Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties.
ABSTRACT: Flu-like symptoms (FLS) are common side effects of interferon beta (IFN-?) treatment in patients with Multiple Sclerosis (PwMS) and are associated with post-injection cytokine surge. We hypothesized that vitamin D3 supplementation would ameliorate FLS by decreasing related serum cytokines' levels.In a randomized, double blind study of 45 IFN?-treated PwMS, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 24 patients received 4,370 IU per day (high dose) for one year. FLS were assessed monthly by telephonic interviews. Serum levels of 25-hydroxy-D (25-OH-D), calcium, PTH, IL-17, IL-10 and IFN-? were measured periodically. EDSS, relapses, adverse events and quality of life (QoL) were documented.25-OH-D levels increased to a significantly higher levels and PTH levels decreased in the high dose group. There was no significant change in FLS. IL-17 levels were significantly increased in the low dose group, while patients receiving high dose vitamin D had a heterogeneous IL-17 response. No significant differences in relapse rate, EDSS, QoL, serum IL-10 and IFN? were found. Hypercalcemia or other potential major adverse events were not observed.Vitamin D supplementation to IFN-? treated PwMS, at the doses used, seems safe and associated with dose-dependent changes in IL-17 serum levels, while not affecting IFN-? related FLS.ClinicalTrials.gov ID: NCT01005095.
Project description:In most cases, multiple sclerosis (MS) patients reduce physical activity with disease progression and many patients are found to be vitamin D deficient. The aim of this study was to explore correlations between daily physical activity in everyday life and 25-hydroxyvitamin-D3 (25(OH)D3) serum levels in mildly disabled patients with an Expanded Disability Status Scale (EDSS) ? 4. We analyzed serum 25(OH)D3 levels and recorded daily physical activity (activity duration, number of steps, distance, energy expenditure) using an activity tracker for 14-days in 25 women and 15 men. Participants recorded their daily sunlight exposure time by diary during the study period. We found a positive correlation between physical activity and 25(OH)D3 levels in both, Pearson correlation (r = 0.221) and multivariate regression analysis (? = 0.236), which was stronger than correlation with sunlight exposure time (? = -0.081). EDSS and physical activity were weakly correlated (r = -0.228), but no correlation between EDSS and 25(OH)D3 levels was found (r = -0.077). There were no relevant differences in physical activity (p = 0.803) and 25(OH)D3 concentrations (p = 0.385) between the EDSS groups 0 - 1.5 and 2.0 - 4.0. In conclusion, physical activity has an effect on vitamin D levels independent of sunlight exposure time in people with MS (pwMS) with low-grade disability.
Project description:One of the most common adverse event of interferon beta (IFN?) therapy for multiple sclerosis is flu-like syndrome (FLS), which has been reportedly related to increased levels of cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-?). Average cytokine levels can be affected by single nucleotide polymorphism in the gene promoter regions. To investigate whether IL-6 -174 G>C and TNF-? -376 G>A polymorphisms could be correlated to the incidence of FLS, and whether an anti-inflammatory/antipyretic therapy may influence FLS development, a prospective observational study was performed in 190 treatment naïve, multiple sclerosis patients who started IM IFN?-1a 30mcg once weekly. The identification of IL-6 -174 G>C and TNF-? -376 G>A polymorphisms was achieved by performing an amplification-refractory mutation system. Serum IL-6 levels were measured using enzyme-linked immunosorbent assay in blood samples taken before therapy and then after the first and last IFN?-1a injection of the follow-up. FLS-related symptoms were recorded by patients once per week during the first 12 weeks of therapy into a self-reported diary. We found that patients carrying at least one copy of the C allele at position -174 in the promoter of IL-6 gene produced lower levels of IL-6 and were less prone to develop FLS, which was also less severe. On the contrary, the polymorphism of TNF-? had no effect on FLS. Patients taking the first dose of anti-inflammatory/antipyretic therapy in the peri-injection period (within 1 hour) experienced a reduced FLS severity. In conclusion, the study of IL-6 -174 G>C polymorphism would allow the identification of patients lacking the C nucleotide on both alleles who are at risk of a more severe FLS, and may be addressed to a timely and stronger anti-inflammatory/antipyretic therapy for a more effective FLS prevention.
Project description:Th17 cells, while indispensable in host defense, may play pathogenic roles in many autoimmune diseases, including rheumatoid arthritis (RA). However, the mechanisms by which human Th17 cells drive autoimmunity have not been fully defined. We assessed the potential of the human Th17 CD4 T cell subset to induce expression of cell-cell interaction molecules and inflammatory mediators by fibroblast-like synoviocytes (FLS), and the roles of IFN-? and IL-17 in these interactions.Th1 or Th17 cells were induced from healthy adult donor CD4 T cells and were co-cultured with FLS for 48 h with/without neutralization of IFN-?, IL-17A, or both. Alternatively, FLS were treated only with IFN-? or IL-17 for 48 h. FLS expression of CD40, CD54, and MHC-II, as well as IL-6 and IL-8 secretion, were assessed by surface staining followed by flow cytometry and ELISA, respectively.Both Th1 and Th17 cells secreted IL-17 as well as IFN-?, although IFN-? production was much greater from Th1 cells. FLS expression of CD40, CD54, and MHC-II significantly increased upon co-culture with Th1 cells, while Th17 cells increased only the percentage of FLS that were CD54+. Both T cell subsets induced IL-6 and IL-8 secretion by RA FLS. Neutralization of IL-17A did not reduce FLS expression of CD40, MHC-II, or CD54, but did inhibit IL-6 and IL-8 secretion. Although IFN-? was a weak inducer of IL-6 secretion and significantly inhibited IL-8 secretion from FLS when used as a single stimulus, neutralization of IFN-? inhibited the secretion of both cytokines in Th17/FLS co-cultures with RA but not OA FLS.FLS cell-cell interaction molecules and soluble inflammatory mediators are differentially regulated by IFN-? and IL-17. The effects of IFN-? may depend in part on the particular milieu of other co-existing cytokines and its potential to induce cell-cell interactions. The potential benefit of therapeutic neutralization of either IL-17 or IFN-? could depend on the relative proportions of these cytokines in the synovial compartment of an RA patient.
Project description:BACKGROUND:Tonsils have an active role in immune defence and inducing and maintaining tolerance to allergens. Vitamins A, D, and E, and antimicrobial peptide LL-37 may have immunomodulatory effects. We studied how their serum levels were associated with allergy status, intratonsillar/nasopharyngeal virus detection and intratonsillar expression of T cell- and innate immune response-specific cytokines, transcription factors and type I/II/III interferons in patients undergoing tonsillectomy. METHODS:110 elective tonsillectomy patients participated. Serum levels of vitamins A, 25(OH)D, and E, LL-37 and allergen-specific IgE as well as nasopharyngeal/intratonsillar respiratory viruses were analyzed. The mRNA expression of IFN-?, IFN-?, IFN-?, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-?, FOXP3, GATA3, RORC2 and Tbet in tonsils were analyzed by quantitative RT-PCR. RESULTS:The median age of the patients was 16 years (range 3-60), 28% of subjects had atopy, and 57% carried ?1 respiratory virus in nasopharynx. Detection of viruses decreased by age. Higher vitamin A levels showed borderline significance with less viral detection (P = 0.056). Higher 25(OH)D was associated with less allergic rhinitis and atopy (P < 0.05) and higher vitamin E with less self-reported allergy (P < 0.05). In gene expression analyses, 25(OH)D was associated with higher IL-37, vitamin A with higher IFN-? and vitamin E with less IL-28 (P < 0.05). LL-37 was associated with less FOXP3, RORC2 and IL-17 in tonsils (P < 0.05). CONCLUSIONS:Vitamin D and E levels were associated with less allergic disorders. Vitamin A was linked to antiviral and vitamin D with anti-inflammatory activity. LL-37 and was linked to T regulatory cell effects.
Project description:BACKGROUND:Lowserum vitamin D levels are associated with susceptibility to, and severity of, multiple sclerosis. High dose vitamin D has been proposed as a potential immunomodulator in multiple sclerosis. OBJECTIVES:We performed a single centre, investigator-led, exploratory, double-blind, randomised, placebo controlled, trial of vitamin D3 in clinically isolated syndrome and healthy control participants to assess its immunological effects. Secondary end-points included clinical and magnetic resonance imaging outcomes and safety. METHODS:Clinically isolated syndrome patients and healthy control participants were randomised to: placebo, 5000?IU or 10,000?IU vitamin D3/day (Vigantol oil). Study duration was 24 weeks. RESULTS:The trial did not meet its primary end point, with no difference in the frequency of pro-inflammatory CD4+ T cells (interleukin (IL)-17+/interferon (IFN)-?+) seen. A higher level of disease freedom (67% versus 50%) was seen in those with serum 1,25 (OH) vitamin D levels>100?nmol/l but this did not reach significance. High dose vitamin D3 was well tolerated with no safety signal. CONCLUSIONS:High dose vitamin D3 over 24 weeks was well tolerated but without immunological, magnetic resonance imaging or clinical evidence of benefit. The hypothesised therapeutic effects in clinically isolated syndrome or multiple sclerosis patients may require longer periods of administration or may only be seen in patients treated with vitamin D3 as an adjunct to established disease modifying therapies.
Project description:<h4>Objective</h4>Multiple sclerosis is now more common among minority ethnic groups in the UK but little is known about their experiences, especially in advanced stages. We examine disease progression, symptoms and psychosocial concerns among Black Caribbean (BC) and White British (WB) people severely affected by MS.<h4>Design</h4>Mixed methods study of 43 BC and 43 WB people with MS (PwMS) with an Expanded Disability Status Scale (EDSS) ?6 involving data from in clinical records, face-to-face structured interviews and a nested-qualitative component. Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) were calculated. To control for selection bias, propensity scores were derived for each patient and adjusted for in the comparative statistical analysis; qualitative data were analysed using the framework approach.<h4>Results</h4>Median EDSS for both groups was (6.5; range: 6.0-9.0). Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) based on neurological assessment of current EDSS scores identified BC PwMS were more likely to have aggressive disease (PI F?=?4.04, p?=?0.048, MSSS F?=?10.30, p<0.001). Patients' reports of the time required to reach levels of functional decline equivalent to different EDSS levels varied by group; EDSS 4: BC 2.7 years v/s WB 10.2 years (U?=?258.50, p?=?0.013), EDSS 6?6.1 years BC v/s WB 12.7 years (U?=?535.500, p?=?0.011), EDSS 8: BC 8.7 years v/s WB 10.2 years. Both groups reported high symptom burden. BC PwMS were more cognitively impaired than WB PwMS (F?=?9.65, p?=?0.003). Thematic analysis of qualitative interviews provides correspondence with quantitative findings; more BC than WB PwMS referred to feelings of extreme frustration and unresolved loss/confusion associated with their rapidly advancing disease. The interviews also reveal the centrality, meanings and impact of common MS-related symptoms.<h4>Conclusions</h4>Delays in diagnosis should be avoided and more frequent reviews may be justified by healthcare services. Culturally acceptable interventions to better support people who perceive MS as an assault on identity should be developed to help them achieve normalisation and enhance self-identity.
Project description:Objective: To investigate the associations between hypovitaminosis D and disease activity in a cohort of relapsing remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) patients. Methods: In 51 RRMS and 2 CIS patients on stable interferon-?-1b (IFN-?-1b) treatment recruited to the EVIDIMS study (Efficacy of Vitamin D Supplementation in Multiple Sclerosis (NCT01440062) baseline serum vitamin D levels were evaluated. Patients were dichotomized based on the definition of vitamin D deficiency which is reflected by a < 30 vs. ? 30 ng/ml level of 25-hydroxyvitamin D (25(OH)D). Possible associations between vitamin D deficiency and both clinical and MRI features of the disease were analyzed. Results: Median (25, 75% quartiles, Q) 25(OH)D level was 18 ng/ml (12, 24). Forty eight out of 53 (91%) patients had 25(OH)D levels < 30 ng/ml (p < 0.001). Patients with 25(OH)D ? 30 ng/ml had lower median (25, 75% Q) T2-weighted lesion counts [25 (24, 33)] compared to patients with 25(OH)D < 30 ng/ml [60 (36, 84), p = 0.03; adjusted for age, gender and disease duration: p < 0.001]. Expanded disability status scale (EDSS) score was negatively associated with serum 25(OH)D levels in a multiple linear regression, including age, sex, and disease duration (adjusted: p < 0.001). Interpretation: Most patients recruited in the EVIDIMS study were vitamin D deficient. Higher 25(OH)D levels were associated with reduced T2 weighted lesion count and lower EDSS scores.
Project description:Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively.An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score.Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls.High-dose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects.This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes.
Project description:BACKGROUND: Economic costs related to treatment of multiple sclerosis (MS) must be justified by health state, quality of life (QOL) and social participation improvement. This study aims to describe correlations between social participation, economic costs, utility and MS-specific QOL in a sample of patients with MS (pwMS). METHODS: We interviewed 42 pwMS receiving natalizumab and collected clinical data, direct medical costs, productivity loss, utility (EQ5D-VAS), MS-specific QOL (SEP-59), social participation with the Impact on Participation and Autonomy questionnaire (IPA). We performed descriptive and correlation analyses. RESULTS: 41 pwMS, with a mean Expanded Disability Status Scale (EDSS) score of 4.0, completed questionnaires. Mean annual global cost per patient was 68448 +/-33374 Euros and increased with EDSS (r = 0.644), utility (r = -0.456) and IPA (r = 0.519-0.671) worsening. Mean utility was 0.52 +/- 0.28. Correlations between IPA and QOL (EQ5D-VAS or SEP-59) were observed (r = -0.53 to -0.78). Association between QOL and EDSS was smaller (EQ5D-VAS) or absent. Productivity losses were poorly correlated to EDSS (r = 0.375). CONCLUSION: Moderate to strong correlations of social participation with clinical status (EDSS), QOL, utility and economic costs encourage exploring better these links in larger cohorts. The stronger correlation between social participation and QOL than between EDSS and QOL needs to be confirmed.
Project description:Persons with multiple sclerosis (PwMS) often complain about sleep problems. There is less known about objective sleep-electroencephalography (EEG) dimensions within naturalistic conditions (i.e., home and/or familiar setting). The present cross-sectional study examined the associations between objective and subjective sleep, depression, physical activity scores, and MS-related information among PwMS in their familiar setting. The sample consisted of 16 PwMS (mean age: 50.3 years; median Expanded Disability Status Scale (EDSS): 5.5) who completed questionnaires covering subjective sleep (symptoms of insomnia, restless legs syndrome (RLS) and sleep-disordered breathing), as well as daytime sleepiness, subjective physical activity, depression, and MS-related information (fatigue, EDSS; disease-modifying treatments). Objective sleep was assessed with a mobile sleep-EEG device under naturalist conditions within the home. Descriptively, better objective sleep patterns were associated with lower sleep complaints (rs = -0.51) and daytime sleepiness (rs = -0.43), and with lower symptoms of RLS (rs = -0.35), but not with sleep-disordered breathing (rs = -0.17). More deep sleep was associated with higher moderate physical activity levels (rs = 0.56). Objective sleep parameters were not associated with vigorous physical activity levels (rs < 0.25). Descriptively, moderate and vigorous physical activity scores were associated with lower symptoms of RLS (rs = -0.43 to -0.47). Results from this small study carried out under naturalistic conditions suggest that among PwMS, better objective sleep correlated with better subjective sleep and higher moderate physical activity levels.