Season of birth is associated with multiple sclerosis and disease severity.

BACKGROUND: The latitude gradient in multiple sclerosis incidence indicates that low sun exposure and therefore vitamin D deficiency is associated with multiple sclerosis risk. OBJECTIVE: Investigation of the effect of month of birth, which influences postnatal vitamin D levels, on multiple sclerosis risk and severity in Sweden. METHODS: Patients and population-based controls were included from three nationwide cohorts. Differences in month of birth between cases and controls were analyzed using logistic regression and examined for effect modification by calendar year and geographic region at birth. RESULTS: Males had a reduced risk of multiple sclerosis if born in the winter and increased risk if born in the early fall. Individuals born before 1960 had an increased risk if born in summer or fall. Being born in late summer and early fall was associated with more severe disease. CONCLUSIONS: We identified a birth cohort effect on the association between the month of birth and multiple sclerosis, with a more significant effects for births before 1960. This coincides with a period of lower breastfeeding rates, recommended intake of vitamin D, and sun exposure, resulting in a lower vitamin D exposure during the fall/winter season for infants born in the summer.

Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis.

BACKGROUND AND PURPOSE: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. METHODS: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). CONCLUSIONS: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

Cotinine as a measure of smoking in observational studies of multiple sclerosis.

Studies using cotinine levels to define smokers have generally failed to detect an association between smoking and multiple sclerosis (MS). Using a Swedish population-based case-control study, we show that associations in relation to MS risk and progression differ considerably depending on how smoking is measured. The risk of conversion into secondary progressive disease was increased among smokers when self-reported smoking history, but not presumed cotinine levels, was used to define smokers. Defining smoking by cotinine levels without distinguishing between different sources of nicotine may lead to severely biased estimates of the association between smoking and both MS risk and progression.

Stressful life events are associated with the risk of multiple sclerosis.

BACKGROUND AND PURPOSE: Unexpected stressful life events may alter immune function and affect susceptibility to autoimmune diseases including multiple sclerosis (MS). Current results from epidemiological investigations examining the role of stress in MS remain inconsistent. The aim was to conduct the hitherto largest population-based case-control study on this topic. METHODS: Extensive questionnaire information collected on lifestyle environmental factors available for 2930 incident MS cases and 6170 controls were used to assess the association of 10 major life events that had occurred before disease onset with the risk of MS by unconditional logistic regressions, adjusting for potential confounders. Stratified analyses were also performed by sex and time. RESULTS: Compelling evidence was found for a link between major life events and risk of MS - most events significantly increased disease risk by 17%-30%. It was further observed that women were affected to a greater extent than men under certain stressful scenarios, and that most events that happened recently (≤5 years prior to MS onset) had significant effects on MS, indicating a critical window in disease development. CONCLUSION: Stressful life events may have an adverse effect on the risk of MS. Research into the mechanisms of this observation may give important clues to triggering pathogenetic events in MS.

Breastfeeding is associated with reduced risk of multiple sclerosis in males, predominantly among HLA-DRB1*15:01 carriers.

BACKGROUND: Breastfeeding as an infant appears protective against later development of some autoimmune diseases, but research into its influence on multiple sclerosis (MS) risk has yielded inconclusive results. OBJECTIVE: We investigated the possible impact of breastfeeding on MS risk. METHODS: We used two population-based case-control studies comprising 3670 cases and 6737 matched controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between MS and exposure to prolonged breastfeeding (4 months or longer) versus reduced breastfeeding (less than 4 months). A meta-analysis of case-control studies that assessed the impact of breastfeeding on MS risk among women and men was conducted. RESULTS: Prolonged breastfeeding was associated with reduced MS risk among men (OR 0.7, 95% CI 0.5-0.9) but not among women (OR 0.9, 95% CI 0.8-1.1). Among men, a synergistic effect was observed between HLA-DRB1*15:01 carrier status and reduced breastfeeding. CONCLUSIONS: Findings from the current study add to accumulating evidence that breastfeeding may be a modifiable protective factor for reducing the risk of MS in offspring. When possible, mothers should be supported to breastfeed their infants; however, the mechanism of a sex-specific biologic effect of breastfeeding on MS risk is unclear.

Pathogenesis of type 2 diabetes risk in black Africans: a South African perspective.

The prevalence of type 2 diabetes (T2D) is higher in black Africans than their European counterparts. This review summarizes the research exploring the pathogenesis of T2D in populations of African ancestry compared to white Europeans and shows that the pathogenesis differs by ethnicity. Black Africans present with a phenotype of low insulin sensitivity and hyperinsulinaemia as a result of increased insulin secretion and reduced hepatic insulin clearance. Whether hyperinsulinaemia precedes insulin resistance or is merely a compensatory mechanism is yet to be determined. Black Africans have lower visceral adipose tissue and ectopic fat deposition and greater peripheral (gluteo-femoral) fat deposition than their European counterparts. This suggests that black Africans are more sensitive to the effects of ectopic fat deposition, or alternatively, that ectopic fat is not an important mediator of T2D in black Africans. Importantly, ethnic disparities in T2D risk factors may be confounded by differences in sociocultural and lifestyle factors. Future longitudinal and dietary intervention studies, in combination with genetic analyses, are needed for a better understanding of the pathophysiology of T2D in black Africans. This will be key for effective prevention and management strategies.

Longitudinal relationships among depressive symptoms, cortisol, and brain atrophy in the neocortex and the hippocampus.

OBJECTIVE: Depression is associated with accelerated aging and age-related diseases. However, mechanisms underlying this relationship remain unclear. The aim of this study was to longitudinally assess the link between depressive symptoms, brain atrophy, and cortisol levels. METHOD: Participants from the Betula prospective cohort study (mean age = 59 years, SD = 13.4 years) underwent clinical, neuropsychological and brain 3T MRI assessments at baseline and a 4-year follow-up. Cortisol levels were measured at baseline in four saliva samples. Cortical and hippocampal atrophy rates were estimated and compared between participants with and without depressive symptoms (n = 81) and correlated with cortisol levels (n = 49). RESULTS: Atrophy in the left superior frontal gyrus and right lingual gyrus developed in parallel with depressive symptoms, and in the left temporal pole, superior temporal cortex, and supramarginal cortex after the onset of depressive symptom. Depression-related atrophy was significantly associated with elevated cortisol levels. Elevated cortisol levels were also associated with widespread prefrontal, parietal, lateral, and medial temporal atrophy. CONCLUSION: Depressive symptoms and elevated cortisol levels are associated with atrophy of the prefrontal and limbic areas of the brain.

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. METHODS: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

A Paleolithic-type diet results in iodine deficiency: a 2-year randomized trial in postmenopausal obese women.

BACKGROUND/OBJECTIVES: Different diets are used for weight loss. A Paleolithic-type diet (PD) has beneficial metabolic effects, but two of the largest iodine sources, table salt and dairy products, are excluded. The objectives of this study were to compare 24-h urinary iodine concentration (24-UIC) in subjects on PD with 24-UIC in subjects on a diet according to the Nordic Nutrition Recommendations (NNR) and to study if PD results in a higher risk of developing iodine deficiency (ID), than NNR diet. SUBJECTS/METHODS: A 2-year prospective randomized trial in a tertiary referral center where healthy postmenopausal overweight or obese women were randomized to either PD (n=35) or NNR diet (n=35). Dietary iodine intake, 24-UIC, 24-h urinary iodine excretion (24-UIE), free thyroxin (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) were measured at baseline, 6 and 24 months. Completeness of urine sampling was monitored by para-aminobenzoic acid and salt intake by urinary sodium. RESULTS: At baseline, median 24-UIC (71.0 µg/l) and 24-UIE (134.0 µg/d) were similar in the PD and NNR groups. After 6 months, 24-UIC had decreased to 36.0 µg/l (P=0.001) and 24-UIE to 77.0 µg/d (P=0.001) in the PD group; in the NNR group, levels were unaltered. FT4, TSH and FT3 were similar in both groups, except for FT3 at 6 months being lower in PD than in NNR group. CONCLUSIONS: A PD results in a higher risk of developing ID, than a diet according to the NNR. Therefore, we suggest iodine supplementation should be considered when on a PD.

The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction.

The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.

VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis.

Rheumatoid arthritis (RA) patients can be stratified into two subgroups defined by the presence or absence of antibodies against citrullinated circular peptides (anti-CCP) with most of the genetic association found in anti-CCP positive RA. Here we addressed the role of VAV1, previously associated to multiple sclerosis (MS), in the pathogenesis of RA in experimental models and in a genetic association study. Experimental arthritis triggered by pristane or collagen type II was induced in DA rats and in the DA.BN-R25 congenic line that carries a polymorphism in Vav1. Difference in arthritis severity was observed only after immunization with pristane. In a case-control study, 34 SNPs from VAV1 locus were analyzed by Immunochip genotyping in 11475 RA patients (7573 anti-CCP positive and 3902 negative) and 15,870 controls in six cohorts of European Caucasians. A combination of the previous MS-associated haplotype and two additional SNPs was associated with anti-CCP negative RA (alleles G-G-A-A of rs682626-rs2546133-rs2617822-rs12979659, OR=1.13, P=1.27 × 10-5). The same markers also contributed to activity of RA at baseline with the strongest association in the anti-CCP negative group for the rs682626-rs12979659 G-A haplotype (ß=-0.283, P=0.0048). Our study suggests a role for VAV1 and T-cell signaling in the pathology of anti-CCP-negative RA.

High consumption of coffee is associated with decreased multiple sclerosis risk; results from two independent studies.

OBJECTIVE: Previous studies on consumption of caffeine and risk of multiple sclerosis (MS) have yielded inconclusive results. We aimed to investigate whether consumption of coffee is associated with risk of MS. METHODS: Using two population-representative case-control studies (a Swedish study comprising 1620 cases and 2788 controls, and a US study comprising 1159 cases and 1172 controls), participants with different habits of coffee consumption based on retrospective data collection were compared regarding risk of MS, by calculating ORs with 95% CIs. Logistic regression models were adjusted for a broad range of potential confounding factors. RESULTS: Compared with those who reported no coffee consumption, the risk of MS was substantially reduced among those who reported a high consumption of coffee exceeding 900 mL daily (OR 0.70 (95% CI 0.49 to 0.99) in the Swedish study, and OR 0.69 (95% CI 0.50 to 0.96) in the US study). Lower odds of MS with increasing consumption of coffee were observed, regardless of whether coffee consumption at disease onset or 5 or 10 years prior to disease onset was considered. CONCLUSIONS: In accordance with studies in animal models of MS, high consumption of coffee may decrease the risk of developing MS. Caffeine, one component of coffee, has neuroprotective properties, and has been shown to suppress the production of proinflammatory cytokines, which may be mechanisms underlying the observed association. However, further investigations are needed to determine whether exposure to caffeine underlies the observed association and, if so, to evaluate its mechanisms of action.

Strong and persistent effect on liver fat with a Paleolithic diet during a two-year intervention.

BACKGROUND/OBJECTIVES: Our objective was to investigate changes in liver fat and insulin sensitivity during a 2-year diet intervention. An ad libitum Paleolithic diet (PD) was compared with a conventional low-fat diet (LFD). SUBJECTS/METHODS: Seventy healthy, obese, postmenopausal women were randomized to either a PD or a conventional LFD. Diet intakes were ad libitum. Liver fat was measured with proton magnetic resonance spectroscopy. Insulin sensitivity was evaluated with oral glucose tolerance tests and calculated as homeostasis model assessment-insulin resistance (HOMA-IR)/liver insulin resistance (Liver IR) index for hepatic insulin sensitivity and oral glucose insulin sensitivity (OGIS)/Matsuda for peripheral insulin sensitivity. All measurements were performed at 0, 6 and 24 months. Forty-one women completed the examinations for liver fat and were included. RESULTS: Liver fat decreased after 6 months by 64% (95% confidence interval: 54-74%) in the PD group and by 43% (27-59%) in the LFD group (P<0.01 for difference between groups). After 24 months, liver fat decreased 50% (25-75%) in the PD group and 49% (27-71%) in the LFD group. Weight reduction between baseline and 6 months was correlated to liver fat improvement in the LFD group (rs=0.66, P<0.01) but not in the PD group (rs=0.07, P=0.75). Hepatic insulin sensitivity improved during the first 6 months in the PD group (P<0.001 for Liver IR index and HOMA-IR), but deteriorated between 6 and 24 months without association with liver fat changes. CONCLUSIONS: A PD with ad libitum intake had a significant and persistent effect on liver fat and differed significantly from a conventional LFD at 6 months. This difference may be due to food quality, for example, a higher content of mono- and polyunsaturated fatty acids in the PD. Changes in liver fat did not associate with alterations in insulin sensitivity.

Smoking is a major preventable risk factor for multiple sclerosis.

BACKGROUND: Both smoking and exposure to passive smoking have repeatedly been associated with increased multiple sclerosis (MS) risk, but have never before been studied together. We assessed the public health impact of these factors. METHODS: In a Swedish population-based case-control study (2455 cases, 5336 controls), we calculated odds ratios of developing MS associated with different categories of tobacco smoke exposure, together with 95% confidence intervals, by using logistic regression. The excess proportion of cases attributable to smoking and passive smoking was calculated as a percentage. RESULTS: Both smoking and exposure to passive smoking contribute to MS risk in a dose-dependent manner. At the population level, 20.4% of all cases were attributable to smoke exposure. Among subjects carrying the genetic risk factor HLA-DRB1*15 but lacking HLA-A*02, 41% of the MS cases were attributable to smoking. CONCLUSIONS: From a public health perspective, the impact of smoking and passive smoking on MS risk is considerable. Preventive measures in order to reduce tobacco smoke exposure are, therefore, essential. In particular, individuals with a history of MS in the family should be informed regarding the impact of smoking on the risk of MS, and the importance of preventing their children from being exposed to passive smoke.

Body mass index during adolescence, rather than childhood, is critical in determining MS risk.

OBJECTIVE: Obesity in childhood and during adolescence has repeatedly been associated with increased risk of developing multiple sclerosis (MS). We aimed to investigate whether the most critical period occurs during childhood or later, during adolescence. METHODS: Using a population-based case-control study (1586 cases and 2800 controls), individuals with different body sizes at age 10 and different body mass indices at age 20 were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals. Potential interactions between HLA-DRB1*15 and absence of HLA-A*02, respectively, and both childhood and adolescent obesity were evaluated by calculating the attributable proportion due to interaction. RESULTS: Regardless of body size at age 10, individuals with adolescent obesity had a 90% increased risk of MS. Among participants who were not obese at age 20, no association was observed between body size at age 10 and subsequent MS risk. An interaction was observed between the HLA MS risk genes and adolescent, but not childhood, obesity. CONCLUSIONS: Our results suggest that BMI during adolescence, rather than childhood, is critical in determining MS risk.

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

BACKGROUND: Natalizumab (NTZ) and fingolimod (FGL) are mainly used second line in relapsing-remitting multiple sclerosis (MS), although pivotal trials included mainly treatment-naïve patients. OBJECTIVE: This study aims to provide real-world data on safety and discontinuation rates. METHODS: Using IMSE, a drug monitoring registry for all newer MS drugs in Sweden, we analysed differences in baseline characteristics and 1-year drug survival for patients registered 2011-2013, initiating treatment with NTZ (n=640) or FGL (n=876). Among FGL initiators, n=383 (44%) had previously used NTZ (FGL(afterNTZ)). RESULTS: Compared with NTZ, the FGL cohort was older and more often male (36/38 years, 24%/33% males). Baseline Expanded Disability Status Scale was similar across groups, but MS Severity Score was higher in NTZ patients, and Symbol Digit Modalities Test and MS Impact Scale (MSIS-29) was higher in FGL(afterNTZ) versus FGL(NTZ-naïve) patients. Proportion on drug after 1 year was high, NTZ=87%, FGL(NTZ-naïve)=83% and FGL(afterNTZ)=76%. Adverse events was the most frequent reason for discontinuing FGL (FGL(NTZ-naïve)=9%, FGL(afterNTZ)=12%), and was significantly higher than on NTZ (3%). In contrast, the proportion of patients stopping treatment due to lack of effect was more similar: NTZ=4%, FGL(NTZ-naïve)=3%, FGL(afterNTZ)=8%. CONCLUSION: FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics.