levels provides enhanced preconditions for a better tissue oxygenation on a cellular level.

Topics: Adult; Cholecalciferol; Erythrocyte Count; Erythrocyte Indices; Female; Hematocrit; Humans; Male; Middle Aged; Multiple Sclerosis; Vitamin D

Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; B7-2 Antigen; Calcitriol; CD4-Positive T-Lymphocytes; Cholecalciferol; CTLA-4 Antigen; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Macrophages; Mice; Microglia; Multiple Sclerosis; Vitamin D Response Element

In our previous study, a Seesaw model was proposed for the fluctuation of crucial anti- (IL-10) and pro-inflammatory (Il-6 & IL-17A) cytokines through vitamin D3. In this paper, however, it is intended to extend the mentioned model by assessing the expression mRNA levels of IL-27 and TGF-β1 as well as the changes of plasma levels of IL-27, TGF-β1, IL-17A, IL-10, and IL-6 after treatment by vitamin D3.. Venous blood samples were drawn from Healthy Participants (HP, n = 25) and First-Degree Relative Participants (FDRP, n = 25) as control groups and Multiple Sclerosis Participants (MSP, n = 25) before and after eight weeks of supplementation with 50000 IU vitamin D3. The mRNA expression and plasma concentrations were gauged by using Real-Time PCR and ELISA assay, respectively.. The mRNA surfaces of IL-27, as well as TGF-β1, were up-regulated. However, the plasma levels of TGF-β1, IL-17A, and IL-6 were significantly different among the three groups. In addition, the plasma levels of IL-27, TGF-β1, IL-10, IL-17A, and IL-6 significantly changed following the administration of vitamin D3.. The findings of this paper illustrate that anti-inflammatory cytokines could have a key role in immunomodulatory functions due to their anti-inflammatory functions. To conclude, this might contribute to preventing the pathophysiological process of MS. Also, the proposed model could be used as a preventive way on disposed people to multiple sclerosis, particularly in first degree relatives of these patients.

Topics: Adult; Cholecalciferol; Enzyme-Linked Immunosorbent Assay; Family; Female; Healthy Volunteers; Humans; Inflammation; Interleukins; Male; Multiple Sclerosis; Real-Time Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta1; Treatment Outcome; Up-Regulation; Young Adult

To determine the effect of vitamin D3 on interferon-β (IFN-β) response and immune regulation in MS mononuclear cells (MNCs).. MNCs from 126 subjects, including therapy-naive patients with different forms of MS, plus patients with MS receiving IFN-β or glatiramer treatment, plus healthy controls were incubated in vitro with IFN-β-1b ± vitamin D3 (calcitriol). Activation of the IFN-β-induced transcription factor, p-Y-STAT1, and antiviral myxovirus A (MxA) protein was measured with flow cytometry and Western blots; serum proteins were measured with a customized 31-protein multiplex assay.. Vitamin D enhanced in vitro IFN responses, as measured by induction of p-Y-STAT1 and MxA in MNCs, T cells, and monocytes. Vitamin D augmentation of IFN responses was seen in untreated and in IFN-β-1b-treated MS. The combination of vitamin D plus IFN-β reduced Th1 and Th17 cytokines, and increased Th2 responses, reversing the effect of IFN-β alone. Exacerbations and progression in untreated patients reduced the vitamin D enhancement of IFN responses. Vitamin D had less effect on IFN response in clinically stable glatiramer-treated than in IFN-β-treated patients.. Vitamin D enhances IFN-β induction of multiple proteins and also reverses the Th1/Th2 bias in MS seen with IFN-β alone. The combination of vitamin D and IFN-β has potential benefit in ameliorating MS.

Topics: Adult; Cholecalciferol; Female; Humans; Immunologic Factors; Interferon-beta; Leukocytes, Mononuclear; Male; Middle Aged; Multiple Sclerosis

Vitamin D and sunlight have each been reported to protect against the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). To date, the contribution of each has been unclear as ultra violet (UV) exposure also causes the generation of vitamin D in the skin. To examine whether the UV based suppression of EAE results, at least, in part from the production of vitamin D, we studied the effect of UV light on EAE in mice unable to produce 7-dehydroxycholesterol (7-DHC), the required precursor of vitamin D. Furthermore, we examined UV suppression of EAE in mice devoid of the vitamin D receptor (VDR). Our results demonstrate that UV light suppression of EAE occurs in the absence of vitamin D production and in the absence of VDR. Future investigations will focus on identifying the pathway responsible for the protective action of UV in EAE and presumably human MS.

Topics: Animals; Cholecalciferol; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Male; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Phototherapy; Receptors, Calcitriol; Skin; Ultraviolet Rays; Vitamin D

Topics: Autoimmunity; Calcium; Cholecalciferol; Humans; Hypercalcemia; Multiple Sclerosis; T-Lymphocytes; Vitamin D

Topics: Cholecalciferol; Dietary Supplements; Humans; Hypercalcemia; Multiple Sclerosis; Vitamin D

Metastatic calcinosis cutis results from abnormal calcium levels leading to the precipitation of insoluble calcium salts in the skin and subcutaneous tissue. Here, we present the case of a 67-year-old man with multiple sclerosis on chronic dexamethasone and concurrent supplementation of calcium and daily cholecalciferol presenting with painful calcified lesions. During initial presentation, corrected calcium was 13.8 mg/dL (reference range: 8.5-10.1 mg/dL), ionised calcium was 1.70 mg/dL (reference range: 1.13-1.32 mg/dL) and 25-hydroxyvitamin D was 41.6 ng/mL (reference range 30-100 ng/mL). Normocalcaemia was restored with the off-label use of denosumab, usually reserved for hypercalcaemia of malignancy and intractable osteoporosis. We discuss potential aetiologies of this patient's hypercalcaemia, calcinosis cutis diagnosis and management and the off-label use of denosumab.

Topics: Calcinosis; Calcium; Cholecalciferol; Denosumab; Dexamethasone; Humans; Hypercalcemia; Male; Middle Aged; Multiple Sclerosis; Off-Label Use; Skin Diseases; Treatment Outcome

The administration of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases, such as multiple sclerosis (MS). Specifically, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most widely studied approaches, as it has evidenced significant immune regulatory properties, both

Topics: Biomarkers; Cholecalciferol; Cytokines; Dendritic Cells; Disease Susceptibility; Humans; Immune Tolerance; Immunohistochemistry; Immunophenotyping; Inflammation Mediators; Microtubule-Associated Proteins; Mucins; Multiple Sclerosis; Signal Transduction

Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit. To model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol, representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in patients with multiple sclerosis. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant experimental autoimmune encephalomyelitis with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger multiple sclerosis disease activity by raising mean levels of T-cell excitatory calcium.

Topics: Animals; Autoimmunity; Blood-Brain Barrier; Calcifediol; Calcium; Calcium Signaling; Chlorides; Cholecalciferol; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Hypercalcemia; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis; Phosphates; Sodium; T-Lymphocyte Subsets; Th1 Cells; Th17 Cells; Vitamin D; Vitamin D Deficiency

Topics: Cholecalciferol; Dietary Supplements; Humans; Multiple Sclerosis; Vitamin D

In addition to the widely known effect of vitamin D. The assessment of biochemical and densitometric markers of calcium-phosphate metabolism in the groups of patients with relapsing-remitting multiple sclerosis (RRMS) selected due to the serum level of vitamin D. The concentrations of biochemical markers and indices of lumbar spine bone densitometry (DXA) were determined in 82 patients divided into vitamin D. The highest level of the parathyroid hormone (PTH) and the highest prevalence of hypophosphatemia and osteopenia were demonstrated in VitDd group compared to VitDi and VitDn. However, in VitDd, VitDi, and VitDn subgroups no significant differences were observed in the levels of alkaline phosphatase (ALP) and ionized calcium (Ca. It is necessary to assess calcium-phosphate metabolism and supplementation of vitamin D

Topics: Adult; Calcium; Cholecalciferol; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Parathyroid Hormone; Phosphates; Poland; Vitamin D; Vitamin D Deficiency

Topics: Cholecalciferol; Dietary Supplements; Humans; Multiple Sclerosis; Vitamin D Deficiency

Topics: Cholecalciferol; Dietary Supplements; Humans; Multiple Sclerosis; Vitamin D Deficiency

Topics: Cholecalciferol; Dietary Supplements; Humans; Multiple Sclerosis; Vitamin D Deficiency

Low vitamin D levels have been associated with an increased risk of multiple sclerosis (MS), although it remains unknown whether this relationship varies by age.. The objective of this paper is to investigate the association between vitamin D3 supplementation through cod liver oil at different postnatal ages and MS risk.. In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis (EnvIMS), a total of 953 MS patients with maximum disease duration of 10 years and 1717 controls reported their cod liver oil use from childhood to adulthood.. Self-reported supplement use at ages 13-18 was associated with a reduced risk of MS (OR 0.67, 95% CI 0.52-0.86), whereas supplementation during childhood was not found to alter MS risk (OR 1.01, 95% CI 0.81-1.26), each compared to non-use during the respective period. An inverse association was found between MS risk and the dose of cod liver oil during adolescence, suggesting a dose-response relationship (p trend = 0.001) with the strongest effect for an estimated vitamin D3 intake of 600-800 IU/d (OR 0.46, 95% CI 0.31-0.70).. These findings not only support the hypothesis relating to low vitamin D as a risk factor for MS, but further point to adolescence as an important susceptibility period for adult-onset MS.

Topics: Adolescent; Adult; Age Factors; Case-Control Studies; Cholecalciferol; Cod Liver Oil; Dietary Supplements; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Norway; Registries; Risk; Young Adult

Vitamin D status, smoking, and Epstein-Barr virus infection (EBV) may all contribute to explain differences in disease prevalence and incidence of Multiple Sclerosis (MS). MS affects women more often than men, and recent cross-sectional study assessments provide evidence of increased female to male prevalence in relapsing remitting MS patients, suggesting that sex hormones may exert an active role in disease pathogenesis. Studies in both humans and animal disease models demonstrate a functional synergy for the immunomodulatory effects of Vitamin D3 and 17-β estradiol. Both smoking and EBV infection clearly increase MS risk, and smoking history has also been associated with poorer disease prognosis. However, neither factor can explain the recent trend indicating greater female prevalence. Therefore, large population-based case-control studies from well defined geographic areas with homogeneous populations should be performed, in order to define environmental factor effects, and sex hormone influences, to better understand prevalence and incidence gender differences observed.

Topics: Animals; Cholecalciferol; Epigenesis, Genetic; Epstein-Barr Virus Infections; Estradiol; Female; Herpesvirus 4, Human; Humans; Male; Multiple Sclerosis; Risk Factors; Sex Factors; Smoking

Multiple risk factors are introduced for Multiple Sclerosis (MS). Recent studies have suggested a possible correlation between vitamin D deficiency and an increase risk of MS. This study was therefore undertaken to compare vitamin D levels in new cases of MS and their relatives as healthy controls. Seventy five new diagnosed MS patients and 100 matched healthy controls among their relatives were enrolled in this study. Two groups were matched for gender, age, season in which serum level of vitamin D was checked and region and diet. Serum levels of 25-hydroxy vitamin D was measured, recorded and analyzed. Seventy five patients (57 female and 18 male) and 100 healthy subjects (75 female and 25 male) were enrolled in this study. The mean serum levels of 25-hydroxy vitamin D in case and control groups were 11.31 and 17.9 ng/ml, respectively (P=0.003). Compared to the healthy subject, serum levels of vitamin D were significantly lower in patients with MS. This difference was only significant in women. Observed difference of vitamin D levels of both groups were significant in summer. This study continues to support the role of vitamin D deficiency in MS.

Topics: Adult; Cholecalciferol; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Retrospective Studies; Risk Factors; Spinal Puncture; Time Factors; Vitamin D Deficiency; Vitamins; Young Adult

We describe here the effects of three drugs that are either approved or have the potential for treating multiple sclerosis (MS) patients through the in vitro activities of human natural killer (NK) cells and dendritic cells (DCs). Our results indicate that 1,25(OH)2D3, the biologically active metabolite of vitamin D3, calcipotriol and FTY720 augment IL-2-activated NK cell lysis of K562 and RAJI tumor cell lines as well as immature (i) and mature (m) DCs, with variable efficacies. These results are corroborated with the ability of the drugs to up-regulate the expression of NK cytotoxicity receptors NKp30 and NKp44, as well as NKG2D on the surfaces of NK cells. Also, they down-regulate the expression of the killer inhibitory receptor CD158. The three drugs down-regulate the expression of CCR6 on the surface of iDCs, whereas vitamin D3 and calcipotriol tend to up-regulate the expression of CCR7 on mDCs, suggesting that they may influence the migration of DCs into the lymph nodes. Finally, vitamin D3, calcipotriol and FTY720 enhance NK17/NK1 cell lysis of K562 cells, suggesting that a possible mechanism of action for these drugs is via activating these newly described cells. In conclusion, our results show novel mechanisms of action for vitamin D3, calcipotriol and FTY720 on cells of the innate immune system.

Topics: Calcitriol; Cell Line, Tumor; Cholecalciferol; Cytotoxicity, Immunologic; Dendritic Cells; Down-Regulation; Fingolimod Hydrochloride; Gene Expression Regulation, Neoplastic; Humans; Interleukin-2; K562 Cells; Killer Cells, Natural; Membrane Proteins; Multiple Sclerosis; Natural Cytotoxicity Triggering Receptor 2; Natural Cytotoxicity Triggering Receptor 3; NK Cell Lectin-Like Receptor Subfamily K; Propylene Glycols; Receptors, CCR6; Receptors, CCR7; Sphingosine; Up-Regulation

Multiple sclerosis is a neurological disorder that presents with symptoms including inflammation, neurodegeneration, and demyelination of the central nervous system (CNS). Secondary progressive multiple sclerosis (SPMS) manifests with serious physical disability. To quantitatively analyze differential protein expression in patients with SPMS, we performed two-dimensional fluorescence difference in-gel electrophoresis, followed by mass spectrometry on the cerebrospinal fluid of these patients and patients with other neurological diseases. Vitamin D-binding protein (DBP), gelsolin, albumin, etc. showed more than a 1.5-fold difference between the two groups. Based on these results, an experimental allergic encephalomyelitis (EAE) model of multiple sclerosis in Lewis rats was used to investigate DBP's role in the disease. Protein levels, mRNA transcripts, and ligands of DBP in different regions of the CNS were evaluated under various vitamin D intake levels. Here, DBP levels increased in the experimental rat groups compared to the control groups regardless of vitamin D intake. Moreover, DBP mRNA levels varied in different parts of the CNS including spinal cords in the experimental groups. The observed differences between DBP protein and mRNA levels in the experimental groups' spinal cords could be derived from the disruption of the blood-brain barrier. Furthermore, an interaction between DBP and actin was confirmed using coimmunoprecipitation and western blot. These results indicate a role for DBP in the actin scavenge system. Moreover, in the experimental group that received oral vitamin D3 supplement, we observed both delayed onset and diminished severity of the disease. When DBP was upregulated, however, the benefits from the vitamin D3 supplements were lost. Thus, we inferred that high levels of DBP were adverse to recovery. In conclusion, here we observed upregulated DBP in the cerebrospinal fluid could serve as a specific diagnostic biomarker for the progression of multiple sclerosis. Next, we demonstrate the vital function of increased levels of free vitamin D metabolites for multiple sclerosis treatment. Finally, vitamin D supplements may be particularly beneficial for SPMS patients.

Topics: Adult; Aged; Animals; Biomarkers; Blotting, Western; Cholecalciferol; Disease Models, Animal; Disease Progression; Electrophoresis, Gel, Two-Dimensional; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Rats; Rats, Inbred Lew; Reproducibility of Results; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spinal Cord; Up-Regulation; Vitamin D-Binding Protein

Topics: Cholecalciferol; Dietary Supplements; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Receptors, Calcitriol; Ultraviolet Rays; Vitamin D; Vitamin D Deficiency; Vitamins

Topics: Adjuvants, Immunologic; Cholecalciferol; Female; Humans; Interferon beta-1b; Interferon-beta; Male; Multiple Sclerosis; Vitamins

Mounting evidence correlate vitamin D3 (cholecalciferol) supplementation or higher serum levels of vitamin D (25(OH)D) with a lower risk of developing multiple sclerosis (MS), reduced relapse rate, slower progression or fewer new brain lesions. We present here the case of a woman who was diagnosed with MS in 1990. From 1980 to 2000, her ability to walk decreased from ~20 to 1 km per day. Since January 2001, a vitamin D3 supplement was ingested daily. The starting dose was 20 mcg (800 IU)/day and escalated to 100 mcg (4000 IU)/day in September 2004 and then to 150 mcg (6000 IU)/day in December 2005. Vitamin D3 intake reduced muscular pain and improved ambulation from 1 (February 2000) to 14 km/day (February 2008). Vitamin D intake over 10 years caused no adverse effects: no hypercalcaemia, nephrolithiasis or hypercalciuria were observed. Bowel problems in MS may need to be addressed as they can cause malabsorption including calcium, which may increase serum PTH and 1,25(OH)2D levels, as well as bone loss. We suggest that periodic assessment of vitamin D3, calcium and magnesium intake, bowel problems and the measurement of serum 25(OH)D, PTH, Ca levels, UCa/Cr and bone health become part of the integral management of persons with MS.

Topics: Bone Density; Bone Density Conservation Agents; Cholecalciferol; Dietary Supplements; Female; Humans; Longitudinal Studies; Multiple Sclerosis; Pain Management; Parathyroid Hormone; Vitamin D; Walking

To characterize the effect of vitamin D(3) intake on urinary calcium:creatinine ratios across predefined ranges of serum 25(OH)D.. Patients with multiple sclerosis (n=25) received escalating doses of vitamin D(3) (4000-40,000IU/d) with calcium (1200mg/d).. Urinary calcium:creatinine was driven by increased 25(OH)D when concentrations were <75nmol/L (r=0.424, p=0.009) and >200nmol/L (r=0.281, p=0.01), but no relationship existed when 25(OH)D concentrations were 76-200nmol/L.. A "safe", physiological range of 25(OH)D concentrations is 75-200nmol/L.

Topics: Adult; Calcium; Cholecalciferol; Creatinine; Dietary Supplements; Dose-Response Relationship, Drug; Humans; Multiple Sclerosis; Regression Analysis

How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D(3), including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.

Topics: Animals; Antigens, CD; Case-Control Studies; Cholecalciferol; Cohort Studies; CTLA-4 Antigen; Down-Regulation; Female; Genetic Variation; Glycosylation; Haplotypes; Humans; Male; Mice; Mice, Inbred Strains; Multiple Sclerosis; N-Acetylglucosaminyltransferases; Receptors, Interleukin-2; Receptors, Interleukin-7; Risk Factors; Signal Transduction; Sunlight

Vitamin D has been proposed as a promoter of immune homeostasis in multiple sclerosis (MS). During the past decade, the focus of the effects of vitamin D has been on dendritic cells and on T cells. Since there is an increasing interest in the role of B cells in the pathophysiology of MS, we studied the role of vitamin D on B cells in vivo in patients with MS.. We explored the effects of 12 weeks high-dose vitamin D(3) supplementation on peripheral B cell differentiation, immunoglobulin production and levels of B cell activating factor (BAFF) in 15 patients with MS.. Circulating B cell subsets were characterized by flow cytometry. Plasma immunoglobulin levels were assessed by nephelometry. Plasma BAFF levels were assessed by enzyme-linked immunosorbent assay (ELISA).. Although a significant increase serum 25-hydroxyvitamin D was induced, we found no significant shift in B cell differentiation, isotype switching, or plasma BAFF levels.. In patients with MS, supplementation of high doses vitamin D(3) does not have substantial effects on phenotypic markers of B cell differentiation in circulating B cells. Future studies may unravel more subtle changes in the B cell compartment, either in the circulation or in the central nervous system.

Topics: Adult; B-Cell Activating Factor; B-Lymphocyte Subsets; B-Lymphocytes; Cell Differentiation; Cholecalciferol; Dietary Supplements; Humans; Immunoglobulin Class Switching; Multiple Sclerosis

Low expression of NR4A gene family members (NR4A1, NR4A3) and 1-alpha, 25-dihydroxyvitamin D(3) receptor (VDR) genes was demonstrated in peripheral blood mononuclear cells (PBMC) of subjects evaluated during the pre-disease state of multiple sclerosis (MS-to-be, MS2b), in patients with clinically isolated syndrome (CIS) during the very early presentation of neurological symptomatology and in relapsing-remitting MS (RRMS) patients. Both NR4A1 and NR4A3 are known to be involved in T-cell receptor-induced apoptosis and are regulated by VDR. We further evaluated the precise implications of apoptosis signaling regulators in relation to MS pathogenesis at the cellular level by studying the effects of 1-alpha, 25-dihydroxyvitamin D(3) (Vit D(3)) upon NR4A1 expression. We demonstrated that the low apoptotic level in MS patients was repaired by Vit D(3) mainly through NR4A1 and to a lesser extent thorough BCL2-associated X protein (BAX). These findings prove a role for Vit D(3) as a possible therapeutic intervention in MS patients aimed to activate the repressed apoptosis and enhance better control of the disease.

Topics: Adult; Apoptosis; bcl-2-Associated X Protein; Cholecalciferol; DNA-Binding Proteins; Female; Humans; Male; Multiple Sclerosis; Nuclear Receptor Subfamily 4, Group A, Member 1; Primary Cell Culture; Receptors, Calcitriol; Receptors, Steroid; Receptors, Thyroid Hormone; T-Lymphocytes; Young Adult

In this report, we describe the management of a multiple sclerosis patient with a femoral fracture who had severe vitamin D deficiency. After the patient's preoperative laboratory studies revealed a normal platelet count, the orthopedic surgeon performed an intramedullary rod fixation on the patient's left femoral fracture. After the surgery, the diagnosis of vitamin D deficiency was made by measuring the circulating serum concentration of 25-dihydroxyvita-min D (25(OH)D) via Disorin's Vitamin D immunochemiluminometric assay LIASION by LabCorp (Laboratory Corporation of America). The patient's postoperative management included the oral administration of 4000 IU of vitamin D3 in a gel-cap suspension that resulted in an elevation of the blood serum concentration of 25(OH)D to an optimal concentration of >80 nmol/L (32 ng/ml).

Topics: Aged; Bone Nails; Calcifediol; Cholecalciferol; Femoral Fractures; Fracture Fixation, Intramedullary; Humans; Male; Multiple Sclerosis; Postoperative Care; Vitamin D Deficiency

Topics: Cholecalciferol; Dietary Supplements; Female; Humans; Hydrocortisone; Infant, Newborn; Melatonin; Multiple Sclerosis; Pregnancy; Premature Birth; Prenatal Exposure Delayed Effects; Schizophrenia; Stress, Physiological

Vitamin D is important for bone health and immune regulation, and has been shown to be low in multiple sclerosis (MS). We sought to determine the effect of over the counter low dose cholecalciferol (LDC) and high dose ergocalciferol (HDE) on the vitamin D levels in MS patients.. We retrospectively evaluated serum 25-hydroxy-vitamin D [25(OH)D] levels of 199 patients (CIS, n = 32; RRMS, n = 115; PPMS, n = 10; SPMS, n = 16; Transverse Myelitis (TM), n = 9; other neurological diseases, n = 16) attending our clinic between 2004 and 2008. We examined the change in 25(OH)D levels in 40 MS patients who took either LDC (< or =800 IU/day) or HDE (50,000 IU/day for 7-10 days, followed by 50,000 IU weekly or biweekly).. The average 25(OH)D level was 71 +/- 39 nmol/L (Mean +/- SD), and 167(84%) patients had insufficient levels (< or =100 nmol/L) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels. However, 25(OH)D levels increased by 42 nmol/L (P = 0.01) in the patients originally taking LDC and then prescribed HDE. Optimal levels (> or =100 nmol/L) were only achieved in less than 40% of patients.. We conclude that large numbers of patients with MS and TM in our cohort are deficient in vitamin D. HDE significantly elevated 25(OH)D levels in MS patients and was more effective at increasing 25(OH)D levels than LDC. Prospective studies are required to determine appropriate dosing regimen to achieve optimal levels in the majority of MS patients and to ascertain the safety, immunological response, and ultimately the clinical efficacy of vitamin D replacement therapy.

Topics: Adult; Cholecalciferol; Demyelinating Diseases; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Longitudinal Studies; Male; Middle Aged; Multiple Sclerosis; Retrospective Studies; Vitamin D Deficiency; Vitamins

Vitamin D3 may have therapeutic potential in several diseases, including multiple sclerosis. High doses of vitamin D(3) may be required for therapeutic efficacy, and yet tolerability--in the present context, defined as the serum concentration of 25-hydroxyvitamin D [25(OH)D] that does not cause hypercalcemia--remains poorly characterized.. The objective of the study was to characterize the calcemic response to specific serum 25(OH)D concentrations.. In a 28-wk protocol, 12 patients in an active phase of multiple sclerosis were given 1200 mg elemental Ca/d along with progressively increasing doses of vitamin D3: from 700 to 7000 microg/wk (from 28 000 to 280 000 IU/wk).. Mean (+/- SD) serum concentrations of 25(OH)D initially were 78 +/- 35 nmol/L and rose to 386 +/- 157 nmol/L (P < 0.001). Serum calcium concentrations and the urinary ratio of calcium to creatinine neither increased in mean values nor exceeded reference values for any participant (2.1-2.6 mmol/L and <1.0, respectively). Liver enzymes, serum creatinine, electrolytes, serum protein, and parathyroid hormone did not change according to Bonferroni repeated-measures statistics, although parathyroid hormone did decline significantly according to the paired t test. Disease progression and activity were not affected, but the number of gadolinium-enhancing lesions per patient (assessed with a nuclear magnetic brain scan) decreased from the initial mean of 1.75 to the end-of-study mean of 0.83 (P = 0.03).. Patients' serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data support the feasibility of pharmacologic doses of vitamin D3 for clinical research, and they provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.

Topics: Adult; Bone Density Conservation Agents; Calcium; Cholecalciferol; Creatinine; Dietary Supplements; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Hypocalcemia; Liver; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; No-Observed-Adverse-Effect Level; Parathyroid Hormone; Reference Values; Risk Factors; Safety; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency

The prevalence of multiple sclerosis (MS) increases significantly with decreasing UV B light exposure, possibly reflecting a protective effect of vitamin D(3). Consistent with this theory, previous research has shown a strong protective effect 1,25-dihydroxyvitamin D(3) in experimental autoimmune encephalomyelitis (EAE), an MS model. However, it is not known whether the hormone precursor, vitamin D(3), has protective effects in EAE. To address this question, B10.PL mice were fed a diet with or without vitamin D(3), immunized with myelin basic protein, and studied for signs of EAE and for metabolites and transcripts of the vitamin D(3) endocrine system. The intact, vitamin D(3)-fed female mice had significantly less clinical, histopathological, and immunological signs of EAE than ovariectomized females or intact or castrated males. Correlating with reduced EAE, the intact, vitamin D(3)-fed female mice had significantly more 1,25-dihydroxyvitamin D(3) and fewer CYP24A1 transcripts, encoding the 1,25-dihydroxyvitamin D(3)-inactivating enzyme, in the spinal cord than the other groups of mice. Thus, there was an unexpected synergy between vitamin D(3) and ovarian tissue with regard to EAE inhibition. We hypothesize that an ovarian hormone inhibited CYP24A1 gene expression in the spinal cord, so the locally-produced 1,25-dihydroxyvitamin D(3) accumulated and resolved the inflammation before severe EAE developed. If humans have a similar gender difference in vitamin D(3) metabolism in the CNS, then sunlight deprivation would increase the MS risk more significantly in women than in men, which may contribute to the unexplained higher MS incidence in women than in men.

Topics: Animals; Cholecalciferol; Dietary Supplements; Encephalomyelitis, Autoimmune, Experimental; Female; Male; Mice; Multiple Sclerosis; Myelin Basic Protein; Ovariectomy; RNA, Messenger; Sex Factors; Spinal Cord; Steroid Hydroxylases; Vitamin D3 24-Hydroxylase