Lots of research (I mean lots) and useful evidence but no patient focussed recommendation from ECTRIMS, so sad.
Vitamin D Abstracts ECTRIMS 2012
The effects of Vitamin D on the adaptive immune system (T and B cells) in relation to clinical manifestations in MS
R.M. Hupperts, J. Smolders, J. Damoiseaux (Sittard-Geleen, NL)
T cells are considered to be critically involved in the inflammation of the CNS at disease onset in MS patients. Whereas Th1 cells were originally thought to initiate MS inflammation, this detrimental role is nowadays attributed to Th17 cells, while Th1 cells might be involved in the continuation of the inflammatory response. Activation of these pathogenic Th1 and Th17 cells is likely to be facilitated by a functional deficit within the Treg compartment.
Besides to multiple studies on the association between vitamin D status and MS prevalence, vitamine D status is also positively associated with relapse rate and disability in MS. We hypothesize that at least this latter association is driven by a disturbance in T cell homeostasis and concommitant loss of self-tolerance. Indeed, cells of the adaptive immune system express enzymes involved in the metabolism of vitamin D, and express the vitamin D receptor upon activation. In vitro experiments show that vitamin D skews the T cell compartment towards a more anti-inflammatory state. In addition, vitamin D status is positively correlated with Treg function in RRMS patients
Next to the pathogenic potential of T cells, B cells are increasingly recognized as important participants in the pathogenesis of MS. On the one hand pro-inflammatory characteristics of B cells may aggravate disease, while IL-10 producing Breg may reduce progression, potentially via restoration of the defective Treg compartment. The effect of vitamin D on B cell functions is ill defined and thus far studies have revealed contradicting results.
Recent pilot studies have suggested that vitamin D supplementation may have beneficial effects on relapse rate in MS as associated with a shift towards anti-inflammatory T cell responses. These promissing data have led to the start of large placebo controlled multicenter studies like the SOLAR trial.
This study is based on clinical end points and is combined with immunological readouts in a substudy (SOLARIUM).
From physico-chemical agents exposure to MS
S. Ramagopalan (London/Oxford, UK)
Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near MS associated genes identified from genome-wide association (GWA) studies. VDR-binding regions overlapped with active regulatory regions much more than expected by chance. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS associated genomic regions.
An age at exposure effect in the association between sun exposure and the risk of MS in Norway and Italy. The EnvIMS study
K. Bjørnevik, T. Riise, K. Wesnes, E. Granieri, I. Casetta, J. Drulovic, K.M. Myhr, K. Lauer, M. Kampman, S. Magalhaes, T. Pekmezovic, T. Holmøy, A.M. Landtblom, C. Wolfson, M. Pugliatti (Bergen, NO; Ferrara, IT; Belgrade, RS; Griesheim, DE; Tromsø, NO; Montreal, CA; Oslo, NO; Linköping, SE; Sassari, IT)
Background: Vitamin D insufficiency is one of the factors that most consistently have been shown to be associated with an increased risk of developing multiple sclerosis (MS). This study aims to estimate the association between sun exposure as an indirect measure of vitamin D status at various age periods during childhood and adolescence and the risk of MS and to look for possible differences between Norway and Italy.
Methods: The data for this study are from EnvIMS, a large multinational case-control study, and includes 733 cases and 1438 population based controls from Italy and 959 cases and 1718 population based controls from Norway. The exposure information was collected by means of a standardized self-administered questionnaire that included questions about sun habits during different periods in childhood and adolescence. The participants were asked to recall the amount of time spent outdoors and use of sunscreen during the same time periods. Effect estimates were calculated using logistic regression contrasting “no outdoor activity” with “being outside most of the time ” adjusting for relevant possible confounding factors.
Results: Adjusting for sex we found a significant inverse association between time spent outdoors and MS both in Norway and in Italy. In Norway the association was strongest with little sun exposure in the summer between age 16 and 18 years (OR=1.79, 95% Cl[1.28 - 2.52]), while the period from age 0 to 5 years showed the strongest effect in Italy (OR= 1.57, 95% Cl [1.17 - 2.12]). We also found a statistically significant inverse association in the winter in Italy (OR= 1.45, 95% Cl [1.05 - 2.00]), but not in Norway. High sunscreen use between the age of 0 and 6 years was associated with an increased risk of MS in Norway (OR=1.59, 95% Cl [1.23 - 2.04]) after adjusting for sun exposure during the same period.
Conclusion: Sun exposure was found to be inversely associated with MS both in Norway and in Italy, with the strongest effect in early childhood in Italy and in late adolescence in Norway. The effect of seasonal variations was greater in Norway with no association with sun exposure in the winter. Further, high use of sunscreen in early childhood was linked to MS in Norway. Using sun exposure as a proxy of vitamin D exposure, this study gives further support for the importance of vitamin D in relation to MS. The findings suggest a possible age variation related to country/latitude in risk of MS due to vitamin D insufficiency.
Month of birth is a latitude-dependent risk factor for multiple sclerosis in Norway
N. Grytten Torkildsen, O. Torkildsen, J. Aarseth, E. Benjaminsen, E. Gulowsen Celius, O. Dahl, T. Holmoey, K. Loeken-Amsrud, R. Midgard, K.-M. Myhr, G. Risberg, A. Vatne, M. Kampman (Bergen, Bodø, Oslo, Namsos, Lillehammer, Molde, Kristiansand, Tromsø, NO)
Background: Previous studies have pointed to increased risk of multiple sclerosis (MS) in April and May births, and reduced risk of MS in November births in the Northern hemisphere. Inverse results are reported in the Southern hemisphere. Studies are also indicating that higher levels of Vitamin D reduce the risk of MS.
Objectives: Estimate the month of birth effect for MS in Norway and study variations related to latitude.
Methods: All patients registered in Norwegian MS Registry & Biobank born between 1930 and 1979 and all patients diagnosed with MS in previously published studies on MS prevalence in Norway were included (n= 6935). The distribution of month of birth in the study population was compared with the distribution of month of birth in the Norwegian population born during 1930 to 1979 (data provided by Statistics Norway) by Chi square test. Numbers were calculated for each month of birth, based on the number of patients born during the month and provided for each time period relative to the general population. The latitude gradient was divided in the south (> 58° N), middle (65° N to 68° N) and north (> 68° N) of Norway, corresponding to the regional yearly mean vitamin D effective UV-dose for the period 1979-98 [kJ/m2] (Edvardsen K. et al. 2011)
Results: The risk of MS was increased in individuals born in April and May and decreased in individuals born in November and February. In the South, the excess of MS- births in April/May vs. November was 1.02 (95% CI: 0.78, 1.33), in Middle-Norway 1.12 (95% CI: 0.88, 1.42) and in Northern Norway 1.47 (95% CI: 0.92, 2.34) (p= 0.02).
Conclusion: We report an increased risk of MS for those born in April/May and a decreased risk of MS for those born in the winter months. The month of birth effect was strongest in the northern parts of Norway, supporting the role of environmental factors such as vitamin D in prenatal life.
Reference: Edvardsen K., Veierød M., Brustad M et al. Vitamin D-effective solar UV radiation, dietary vitamin D and breast cancer risk. Int J Cancer 128, 1425-1433 (2011)
Fatty fish intake decrease multiple sclerosis risk among people exposed to low levels of ultraviolet radiation
M. Bäärnhielm, T. Olsson, L. Alfredsson (Stockholm, SE)
Background: The aim of this study was to estimate the relationship between intake of fatty fish and risk of developing multiple sclerosis (MS).
Methods: This study is based on the ongoing project Epidemiological Investigation of MS (EIMS) which is a population-based case-control study, comprising the general population aged 16-70 years in defined areas of Sweden. The present analysis involved 1404 incident cases of multiple sclerosis (MS) and 3097 controls, randomly selected from the study base, with consideration taken to age, gender, and residential area.
The incidence of MS among people who reported high intake of fatty fish the last five years before inclusion in the study was compared with the incidence among people who reported low fatty fish intake. Adjustments were made for education level, smoking status, ultraviolet radiation (UVR) exposure habits, body mass index (BMI), vitamin D intake from dairy products and intake of lean fish. We performed sub group analyses stratifying for sun exposure habits, ancestry and gender.
Findings: Subjects who reported fatty fish intake 1-7 times per week had a slightly decreased risk of multiple sclerosis compared with subjects who reported less intake of fatty fish (adjusted odds ratio (OR) 0.9, 95% confidence interval (CI) 0.8-1.1).
In subgroup analyses among subjects who reported low UVR exposure, frequent fatty fish intake significantly decreased the risk of multiple sclerosis (adjusted OR 0.6 (95 CI 0.5-0.9), whereas among subjects who reported high UVR exposure, this was not seen (adjusted OR 1.1 95% CI 0.8-1.4).
Interpretation: Fatty fish intake seems to decrease multiple sclerosis risk among people with low UVR light exposure. A hypothetical explanation is that intake of fatty fish, with relatively high vitamin D content, is a substitute for lack of vitamin D due to low UVR exposure. This gives further strength to the hypothesis of the importance of vitamin D for the development of multiple sclerosis.
Prognostic factors in clinically isolated syndromes: the role of vitamin D
V. Martinelli, G. Dalla Costa, B. Colombo, D. Dalla Libera, L. Leocani, R. Furlan, A. Rubinacci, M. Filippi, G. Comi (Milan, IT)
Objective: to evaluate the correlation between 25(OH)D levels in patients with Clinically Isolated Syndromes (CIS) and the development of Clinically Defined Multiple Sclerosis (CDMS).
Background: the risk of developing MS is related to both genetic and environmental factors. Vitamin D could play a role in CDMS conversion.
Design/Methods: this is a single-Centre retrospective study. 107 CIS patients hospitalized from 2000 to 2009 at San Raffaele Hospital were recruited. We evaluated baseline serum 25(OH)D levels as well as clinical, brain MRI, Multimodal Evoked Potential and CSF data. Results: 21% patients developed CDMS at 12-month follow-up, 36% at 2-year follow-up and 44% at 5 year follow-up. A statistically significant inverse correlation between 25(OH)D levels and the risk to develop CDMS (OR 2.19) was observed. The difference between serum 25(OH)D levels in patients who developed CDMS and patients who did not, is statistically higher during summertime (p< 0,05). Serum 25(OH)D levels better stratify the risk of CDMS in patients with low lesion number at brain MRI and in patients who did not fulfil MRI criteria for dissemination in space. Moreover, low 25(OH)D levels were associated with a shorter interval between CIS and occurrence of second clinical attack (p < 0,05) and with an increased annualized relapse rate, especially in summer (p < 0,02). The presence of CSF Oligoclonal Bands (p< 0,05 ), the clinical type of onset (multifocal vs monofocal p < 0.01), multimodal evoked potential abnormalities (p < 0.05) and the presence of periventricular lesions at baseline MRI (p < 0.01) have a predictive role on short-term risk of developing CDMS.
Conclusions: the presence of at least 3 negative clinical/paraclinical prognostic factors highly predicts short term conversion to CDMS (OR 5.39, p < 0,005). Serum 25(OH)D level has an independent prognostic value for CDMS in CIS patients.
Significant increase in prevalence of multiple sclerosis in Iran, review of literatures and report of new rates
S. Izadi, A. Nikseresht, M. Sharifian Dorche, A. Rezaianzadeh (Shiraz, IR)
Introduction: Multiple sclerosis (MS) is a demylinating disease of central nervous system which is significantly affected young adults especially females. In this study according to new reports of Iran Health Ministry we try to describe the new prevalence rate MS in Iran and each of its provinces separately.
Patients and Methods: This study was performed on the bases of the new reports of Iran Ministry of Health and Medical education about the patients who received beta interferon in Iran. We collected these data from MS registry data and then analyses were performed with the statistical package for social sciences (SPSS) version 17 under supervision of an expert epidemiologist.
Results: To the end of 2011, there were 19940 MS patients who received beta interferon in Iran. With consideration of Iran population in this year (70,495,782) prevalence rate is 28 per 100,000 populations. Maximum prevalence rate was seen in Isfahan province (64.37 per 100000) at the central parts of Iran and the minion prevalence rate is seen in sistan-balochestan province (4.82 per 100000) which is located in southwest of Iran with a warm and dry climate .
Discussion: Previously, Iran was considered to have a low prevalence rate of MS patients, but this rate is significantly increased over time. Many environmental and genetic factors are considered as the etiology of MS. The first explanation of this increasing rate in our country may be the age of population of Iran and some of our neighbors. Iran has a very young population. On the other hand ,Although it is believed that Persian population have enough sun exposure, but vitamin D deficiency is prevalent in our country may be related to life style changes in Iran, such as living of lots of population in apartments which cause a significant decrease in sun exposure among Iranian population. Additionally there are some ethical and cultural difference in Iran comparing to the other countries, for example especial cloths which is socially accepted for Muslim women reduced sun exposure in the significantly. Female to male ratio in Iran is significantly higher than the reports from western countries; this cultural difference may be an explanation of this fact too.
Seasonal variation of relapse rate and ultraviolet radiation levels are sinusoidal and their phase-shifted relationship is latitude-dependent
T. Spelman, O. Gray, M. Trojano, A. Lugaresi, G. Izquierdo, C. Zwanikken, P. Duquette, F. Grand'Maison, V. Shaygannejad, P. Grammond, C. Oreja-Guevara, R. Hupperts, C. Boz, G. Giuliani, T. Petersen, R. Bergamaschi, G. Iuliano, E. van Munster, J. Lechner-Scott, R. Alroughani, M. Barnett, H. Butzkueven on behalf of the MSBase Investigators
Introduction: Multiple Sclerosis relapse rate (RR) and ultraviolet radiation (UVR) levels are known to exhibit sinusoidal seasonal variation, with lowest levels of UVR ( UVR trough) in mid-winter preceding peak relapse probability in early spring. The relationship between UVR and RR variation has not previously been characterised at different latitudes.
Objective: The aim of this study was to characterise the temporal variation of relapse probability at MSBase centres in different latitudes and their reported UVR variation, in order to investigate whether latitude influenced the lag between UVR trough and relapse peak at each location.
Methods: The MSBase study is a global longitudinal, observational registry for Multiple Sclerosis. At time of extraction, the registry contained 18,885 patients from 55 centres in 25 countries adhering to a unified observational plan. A total of 52,617 relapses were analysed. Monthly UVR data for the period 1979-2004 was sourced for all locations. Cyclical models of monthly relapses and monthly UVR were derived using sinusoidal regression. These models permitted derivation of location-specific estimates of the timing and magnitude of both UVR troughs and subsequent relapse peaks. Weighted quantile regression was used to investigate associations between location latitude and this UV trough-to-relapse peak lag.
Results: We confirmed that sinusoidal models were the models of best fit for both seasonal UVR variation and relapse onset variation. The lag between UVR trough and relapse onset peak varied with centre latitude. Increased latitude away from the equator was associated with a statistically significant decrease in the number of months that lapsed between UV trough and relapse peak. Every 10 degree increase of latitude was significantly associated with a median decrease in UV trough to relapse peak lag of 1.62 months (95% CI 0.06-3.18), weighting for the number of patients per location. There was no difference in this association by hemisphere.
Conclusion: The relationship between seasonal UVR variation and relapse onset variation can be modelled as phase-shifted sinusoidal curves. The phase shift (lag) varies significantly with latitude, with shorter lag times in colder climates. As absolute levels of UVR are significantly lower with increasing latitude, this observation is consistent with a causal relationship between low UVR exposure and high relapse probability, possibly mediated by serum vitamin D level change.
Vitamin D deficiency as the enviromental risk factor for child multiple sclerosis
M. Bilska, K. Kotulska-Józwiak (Warsaw, PL)
Vitamin D insufficiency is proposed as a risk factor for many autoimmune diseases including multiple sclerosis. Recently vitamin D has received increased attention for molecular actions on immune system and possible preventive effect in MS, especially in children.
Methods: In 29 children with clinically definite multiple sclerosis and 35 controls at similar age, healthy or affected by nonimmune- mediated neurological diseases, serum 25-hydroxyvitamin D concentration was examined.
Findings: In 25 (86%) MS patients serum 25- hydroxyvitamin D (under 20 ng/ml) level was decreased. Only 4 (14%)MS children had proper vitamin D status . In control group 25 (69%)children presented with vitamin D low level, 10 (31%) had sufficient vitamin supply. Moreover, severe deficiency of vitamin D, defined as serum 25(OH)D concentration lower than 10 ng/ml was more common in MS children then in controls.
Interpretation: Poland is a country of very high risk of MS development with morbidity rate about 39- 60 persons per 100,000 in general population. Low serum concentration of 25- hydroxyvitamin D, which is believed to be the vitamin supply marker, is common in Polish children. However, in MS patients vitamin D deficiency is more frequent and more severe than in healthy controls.
This study is an initial part of our project focused on 25(OH)D serum status and molecular investigation of vitamin D receptors types in Polish children with MS.
The association between sunlight hours and month of birth in multiple sclerosis patients across UK regions
L.A.E. Matthews, M. Oppenheimer, A. Cavey, N. Evangelou, C. Constantinescu, N. Robertson, J. Zajicek, R. Nicholas, M. Boggild, G. Giovannoni, O. Gray, S. Hawkins, P. Rothwell, J. Palace (Oxford, UK)
Introduction: A spring peak and autumn nadir in the births of people who develop MS has previously been reported with a postulated link to maternal vitamin D levels. Our objective was to investigate the date of birth associations in a large UK-wide MS cohort with regional and annual sunlight data.
Methods: The dataset comprised the dates of birth of 18176 people with MS, from regionally defined cohorts scattered across the UK; Cardiff, Nottingham, London (Imperial College and Barts and The London hospitals), Liverpool, Belfast and Plymouth, as well as the national Risk Sharing Scheme cohort covering 72 UK centres including Scotland. UK Office of National Statistics data was used to adjust for the expected birth rate of the general population.
Historical climate data from the UK Met Office documenting the average sunlight hours per region of the country was used to divide the UK into two areas: one of relatively high annual sunlight exposure (>1400 hours) and one of relatively low (<=1400 hours).
Years with high and low variability in sunlight exposure were also indentified using a ratio of summer: winter sunlight hours.
Results: For the whole cohort there was a spring peak and autumn nadir in the number of MS births when compared with the general population, with an observed/ expected ratio of 1.12 in April and 0.85 in November, corrected p<0.01 (Chi-square).There was greater variability in the frequency of MS births in the South and East (SE) region of the UK (with higher sunlight exposure; n=10433) with a coefficient of variation (CoV) of 9.5% compared with the region of low annual sunlight in the North and West (n=6433) with CoV of 6.1%. There were 6.2% more MS births in May in the SE and 15.7% less in November, p<0.05.
Within this SE region the years in the upper quartile of summer: winter sunlight hours (n=1133) had a trend towards a higher variability in the month of MS birth with a CoV of 15.2%, compared with the lower quartile (n=1677) that had a CoV of 10.1%, p=0.12.
Conclusion: The spring peak and autumn nadir in the frequency of MS births is confirmed in a large UK cohort. This pattern is greater in the SE of the UK that receives higher summer sunlight, and in years with a higher summer/ winter sunlight variability that equated to years with good summers.
These results support previous suggestions that greater maternal sunlight exposure may be a protective factor against the risk of developing MS.
Serum 25-hydroxyvitamin D concentrations among patients in BENEFIT predicts conversion to multiple sclerosis, MRI lesions, and brain volume loss
A. Ascherio, K. Munger, C. Simon, L. Kappos, C.H. Polman, M.S. Freedman, H.-P. Hartung, D.H. Miller, X. Montalbán, G. Edan, F. Barkhof, R. White, R. Sandbrink, C. Pohl (Cambridge, US; Basel, CH; Amsterdam, NL; Ottawa, CA; Düsseldorf, DE; London, UK; Barcelona, ES; Rennes, FR; Vancouver, CA; Berlin, DE)
Preliminary evidence suggests that vitamin D insufficiency in clinically isolated syndromes (CIS) is a risk factor for conversion to multiple sclerosis (MS) and may adversely affect MS progression. We examined these hypotheses in BENEFIT, a trial of interferon beta-1b (IFNB-1b) in patients with CIS. The study comprised a placebo-controlled phase of up to 2 years or earlier diagnosis of MS and a follow-up study of up to 5 years where all patients were offered IFNB-1b.
A total of 333 patients with 25-hydroxyvitamin D (25[OH]D) measurements at 6 and 12 months after randomization were analyzed. Multivariate regression models were used to estimate the relation between 25(OH)D levels and 1) time to conversion to clinically definite MS (CDMS) or McDonald MS (MDMS); 2) sustained increase in disability (EDSS); and 3) MRI outcomes (cumulative number of active lesions [CNAL] and rates of percent change in T2 lesion volume [VCT2] and brain volume [PCBV]. Deseasonalized 25(OH)D level was treated as a time-dependent variable, using the average of 6- and 12-month levels for clinical and MRI outcomes after 12 months. Results are adjusted for initial treatment (IFNB-1b or placebo), age, gender, number of T2 lesions at baseline, and monofocal vs multifocal onset.
CIS patients with higher 25(OH)D levels were less likely to convert to MS (hazard ratio [HR] corresponding to a 50 nmol/L increase in 25(OH)D 0.40 [95% confidence interval (CI), 0.20-0.77; p=.005] for CDMS and 0.30 [CI, 0.16-0.56; p<=.001] for MDMS). In analyses by quintiles, HR in the highest quintile (average 25(OH)D > 58 nmol/L) was 42% lower than in the lowest quintile (average 25(OH)D < 33 nmol/L) for conversion to CDMS, and 60% lower for conversion to MDMS. These associations were similar across treatment arms, suggesting an additive effect of 25(OH)D and IFNB-1b (HR for conversion to MDMS for IFNB-1b and a 50 nmol/L increase in 25(OH)D was 0.2). 25(OH)D levels were also associated with lower CNAL (HR 0.46; CI, 0.28-0.76), and slower increase in VCT2 (p=.007) and PCBV (p=.03), but not with sustained changes in EDSS. Similar associations for all end points were observed in men and women.
These results provide evidence that low serum 25(OH)D levels are an important risk factor for conversion from CIS to MS and for long-term progression. They suggest that vitamin D supplementation in combination with IFNB-1b may improve outcomes in CIS, which needs to be prospectively tested in controlled studies.
Month of birth does not seem to interfere with the prevalence or disease progression in multiple sclerosis for South American patients, irrespectively of the latitude
Y. Fragoso, T. Adoni, F. Barbagelata-Aguero, S. Almeida, S. Alves-Leon, W. Arruda, J. Brooks, A. Carra, R. Claudino, E. Comini-Frota, E. Correa, A. Damasceno, B. Damasceno, E. Dias, D. Vizcarra-Escobar, A. Fiore, C. Franco, M. Giacomo, S. Gomes, M. Goncalves, A. Grzesiuk, J. Inojosa, D. Kaimen-Maciel, K. Lin, G. Lourenco, A. Martinez, M. Melcon, N. Morales, R. Morales, M. Moreira, S. Moreira, C. Oliveira, F. Oliveira, J. Ribeiro, S. Ribeiro, C. Rodriguez, L. Russo, J. Safanelli, K. Shearer, F. Siquineli (Santos, São Paulo, BR; Lima, PE; Rio de Janeiro, Curitiba, BR; Buenos Aires, AR; Florianópolis, Belo Horizonte, Brasilia, Campinas, BR; Santiago, CL; Recife, Sao Bernardo do Campo, Joinville, Cuiaba, Londrina, BR; Uberlandia, Juiz de Fora, Uberaba, BR; Aberdeen, UK; Blumenau, BR)
Several studies have shown a relationship between an individual’s month of birth and development of multiple sclerosis (MS) later in life. This relationship, which might be due to the mother’s sun exposure and vitamin D metabolism, is clear in some countries at high Northern latitudes. So far, no similar studies have been carried out at Southern latitudes ranging from zero to 40 degrees. The objective of the present study was to assess the prevalence of MS in relation to patients’ month of birth, in order to observe any correlation with the latitude. Furthermore, disease progression was also considered in order to assess whether the place of birth had any relation with disease severity.
Methods: Data were collected from four South American countries (Argentina, Brazil, Chile and Peru) over a three-month period. A specific Excel file containing all pertinent details of the patient’s medical history was filled out by the neurologist in charge of that particular case. The control cases were males and females of similar ages, born at the same latitude levels. Two-way and one-way ANOVA, linear regression analysis, Pearson’s correlation and Student’s t-test were used to analyze the results.
Results: Analysis on data from 1,207 MS patients and 1,207 control subjects did not show any significant variation in MS prevalence in relation to month of birth, in any of the four latitude zones evaluated (zero to 10; 11 to 20; 21 to 30; and 31 to 40 degrees). As it would be expected, a definite correlation exists between EDSS score and length of the disease at all latitudes, as assessed by Pearson’s correlation testing. However, no significant differences exist between month of birth and disease progression using one-way ANOVA.
Conclusion: The results from this study show that children born from pregnancies at higher latitudes in South America do not show higher incidence of MS later in life, as is the case with the seasonal pattern observed in the Northern hemisphere. Therefore, it cannot be affirmed that there is a clear relationship between lower sun exposure in winter pregnancies and the development of MS later in the offspring’s life in South America. Several other factors, including genetic profiles and infections, may play a more important role in the development and severity of MS in the countries assessed.
Immune system modulation by UV radiation in multiple sclerosis: effects of urocanic acid
J. Correale, M. Farez (Buenos Aires, AR)
Background and goals: One of the most striking features of multiple sclerosis (MS) epidemiology has been its striking geographic prevalence distribution. Ultraviolet (UV) radiation, which correlates closely with latitude, has been the most favored explanation for this phenomenon. Urocanic acid (UCA) absorbs UV radiation in the skin. A trans-isomer formed from histidine in the upper epidermis, it is converted to a systemically-distributed cis-isomer on exposure to sunlight, conferring immunosuppression. The goal of this study was to study the role of cis-UCA in MS pathogenesis.
Methods: Ninety-two patients with relapsing remitting MS were examined, 58 patients in remission and 32 during exacerbations. Forty age and gender-matched healthy subjects served as controls. Trans and cis-UCA plasma levels were measured by HPLC. MBP- and MOG- peptide-specific T cell lines were stimulated with cognate Ags in presence and in the absence of cis-UCA, after which IL-4, IL-10, IL-6, IL-8, IL-17, TGF-b, TNF-a, IFN-g, ERK 1/2, and JNK1/2 were measured using ELISA. CD4+CD25+FoxP3+ regulatory T cells were assessed by flow cytometry.
Results: Plasma levels of cis-UCA were lower in MS patients compared to controls (p= 0.0001). No differences in plasma trans-UCA levels were found, nor was there any association between disease activity and cis-UCA plasma levels.Stimulation of MBP- and MOG-specific T cells with specific Ags in the presence of cis-UCA, significantly increased IL-10, and inhibited IFN-g production. No effect was observed on secretion of other cytokines investigated. PBMCs cultured in the presence of cis-UCA increased CD4+CD25+FoxP3+ regulatory T cell percentages. Finally, dendritic cells (DCs) cultured in the presence of cis-UCA reduced Ags presentation capacity.
Tests using serotonin receptor agonists and antagonists with specificity for various 5HT receptor subtypes revealed cis-UCA activated the 5-HT2a receptor to suppress autoimmune responses. Finally, increase in phosphorylated forms of ERK 1/2 and JNK2 was observed in response to cis-UCA treatment in T cells, an effect abrogated by specific inhibitors such as SP6000125, and PD98059, suggesting strong activation of these pathways.
Conclusions: In addition to Vitamin D, cis-UCA is another UV-mediated immunomodulator binding to the 5HT2a receptor. Immunosuppressive effects are mediated, by ERK1/2 and JNK2. Cis-UCA effects may help explain increased prevalence of MS observed at higher latitudes.
Epstein-Barr virus and vitamin D as risk factors for multiple sclerosis
J. Salzer, M. Nyström, G. Hallmans, H. Stenlund, G. Wadell, P. Sundström (Umeå, SE)
Objective: To examine the association between the antibody reactivity towards Epstein-Barr Nuclear Antigen-1 (EBNA-1) as well as five different EBNA-1 domains and the risk for multiple sclerosis (MS), and to examine whether 25-Hydroxyvitamin D (25[OH]D) status interact with, or confound these associations in prospectively collected blood samples.
Methods: In this nested case-control study two population-based biobanks with 291,500 samples from 164,000 persons collected since 1975 in the northern half of Sweden were used to identify prospectively collected blood samples from MS cases (n=192, controls matched 2:1). Antibody reactivity towards EBNA-1 and specific EBNA-1 domains and 25(OH)D levels were measured using ELISAs, and the risk for MS was analyzed using matched logistic regression.
Results: A higher risk for MS was observed across antibody reactivity tertiles to EBNA-1 and the EBNA-1(402–502) and (385–420) fragments (p trend < 0.001). In young individuals (below median age at sampling, <26.4 years) the association between antibody reactivity tertiles towards EBNA-1 and the EBNA-1 fragments and MS risk was more pronounced. No signs of confounding or interaction were found, although a negative correlation in young individuals between 25(OH)D and antibodies to EBNA-1, as well as to the two fragments showing the strongest association to MS risk, was observed.
Interpretation: We confirm that antibodies towards EBNA-1, and specifically the EBNA-1(385–420) fragment constitute robust risk markers for MS. The finding of a negative correlation between 25(OH)D and antibody reactivity to EBNA-1 in young suggest that 25(OH)D status might influence the immune response towards EBV, and thereby modulate MS risk.
Evaluation of vitamin D-related parameters in a multinational paediatric multiple sclerosis case-control study
H.E. Hanwell, B. Bhan, M.R. Bardini, A. Belman, A. Boiko, O. Bykova, M.-E. Dilenge, K. Farrell, M. Freedman, J. Hahn, M. Iivanainen, J. Kennedy, M. Kremenchutzky, L. Krupp, J.K. Mah, J. Ness, M. Rensel, M. Ruggieri, M. Sevon, C. Stoian, E. Waubant, B. Weinstock-Guttman, S. Tenembaum, E.A. Yeh, R. Vieth, R.A. Marrie, A. Bar-Or, B. Banwell on behalf of the Wadsworth Pediatric Multiple Sclerosis Study Group
Context: Vitamin D is a putative environmental determinant of MS and modulator of MS disease activity. Vitamin D insufficiency is common in adults with MS but there are few data pertaining to vitamin D status and metabolism in paediatric MS. Whether sources of vitamin D or vitamin D metabolism differ in paediatric MS from other children are also unknown.
Objective: To compare vitamin D status (total serum 25-hydroxyvitamin D concentration, [25(OH)D total]), prevalence of vitamin D insufficiency (25(OH)D total <75 nmol/L), vitamin D catabolism (ratio of 24,25(OH)D3 to 25(OH)D total), and exposure to non-solar vitamin D (25(OH)D2 concentration) between children and adolescents with MS and controls from multiple countries.
Methods: Children and adolescents (<20y) were enrolled from Argentina, Canada, Finland, Italy, Russia, and the United States between 2003 and 2005. Serum vitamin D metabolite concentrations (25(OH)D2, 25(OH)D3, and 24,25(OH)2D) were determined via LC-MS/MS with a 2 nmol/L limit of detection. Differences between participants with MS and controls were evaluated using Mann Whitney U and Fisher's Exact Test with a two-sided alpha of 0.05.
Results: Serum was available from 121 children with MS (all countries) and 119 control participants (Argentina, Canada, and US). Those with MS were significantly older than controls (median (interquartile range, IQR) 15.3y (11.9-17.1) vs. 13.5y (9.1-16.4), P=0.007) but were not significantly different in terms of percent females (59% vs. 54%). Overall, 72.1% of participants were vitamin D insufficient. Children with MS did not differ from control participants in terms of seasonally-adjusted vitamin D status (25(OH)D median (IQR), 58.9 (38.4-77.5) nmol/L vs. 57.2 (41.0-77.3) nmol/L), prevalence of vitamin D insufficiency (72% vs. 72%), nor the ratio of 24,25(OH)2D3:25(OH)D total (median (IQR) 0.32 (0.25-0.36) vs. 0.33 (0.29-0.38)). Children with MS were more likely to have detectable 25(OH)D2 levels than control participants (19.0% vs. 3.4%, P<0.001).
Conclusion: There is a high prevalence of vitamin D insufficiency in this multinational cohort of children, irrespective of MS diagnosis. Indicators of vitamin D status and catabolism did not differ between children with MS and controls. Few foods contain vitamin D2; thus, the higher frequency of 25(OH)D2 positivity among participants with MS may indicate more frequent intake of vitamin D2-containing supplements among paediatric MS patients.
The role of vitamin D status in optic neuritis
J.M. Burton, J. Trufyn, C. Tung, M. Eliasziw, F. Costello (Calgary, CA; Boston, US)
Background: Optic neuritis (ON) is a common manifestation of demyelinating disease and a cause of vision loss. The optic nerve provides a model of the nervous system, allowing assessment of both inflammatory and degenerative activity and posited therapies for such using optical coherence tomography (OCT) to measure retinal nerve fiber layer (RFNL) thickness. Vitamin D insufficiency is a risk factor in MS development, and sufficiency ameliorates inflammatory activity with some in-vitro evidence of neuroprotection. Assessment of vitamin D status on ON parameters may provide evidence for neuroprotection and a potential role for vitamin D therapy in demyelinating disease.
Objectives: To study the relationship between vitamin D status and ON recovery by RNFL measures at 6 months using OCT. The hypothesis is that vitamin D sufficiency will be associated with better RNFL outcomes and axonal preservation. Primary outcomes include differences in affected eye RFNL and inter-eye difference at 6 months between vitamin D sufficient and insufficient groups. We will also examine the relationship between vitamin D and ON features at onset.
Methods: In this prospective pilot cohort study, patients with acute ON undergo OCT to assess mean and temporal quadrant RFNL thickness, macular volume (MV) and vitamin D (serum 25(OH)D) status testing at baseline, months 3 and 6. Vitamin D insufficiency is defined as 25(OH)D < 80 nmol/L.
Results: Thirty patients have been enrolled (23 women, 7 men), 17 having completed the study. Vitamin D insufficiency was seen in 67% of patients, and was associated with greater baseline edema with mean RFNL (141 vs 97 µm, p=0.050) and MV (10.27 vs 9.71 mm3, p=0.008). At month 6, edema was subtly present, but inter-eye difference (RFNL unaffected eye minus RFNL ON eye) was significantly greater in vitamin D insufficient patients (16 vs 2 µm, p=0.042).
Conclusions: Interim results suggest that vitamin D insufficiency at ON onset is associated with greater baseline RFNL and macular edema in ON eyes. Edema appears to be present at month 3, possibly at month 6. Despite this, at month 6, ON eye RFNL thickness in vitamin D insufficient patients, as evaluated by inter-eye difference, drops below the RFNL value of the unaffected eye. No significant difference between unaffected and ON eyes in vitamin D sufficient patients at baseline or month 6 occurs, suggesting the magnitude of RFNL thinning in vitamin D insufficiency is greater.
Vitamin A not associated with exacerbations in multiple sclerosis
T.F. Runia, W.C.J. Hop, Y.B. De Rijke, D. Buljevac, R.Q. Hintzen (Rotterdam, NL)
Background: Th17 cells are a subset of CD4+ T cells that produce IL-17. They are effector cells implicated in many autoimmune disorders including multiple sclerosis (MS). Although the exact role for Th17 cells in the pathogenesis of MS remains to be fully elucidated, they are probably involved in the development of relapses in MS.
Vitamin A is a multifunctional vitamin, that has been shown to inhibit Th17 formation in vitro, synergistic with 1,25-diOH-vitamin D. By inhibiting Th17 formation, vitamin A can be hypothesized to be 1) lower in patients than in healthy controls, and 2) associated with relapse risk in patients. We therefore performed two studies: a case-control study of vitamin A levels, and a longitudinal study of vitamin A levels in relapsing-remitting MS (RRMS) patients to investigate the association between vitamin A and relapse risk. We also investigated the association between vitamin A and D.
Methods : All-trans retinol levels were measured in 31 RRMS patients and 29 age and sex matched controls. T test was used to compare serum all-trans retinol concentrations of patients and controls.
Furthermore, a prospective longitudinal study in 73 RR MS patients was performed, in which blood samples for vitamin A measurements were taken every eight weeks. Associations between all-trans retinol concentrations and relapse rates were calculated using Poisson regression with the individual serum levels as time-dependent variable. Associations between vitamin A and vitamin D were calculated using linear regression.
Results: Mean vitamin A levels were a little lower in patients (2.16 µmol/l) than in controls (2.44µmol/l), but this difference was only borderline significant (p=0.05).
In the longitudinal study, during follow-up (mean 1.7 years), 58 patients experienced a total of 139 relapses. Monthly moving averages of all-trans retinol levels were categorized into tertiles: a low (<2.9 µmol/l), medium (2.9-3.7 µ;mol/l) and high level (>3.7 µmol/l). Relapse rates were not associated with serum all-trans retinol levels (p>0.2), in univariate nor in multivariate analysis.
Serum concentrations of all-trans retinol and 25-OH-vitamin D were correlated in a linear manner (R=0.23, p<0.001).
Conclusion: Vitamin A is slightly lower in patients than in controls but is not associated with relapse risk in RRMS patients. We found an association between vitamin A and D levels in the RRMS patients, probably explained by dietary products that contain both fat-soluble vitamins.
Paediatric multiple sclerosis and vitamin D status
N. Ben Achour, I. Kraoua, H. Touaiti, H. Benrhouma, A. Rouissi, I. Turki, N. Gouider- Khouja (Tunis, TN)
Background: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). The mechanisms underlying MS pathobiology remain incompletely understood. However, environmental risk factors are likely operative in this disorder. The increasing recognition of MS in children and adolescents has prompted study of vitamin D status.
Objective: To report the epidemiological, clinical data and vitamin D status in a Tunisian paediatric series of MS.
Methods: Over 7 years (2005-2012), 8 children (6 females, 2 males; mean age: 16 years) were followed in our department for MS. Serum 25-hydroxyvitamin D3 (25(OH)D) levels were measured in all patient. Vitamine D deficiency is defined as 25(OH)D levels less than 10 ng/ ml and vitamine D insufficiency is defined as 25(OH)D levels between 10 and 20 ng/ ml. Epidemiological, clinical data and vitamin D status are discussed.
Results: Five were born in spring and early summer (i.e pregnancy occured in autumn and winter). Three patients had associated type 1 diabetes that preceded the first demyelinating event in all of them. Median age at the initial episode was 13.5 years (range: 5- 17 years). Optic neuritis and pyramidal dysfunction were the most common clinical features. The (25(OH)D) levels were less than 20 ng/ ml in 6 patients (normal range: 25 to 60 ng/ml). We found vitamine D deficiency in 5 patients and vitamin D insufficiency in 1 patient.
Discussion and conclusion: Our results support the hypothesis that abnormal vitamine D status and limited sunlight in childhood are potential risk factors for MS. A lack of vitamin D in utero may explain correlation of MS to birth season (more people with MS being born in the spring). Association with type 1 diabetes in three of our patients support the concept of susceptibility to autoimmune disorders in vitamin D deficiency which require collaborative efforts to develop novel strategies for primary disease prevention.
Mark Walker - Oxfordshire, England. Retired Pharmacist. 12 years of study around MS.
Mark's CCSVI Comment: