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Introduction: Bacillus Calmette-Guérin (BCG) vaccination induces long-lasting effects on the adaptive and innate immune systems and prevents development of experimental autoimmune encephalomyelitis and possibly also inflammatory disease activity in multiple sclerosis (MS)., Objective: The objective is to examine if BCG given in early adulthood decreases MS risk., Methods: From 791,369 (52% females) Norwegians participating in a national tuberculosis screening program from 1963 to 1975, we collected information on BCG vaccination and tuberculosis disease status. Later, MS disease was ascertained through both the Norwegian MS Registry and Biobank and the Norwegian Death Registry. We used logistic regression models to assess the relationship between BCG vaccination and MS risk., Results: In those BCG vaccinated, mean age at vaccination was 15.6 (standard deviation (SD) = 5.5) years. A total of 2862 (65% females) MS cases were retrieved. Overall, we found no association between MS risk and BCG vaccination. Compared to non-BCG-vaccinated individuals with no signs of tuberculosis infection, odds ratio (OR) for MS was 1.00 (95% confidence interval (CI) = 0.80-1.25) in the BCG-vaccinated group. In those not BCG vaccinated because of latent tuberculosis infection, the corresponding OR was 0.86 (95% CI = 0.66-1.13)., Conclusion: We found no evidence of BCG vaccination or latent tuberculosis infection in young adulthood being linked to MS risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD., Methods: Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED)., Results: We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without., Conclusion: GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: B cell depletion therapy is highly effective in relapsing-remitting multiple sclerosis (RRMS). However, the precise underlying mechanisms of action for its biological effects in MS have still not been clarified. Epstein-Barr virus (EBV) is a known risk factor for MS and seems to be a prerequisite for disease development. EBV resides latently in the memory B cells, and may not only increase the risk of developing MS, but also contribute to disease activity and disability progression. Therefore, the effects of B cell depletion in MS could be associated with the depletion of EBV-infected cells and the altered immune response to the virus. In this study, we investigate the impact of B cell depletion on the humoral immune response specific to EBV in patients with MS., Methods: Newly diagnosed, treatment-naïve patients with RRMS were followed up to 18 months after initiation of B-cell depletion therapy in the Overlord-MS study, a phase III trial (NCT04578639). We analyzed serum sampled before treatment and after 3, 6, 12 and 18 months for immunoglobulin γ (IgG) against Epstein-Barr nuclear antigen 1 (EBNA1) and Epstein-Barr viral capsid antigen (VCA). We analyzed antibodies to cytomegalovirus (CMV) and total IgG in serum, as controls for viral and overall humoral immunity. The risk allele, HLA-DRB1*15:01, and the protective allele, HLA-A*02:01, were determined in all participants. In addition, polymerase chain reaction (PCR) for circulating EBV-DNA was performed in the first 156 samples drawn. The associations between time on B cell-depletion therapy and serum anti-EBV antibody levels were estimated using linear mixed-effects models., Results: A total of 290 serum samples from 99 patients were available for analysis. After 6, 12 and 18 months, the EBNA1 IgG levels decreased by 12.7 % (95 % CI -18.8 to -6.60, p < 0.001), 12.1 % (95 % CI -19.8 to -3.7, p = 0.006) and 14.6 % (95 % CI to -25.3 to -2.4, p = 0.02) respectively, compared to baseline level. Carriers of the HLA-DRB1*15:01 allele had higher EBNA1 IgG levels at baseline (p = 0.02). The VCA IgG levels significantly increased by 13.7 % (95 % CI 9.4 to 18.1, p < 0.001) after 3 months, compared to baseline, and persisted at this level throughout the follow-up. CMV IgG levels decreased, but to a lesser extent than the decrease of EBNA1 IgG, and total IgG levels decreased during therapy. Circulating EBV-DNA was found in only three of 156 samples from 64 patients., Conclusions: EBNA1 IgG levels decreased, while VCA IgG levels increased, during B cell depletion therapy. This supports the hypothesis that the mechanism of action for B cell depletion therapy might be mediated by effects on EBV infection, which, in turn, mitigate immune cross-reactivity and disease perpetuation., Competing Interests: Declaration of Competing Interest BER, KB, EU and GN declare no disclosures relevant to the manuscript. SW has received honoraria for lecturing and advice from Biogen, Janssen and Sanofi. His department has received unrestricted institutional grants from Biogen, Merck and Novartis. He is currently collaborating on research projects funded by Merck and EMD Serono. TH has received speaker honoraria, research support/grants and participated in clinical trials for Biogen, Merck, Sanofi, Bristol Myers Squibb, Roche and Novartis. K-MM has received unrestricted research grants to his institution, scientific advisory board or speaker honoraria from Biogen, Novartis, and Sanofi, and has participated in clinical trials organized by Biogen, Merck, Novartis, Roche and Sanofi. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, Sanofi-Aventis, Merck and Novartis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

Introduction: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic., Objective: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS)., Methods: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects., Results: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response., Conclusions: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations., Competing Interests: Competing interests: ARL research fundings from Sanofi. SW has received speaker honoraria from and served on scientific advisory boards for Biogen, Janssen-Cilag, Sanofi and Novartis. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, BMS, Jansen, Sanofi, Merck and Novartis. TH has received speaker honoraria and/or unrestricted research grants from Biogen, Merck, Roche, Novartis, Sanofi and Bristol-Myers Squibb, and participated in clinical trials organised by Merck, Sanofi and Roche. TB has received unrestricted research grants from Biogen Idec and Sanofi Genzyme. MK-M has received unrestricted research grants to his institution; scientific advisory board and speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi, and has participated in clinical trials organised by Biogen, Merck, Novartis, Roche and Sanofi. HFH has received honoraria for lecturing or advice from Biogen, Merck, Roche, Novartis and Sanofi. AS is shareholder of Age Labs, a molecular diagnostics company that discovers, develops and commercialises diagnostic tests for the early detection of age-related diseases. EGC has received honoraria for lecturing and advice from Biogen, BMS, Janssen, Merck, Novartis, Roche and Sanofi., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Knowledge concerning exposure to abuse in adulthood and in pregnancy in people with multiple sclerosis (MS) is sparse., Objective: To determine the occurrence of adult abuse and abuse in relation to pregnancy in women with MS and their risk of revictimization (repeated abuse as adults after childhood abuse)., Methods: This cross-sectional study comprised pregnant women from the Norwegian Mother, Father and Child Cohort study. Information on abuse was acquired through self-completed questionnaires. We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs)., Results: We identified 106 women with MS at enrollment through linkage with national health registries. The reference group consisted of 77,278 women without MS. Twenty-seven women (26%) with MS reported any adult abuse compared to 15,491 women (20%) without MS, aOR 1.33 (0.85-2.09). Twenty-two (21%) women with MS reported systematic emotional abuse compared to 13% without MS, aOR 1.75 (1.08-2.83). Ten women (10%) with MS reported sexual abuse, compared to 6% without MS, aOR 1.72 (0.89-3.33). More women with MS reported rape as an adult, aOR 2.37 (1.02-5.49). Women with MS had higher risk of revictimization as adults, after childhood abuse, aOR 2.23 (1.22-4.10). The risk of abuse during pregnancy or 6 months preceding pregnancy was similar between the groups., Conclusions: Women with MS had increased occurrence of systematic emotional abuse, rape, and revictimization as adults, compared to women without MS., (© 2022. The Author(s).)

Monoclonal antibody therapy is effective for multiple sclerosis, and only small amounts of antibodies are transferred to breast milk. Even though the approved product descriptions advise against breastfeeding during medicinal treatment, several of the most effective MS drugs are compatible with breastfeeding.

Background: Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette-Guérin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk., Methods: Using data from a Norwegian tuberculosis screening programme (1963-1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship., Results: Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76-0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST., Conclusion: A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background and Objectives: The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS)., Methods: We included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status., Results: After 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (β = -21.74, p = 0.039) and higher logT2 lesion volume (β = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (β = -2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (β = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (β = -3.58, p = 0.029)., Discussion: Smoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To study whether exposure to childhood emotional, sexual or physical abuse is associated with subsequent multiple sclerosis (MS) development., Methods: A nationwide, prospective cohort study based on participants in the Norwegian Mother, Father and Child cohort study. Enrolment took place 1999-2008, with follow-up until 31 December 2018. Childhood abuse before age 18 years was obtained from self-completed questionnaires. We identified MS diagnoses through data-linkage with national health registries and hospital records. The Cox model was used to estimate HRs for MS with 95% CIs, adjusting for confounders and mediators., Results: In this prospective cohort study, 14 477 women were exposed to childhood abuse and 63 520 were unexposed. 300 women developed MS during the follow-up period. 71 of these (24%) reported a history of childhood abuse, compared with 14 406 of 77 697 (19%) women that did not develop MS. Sexual abuse (HR 1.65, 95% CI 1.13 to 2.39) and emotional abuse (HR 1.40, 95% CI 1.03 to 1.90) in childhood were both associated with an increased risk of developing MS. The HR of MS after exposure to physical abuse was 1.31 (95% CI 0.83 to 2.06). The risk of MS was further increased if exposed to two (HR 1.66, 95% CI 1.04 to 2.67) or all three abuse categories (HR 1.93, 95% CI 1.02 to 3.67)., Interpretation: Childhood sexual and emotional abuse were associated with an increased risk of developing MS. The risk was higher when exposed to several abuse categories, indicating a dose-response relationship. Further studies are needed to identify underlying mechanisms., Competing Interests: Competing interests: KE has received unrestricted research grant from Novartis. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, Sanofi-Aventis, Merck and Novartis. AB has received unrestricted research from Novartis. EGC has received honoraria for lecturing and advice from Biogen, Bristol Meyers Squibb, Janssen, Novartis, Merck, Roche and Sanofi, and her department has received grants from Novartis and Sanofi. AKD has received project funding from Pfizer. TH has received speaker honoraria from Biogen, Merck, Novartis, Roche, Bristol Myers Squibb, and Sanofi, and has participated in clinical trials organised by Biogen, Merck, and Roche. K-MM has received unrestricted research grants to his institution; scientific advisory board and speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi, and has participated in clinical trials organised by Biogen, Merck, Novartis, Roche and Sanofi. CFT has served on scientific advisory board for Astra Zeneca. SW has received honoraria from Biogen, Novartis and Sanofi. NEG has received honoraria from UCB, Ra, Argenx, Roche, Merck, Immunovant, Alexion. M-HB has received personal honoraria for lecturing from Teva, Lilly, Eisai and Novartis, and consultancy honoraria and unrestricted research support from Novartis. Institutional contract research fees from Sanofi., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Clonally related B cells infiltrate the brain, meninges, and cerebrospinal fluid of MS patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and BCR reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell (ASC) compartments and observed clonally related cells of different isotypes including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the immunoglobulin heavy-chain variable (IGHV)4 gene family with the κ variable (IGKV)1 gene family. The IGHV4-39 gene was most used and showed the highest frequency of pairing with IGKV1-5 and IGKV1(D)-33. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS and indicate that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Objective: To evaluate the effect of a specific communication training for neurologists on how to provide complex information about treatment options to patients with multiple sclerosis (MS)., Design: Single-centre, single-blind, randomised controlled trial., Setting: One university hospital in Norway., Participants: Thirty-four patients with early-stage MS., Intervention: A 3-hour training for neurologists on how to provide complex information about MS escalation therapy., Main Outcome Measures: Patient recall rate, measured with a reliable counting system of provided and recalled information about drugs., Secondary Outcome Measures: Number of information units provided by the physicians. Effects on patient involvement through questionnaires., Methods: Patients with MS were instructed to imagine a disease development and were randomised and blinded to meet a physician to receive information on escalation therapy, before or after the physician had participated in a 3-hour training on how to provide complex information. Consultations and immediate patient recall interviews were video-recorded and transcribed verbatim., Results: Patient recall rate was 0.37 (SD=0.10) pre-intervention and 0.39 (SD=0.10) post-intervention. The effect of the intervention on recall rate predicted with a general linear model covariate was not significant (coefficient parameter 0.07 (SE 0.04, 95% CI (-0.01 to 0.15)), p=0.099).The physicians tended to provide significantly fewer information units after the training, with an average of 91.0 (SD=30.3) pre-intervention and 76.5 (SD=17.4) post-intervention; coefficient parameter -0.09 (SE 0.02, 95% CI (-0.13 to -0.05)), p<0.001. There was a significant negative association between the amount of provided information and the recall rate (coefficient parameter -0.29 (SE 0.05, 95% CI (-0.39 to -0.18)), p<0.001). We found no significant effects on patient involvement using the Control Preference Scale, Collaborate or Four Habits Patient Questionnaire., Conclusion: A brief course for physicians on providing complex information reduced the amount of information provided, but did not improve patient recall rate., Trial Registration Number: ISRCTN42739508., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: To prospectively investigate the long-term relationship between body mass index (BMI) in adolescents and young adults and risk for multiple sclerosis (MS) at the population level., Methods: We used data from the population-based compulsory Norwegian tuberculosis screening program during 1963 to 1975, including objectively measured height and weight from ≈85% of all eligible citizens. This was combined with data from the Norwegian MS registry and biobank up to November 2020. BMI was standardized according to age and sex, and risk for MS was calculated with Cox proportional hazard models., Results: During 30,829,506 years of follow-up, we found 1,409 cases of MS among 648,734 participants in eligible age groups (14-34 years). Overall, obesity was associated with increased MS risk (hazard ratio [HR] 1.53 [95% confidence interval (CI) 1.25-1.88]), and the risk was similar in men (HR 1.4 [95% CI 0.95-2.06] and women (HR 1.59 [95% CI 1.25-2.02]). Risk was highest for the youngest age groups (age 14-16: HR 1.73 [95% CI 1.19-2.53]; 17-19: HR 1.61 [95% CI 1.08-2.39]; 20-24: HR 1.56 [95% CI 1.04-2.36]) and was no longer present for those >30 years of age., Discussion: High BMI in individuals 14 to 24 years of age was associated with increased MS risk later in life in both male and female individuals., (© 2021 American Academy of Neurology.)

Objective: To assess the occurrence of perinatal depression and anxiety in women before and after diagnosis of multiple sclerosis (MS)., Methods: A total of 114,629 pregnant women were included in the Norwegian Mother, Father and Child Cohort study (1999-2008). We assessed depression and anxiety by questionnaires during and after pregnancy. Women with MS were identified from national health registries and hospital records and grouped into (1) MS diagnosed before pregnancy (n = 140) or MS diagnosed after pregnancy with (2) symptom onset before pregnancy (n = 98) or (3) symptom onset after pregnancy (n = 308). Thirty-five women were diagnosed with MS in the postpartum period. The reference group (n = 111,627) consisted of women without MS., Results: Women with MS diagnosed before pregnancy had an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.1) for depression in the third trimester. Risk factors were adverse socioeconomic factors and history of psychiatric disease and physical/sexual abuse. The risk of anxiety was not increased. Women diagnosed with MS in the postpartum period had especially high risk of postpartum depression. Women with MS symptom onset within 5 years after pregnancy had increased risk of both depression and anxiety during pregnancy, whereas women with more than 5 years until symptom onset did not., Conclusion: Women diagnosed with MS have increased risk of perinatal depression. Women with MS symptom onset within 5 years after pregnancy have increased risk of both depression and anxiety during pregnancy., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Low vitamin D levels, tobacco use and high body mass index (BMI) have been linked to adverse disease outcomes in multiple sclerosis (MS), but their influence on long-term disability progression remains unclear. Therefore, we explored whether these modifiable lifestyle factors were associated with 10-year clinical disability progression in patients with MS., Methods: In this prospective study, a cohort of 88 patients with relapsing-remitting MS completed a randomized controlled study on ω-3 fatty acids between 2004 and 2008. During 24 months, serum 25-hydroxyvitamin D (25(OH)D), serum cotinine (nicotine metabolite), and BMI were repeatedly measured. In 2017, a follow-up study was conducted among 80 of the participants, including disability assessment by the Expanded Disability Status Scale (EDSS). Linear regression was used to explore associations between the lifestyle factors and the EDSS change over 10 years., Results: Higher seasonally adjusted 25(OH)D levels were associated with lower 10-year EDSS progression (change in EDSS per 1 SD increase in 25(OH)D in a model adjusted for sex, age and baseline EDSS: -0.45 point, 95% CI: -0.75 to -0.16, p=0.003). Further adjustments for potential confounders related to lifestyle and disease status gave similar results. The association was mainly driven by low 25(OH)D levels during spring, as well as seasonally adjusted levels below 80 nmol/L. No clear association was found for BMI and cotinine., Conclusion: Lower 25(OH)D levels, but apparently not tobacco use or higher BMI, were significantly associated with worse long-term disability progression in MS., (Copyright © 2021. Published by Elsevier B.V.)

B cells are important pathogenic players in multiple sclerosis (MS), but their exact role is not known. We have previously demonstrated that B cells from cerebrospinal fluid (CSF) of MS patients can activate T cells that specifically recognize antigenic determinants (idiotopes) from their B cell receptors (BCRs). The aim of this study was to evaluate whether in silico prediction models could identify antigenic idiotopes of immunoglobulin heavy-chain variable (IGHV) transcriptomes in MS patients. We utilized a previously assembled dataset of CSF IGHV repertoires from MS patients. To guide selection of potential antigenic idiotopes, we used in silico predicted HLA-DR affinity, endosomal processing, as well as transcript frequency from nine MS patients. Idiotopes with predicted low affinity and low likelihood of cathepsins cleavage were inert controls. Peripheral blood mononuclear cells from these patients were stimulated with the selected idiotope peptides in presence of anti-CD40 for 12 h. T cells were then labeled for activation status with anti-CD154 antibodies and CD3 + CD4 + T cells phenotyped as memory (CD45RO + ) or naïve (CD45RO - ), with potential for brain migration (CXCR3 and/or CCR6 expression). Anti-CD14 and -CD8 were utilized to exclude monocytes and CD8 + T cells. Unstimulated cells or insulin peptides were negative controls, and EBNA-1 peptides or CD3/CD28 beads were positive controls. The mean proportion of responding memory CD4 + T cells from all nine MS patients was significantly higher for idiotope peptides with predicted high HLA-DR affinity and high likelihood of cathepsin cleavage, than toward predicted inert peptides. Responses were mainly observed toward peptides affiliated with the CDR3 region. Activated memory CD4 + T cells expressed the chemokine receptor CCR6, affiliated with a Th17 phenotype and allowing passage into the central nervous system (CNS). This in vitro study suggests that that antigenic properties of BCR idiotopes can be identified in silico using HLA affinity and endosomal processing predictions. It further indicates that MS patients have a memory T cell repertoire capable of recognizing frequent BCR idiotopes found in endogenous CSF, and that these T cells express chemokine receptors allowing them to reach the CSF B cells expressing these idiotopes., (Copyright © 2020 Høglund, Bremel, Homan, Torsetnes, Lossius and Holmøy.)

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

Background: The plant-based ω-3 fatty acid α-linolenic acid (ALA) has been associated with lower MS risk. It is currently unknown whether ALA affects disease activity., Objective: To investigate the association between ALA levels and disease activity., Methods: We conducted a cohort study including 87 multiple sclerosis (MS)-patients who originally participated in a randomized trial of ω-3 fatty acids (the OFAMS study). We measured serum levels of ALA during follow-up and used random intercept logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association between ALA levels, new magnetic resonance imaging (MRI) lesions, Expanded Disability Status Scale (EDSS) progression and new relapses adjusting for age at inclusion, sex, and use of interferon beta-1a., Results: In continuous (per 1-SD increase) multivariable-adjusted analyses, higher ALA levels were significantly associated with lower odds of new T2-lesions (OR: 0.59, 95% CI: 0.37-0.95) during follow-up. The effect estimates were similar for new T1Gd + lesions (OR: 0.73, 95% CI: 0.48-1.11), EDSS-progression (OR: 0.62, 95% CI: 0.34-1.16) and new relapses (OR: 0.49, 95% CI: 0.22-1.10), but these estimates did not reach statistical significance. Further adjustment for vitamin D and tobacco use did not materially change the results., Conclusion: We found that higher levels of ALA were associated with lower disease activity in MS-patients.

Introduction: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The latest development of B-cell depletion by anti-CD20 monoclonal antibodies has been a large step forward in the treatment of this devastating disease., Areas Covered: In this manuscript, we review mechanisms of action, efficacy, safety, and tolerance of anti-CD20 therapies for MS, including rituximab, ocrelizumab, and ofatumumab., Expert Opinion: B-cell depletion efficiently suppresses acute inflammatory disease activity in relapsing-remitting MS (RRMS), and may slowdown progression in primary progressive MS (PPMS). The treatment is generally well tolerated, with manageable adverse events related to infusion reactions and infections. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is the first therapy to be approved for the treatment of both RRMS and PPMS.

Background: B cells may contribute to the immunopathogenesis of multiple sclerosis (MS). Dimethyl fumarate (DMF) has recently been shown to reduce the frequency of memory B cells in blood, but it is not known whether the drug influences the cellular composition in the cerebrospinal fluid (CSF)., Methods: A cross-sectional study examining the cellular composition in blood and cerebrospinal fluid (CSF) from 10 patients treated with DMF and 18 patients receiving other disease modifying drugs or no treatment., Results: Patients treated with DMF had reduced proportions of memory B cells in blood compared to other MS patients (p = 0.0007), and the reduction correlated with treatment duration (r s  = -0.75, p = 0.021). In the CSF, the absolute number of mononuclear cells were significantly lower in DMF-treated patients compared to the other patients (p = 0.023), and there was a disproportionate decrease of plasmablasts (p = 0.031)., Conclusion: The results of this exploratory study support a B-cell mediated mechanism of action for DMF in both blood and CSF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Adipokines secreted by fatty tissue have inflammatory properties and are suggested biomarkers of MS disease activity. To assess this, 88 MS patients were followed with nine repeated measurements of leptin and adiponectin and 12 magnetic resonance imaging (MRI) scans for two years; six months without any immunomodulatory treatment followed by 18 months during interferon-beta (IFNB) treatment. Serum levels of leptin dropped and adiponectin increased upon initiation of IFNB-therapy, but were not associated with clinical or MRI disease activity or with treatment response. Our findings indicate that leptin and adiponectin are not useful as biomarkers of MS disease activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Increasing female: male ratio in multiple sclerosis (MS) has been assigned to cohort effects, with females in more recent birth cohorts possibly being more exposed or vulnerable to environmental risk factors than males. We collected MS mortality data in Norway from 1951 to 2015 from The Norwegian Cause of Death registry. Age-Period-Cohort analysis was conducted using log-linear Poisson models, including sex interaction terms. MS was registered as the underlying, contributing or direct cause in 6060 deaths. MS associated mortality remained stable with a slight preponderance among males until after 1980, and have since increased preferentially among females. Throughout the study period the mean annual increase was 1.25% for females and 0.3% for males (p < 0.0001). Age-period-cohort analysis revealed limited evidence of cohort effects for the gender differences; the best fitting model only included gender-age and gender-period interaction terms. The period effect evened out for males in the last three decades but increased for females, especially among the oldest age-groups. In conclusion, the increased female: male mortality ratio in MS associated mortality is driven mainly by increased mortality among females in the three last decades, particularly in the older age groups. It is best explained by disproportional period effects, providing evidence of time-varying external factors including improved access to diagnosis among females.

Background: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting., Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS., Methods: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale., Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09)., Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Background: The mortality of septicaemia, meningitis and encephalitis caused by Listeria monocytogenes is 20-40%. Twenty-one cases of invasive listeriosis associated with alemtuzumab, including at least 16 in patients with multiple sclerosis, have been published or reported to the World Health Organization Case Safety Reports Database. Three cases were fatal, including at least one patient treated for multiple sclerosis in 2016., Case Presentation: We report a patient with multiple sclerosis who developed pyrexia, nausea and abdominal discomfort few hours after the third and last infusion of her second alemtuzumab cycle. An infusion related reaction was suspected. The patient had however eaten soft cheese and raw sausage 3 days prior to treatment, and L. monocytogenes septicaemia was diagnosed based on positive blood cultures., Conclusion: Listeriosis associated with alemtuzumab is a potentially fatal condition that can mimic an infusion related reaction. As in most other previously reported cases symptoms started rapidly after the last infusion, suggesting that the patient already carried the bacteria prior to the alemtuzumab infusions. The summary of product characteristics recommends patients to avoid foods associated with listeria at least 1 month after treatment. This recommendation should include also the last weeks prior to treatment.

Background: Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA)., Methods: We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years., Results: In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score ≤ -2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers., Conclusion: Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases.

Multiple sclerosis often affects women of childbearing age. The availability of more effective immunomodulatory therapy may increase the number of afflicted women wanting to fulfil their desire to have children. The purpose of this article is to provide an up-to-date review of medical issues and dilemmas related to family planning and pregnancy in multiple sclerosis.

Background: Leber's hereditary optic neuropathy (LHON) co-occuring with multiple sclerosis-like disease (LHON-MS) is suggested to be a separate disease entity denoted Harding's disease. Little is known about the response to initiation and discontinuation of potent immunomodulatory treatment in LHON-MS., Case Presentation: We describe a LHON-MS patient with 27 years disease duration who developed severe disease activity peaking 14 months after discontinuation of natalizumab, with extensive new inflammatory lesions throughout the brain and in the spinal cord resembling immune inflammatory reconstitution syndrome. She had previously been clinically and radiologically stable on natalizumab treatment for 6 years, and before that only experienced subtle clinical activity during 9 years on interferon beta1a., Conclusion: This is the first report on severe exacerbation of inflammatory disease activity after discontinuation of natalizumab in LHON-MS, and suggests that late rebound activity can occur in these patients.

Background: Several recent studies have found a higher risk of multiple sclerosis (MS) among people with a low level of education. This has been suggested to reflect an effect of smoking and lower vitamin D status in the social class associated with lower levels of education., Objective: The objective of this paper is to investigate the association between level of education and MS risk adjusting for the known risk factors smoking, infectious mononucleosis, indicators of vitamin D levels and body size., Methods: Within the case-control study on Environmental Factors In MS (EnvIMS), 953 MS patients and 1717 healthy controls from Norway reported educational level and history of exposure to putative environmental risk factors., Results: Higher level of education were associated with decreased MS risk (p trend = 0.001) with an OR of 0.53 (95% CI 0.41-0.68) when comparing those with the highest and lowest level of education. This association was only moderately reduced after adjusting for known risk factors (OR 0.61, 95% CI 0.44-0.83). The estimates remained similar when cases with disease onset before age 28 were excluded., Conclusion: These findings suggest that factors related to lower socioeconomic status other than established risk factors are associated with MS risk., (© The Author(s), 2015.)

Background: 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., Objective: 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., Methods: 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., Results: 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)., Conclusions: 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., (© The Author(s), 2015.)

Background: Epidemiological studies suggest that environmental factors play a significant role in the development of multiple sclerosis. This article presents current knowledge on the impact of the environment on disease risk and disease course., Method: We have conducted searches in PubMed for «multiple sclerosis» combined with «environment» as well as relevant environmental factors., Results: It is highly likely that an interaction between genetic and environmental factors determines who will develop multiple sclerosis. Epstein-Barr virus infection, smoking, and low vitamin D levels are the environmental factors that have shown the strongest and most consistent association with development of the disease. Low vitamin D levels are also associated with high disease activity. Other risk factors include obesity and high salt intake., Interpretation: Although epidemiological studies have identified a number of environmental factors with potential aetiological relevance, and the importance of these is supported by experimental studies, there is still insufficient evidence to establish a causal role for these factors in multiple sclerosis.

Background: Obesity may be a risk factor for developing multiple sclerosis (MS)., Objective: We examined if body size influences the risk of MS in a population-based, case control study., Methods: A total of 953 cases and 1717 controls from Norway and 707 cases and 1333 controls from Italy reported their body size by choosing a silhouette 1 to 9 (largest) every fifth year from age 5 to 30 and at time of study. The body size-related MS risk was defined by odds ratios (ORs) in logistic regression analyses adjusting for age, smoking and outdoor activity., Results: In Norway a large body size (silhouettes 6-9) compared to silhouette 3 increased the risk of MS, especially at age 25 (OR 2.21; 95% CI 1.09-4.46 for men and OR 1.43; 95% CI 0.90-2.27 for women). When comparing silhouette 9 to 1, we found a significant dose-response from age 10 until age 30 peaking at age 25 (sex-adjusted OR 2.83; 95% CI 1.68-4.78). The association was present for at least 15 years prior to disease onset. No significant associations were found in Italy., Conclusions: Obesity from childhood until young adulthood is a likely risk factor for MS with a seemingly stronger effect in Norway than in Italy., (© The Author(s), 2014.)

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system, often resulting in significant neurological disability. The causes of MS are not known; however, the incidence of MS is increasing, thereby suggesting that changes in lifestyle and/or environmental factors may be responsible. On this background, the Environmental Risk Factors in MS Study or EnvIMS study was designed to further explore the etiology of MS. The design and methodology are described, providing details to enable investigators to (i) use our experiences to design their own studies; (ii) take advantage of, and build on the methodological work completed for, the EnvIMS study; (iii) become aware of this data source that is available for use by the research community., Methods: EnvIMS is a multinational case-control study, enrolling 2,800 cases with MS and 5,012 population-based controls in Canada, Italy, Norway, Serbia and Sweden. The study was designed to investigate the most commonly implicated risk factors for MS etiology using a self-report questionnaire., Results/conclusions: The use of a common methodology to study MS etiology across several countries enhances the comparability of results in different geographic regions and research settings, reduces the resources required for study design and enhances the opportunity for data harmonization., (© 2015 S. Karger AG, Basel.)

Background: Previous reports indicate an association between Epstein-Barr virus (EBV) antibody levels and multiple sclerosis (MS) disease activity, but the results have been conflicting., Objectives: The objective of this paper is to study if EBV antibody levels reflect MRI disease activity in MS and examine the potential for EBV antibody levels as biomarkers for treatment response., Methods: A total of 87 MS patients were followed for two years prior to and during interferon beta (IFNB) treatment, with MRI examinations and serum measurement of IgM and IgG antibodies to viral capsid antigen (VCA), EBV nuclear antigen 1 (EBNA-1) and early antigen (EA). Associations between EBV antibody levels and MRI activity were assessed by a logistic regression model., Results: Higher anti-EBNA-1 IgG levels were associated with increased MRI activity, OR = 2.95 (95% CI 1.07-8.10; p = 0.036) for combined unique activity (CUA; the sum of T1Gd+ lesions and new or enlarging T2 lesions). Although most patients were anti-VCA IgM negative, there was an inverse association, OR = 0.32 (95% CI 0.12-0.84; p = 0.021) with CUA during IFNB treatment., Conclusions: This study supports an association between anti-EBNA-1 IgG levels and MS disease activity. We also found an inverse association with anti-VCA IgM levels during IFNB treatment not previously described, indicating anti-VCA IgM as a possible biomarker for IFNB treatment response., (© The Author(s), 2014.)

Epstein-Barr virus (EBV) has long been suggested as a pathogen in multiple sclerosis (MS). Here, we used high-throughput sequencing to determine the diversity, compartmentalization, persistence, and EBV-reactivity of the T-cell receptor (TCR) repertoires in MS. TCR-β genes were sequenced in paired samples of cerebrospinal fluid (CSF) and blood from patients with MS and controls with other inflammatory neurological diseases. The TCR repertoires were highly diverse in both compartments and patient groups. Expanded T-cell clones, represented by TCR-β sequences >0.1%, were of different identity in CSF and blood of MS patients, and persisted for more than a year. Reference TCR-β libraries generated from peripheral blood T cells reactive against autologous EBV-transformed B cells were highly enriched for public EBV-specific sequences and were used to quantify EBV-reactive TCR-β sequences in CSF. TCR-β sequences of EBV-reactive CD8+ T cells, including several public EBV-specific sequences, were intrathecally enriched in MS patients only, whereas those of EBV-reactive CD4+ T cells were also enriched in CSF of controls. These data provide evidence for a clonally diverse, yet compartmentalized and persistent, intrathecal T-cell response in MS. The presented strategy links TCR sequence to intrathecal T-cell specificity, demonstrating enrichment of EBV-reactive CD8+ T cells in MS., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: The objective of this paper is to estimate the association between multiple sclerosis (MS) and measures of sun exposure in specific age periods in Norway and Italy., Methods: A total of 1660 MS patients and 3050 controls from Italy and Norway who participated in a multinational case-control study (EnvIMS) reported sun habits during childhood and adolescence., Results: A significant association between infrequent summer outdoor activity and increased MS risk was found in Norway and in Italy. The association was strongest between the ages of 16 and 18 years in Norway (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.30-2.59), and between birth and age 5 years in Italy (OR 1.56, 95% CI 1.16-2.10). In Italy a significant association was also found during winter (OR 1.42, 95% CI 1.03-1.97). Frequent sunscreen use between birth and the age of 6 years was associated with MS in Norway (OR 1.44, 95% CI 1.08-1.93) after adjusting for outdoor activity during the same period. Red hair (OR 1.67, 95% CI 1.06-2.63) and blonde hair (OR 1.36, 95% CI 1.09-1.70) were associated with MS after adjusting for outdoor activity and sunscreen use., Conclusion: Converging evidence from different measures underlines the beneficial effect of sun exposure on MS risk., (© The Author(s) 2014.)

To explore the relationships between vitamin A, D and E and inflammation in relapsing remitting multiple sclerosis, we assessed their associations with 11 inflammation markers in 9 serial serum samples from 85 patients, before and during interferon-β1a treatment. A negative association was found between vitamin A and pentraxin 3 independent of interferon-β1a use, whereas positive associations between vitamin D and interleukin-1 receptor antagonist and secreted frizzled-related protein 3 were seen before, and between vitamin E and chemokine (C-X-C motif) ligand 16 during interferon-β1a treatment. These findings suggest associations with diverse inflammatory pathways, which may be differentially influenced by interferon-β1a treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Seasonal fluctuations in solar radiation and vitamin D levels could modulate the immune response against Epstein-Barr virus (EBV) infection and influence the subsequent risk of multiple sclerosis (MS)., Methods: Altogether 1660 MS patients and 3050 controls from Norway and Italy participating in the multinational case-control study of Environmental Factors In Multiple Sclerosis (EnvIMS) reported season of past infectious mononucleosis (IM)., Results: IM was generally reported more frequently in Norway (p=0.002), but was associated with MS to a similar degree in Norway (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.64-2.73) and Italy (OR 1.72, 95% CI 1.17-2.52). For all participants, there was a higher reported frequency of IM during spring compared to fall (p<0.0005). Stratified by season of IM, the ORs for MS were 1.58 in spring (95% CI 1.08-2.31), 2.26 in summer (95% CI 1.46-3.51), 2.86 in fall (95% CI 1.69-4.85) and 2.30 in winter (95% CI 1.45-3.66)., Conclusions: IM is associated with MS independently of season, and the association is not stronger for IM during spring, when vitamin D levels reach nadir. The distribution of IM may point towards a correlation with solar radiation or other factors with a similar latitudinal and seasonal variation.

Background: Serum markers of inflammation are candidate biomarkers in multiple sclerosis (MS). ω-3 fatty acids are suggested to have anti-inflammatory properties that might be beneficial in MS. We aimed to explore the relationship between serum levels of inflammation markers and MRI activity in patients with relapsing remitting MS, as well as the effect of ω-3 fatty acids on these markers., Methods: We performed a prospective cohort study in 85 relapsing remitting MS patients who participated in a randomized clinical trial of ω-3 fatty acids versus placebo (the OFAMS study). During a period of 24 months 12 repeated magnetic resonance imaging (MRI) scans and nine serum samples were obtained. We measured 10 inflammation markers, including general down-stream markers of inflammation, specific markers of up-stream inflammatory pathways, endothelial action, and matrix regulation., Results: After Bonferroni correction, increasing serum levels of CXCL16 and osteoprotegerin were associated with low odds ratio for simultaneous MRI activity, whereas a positive association was observed for matrix metalloproteinase (MMP) 9. CXCL16 were also associated with low MRI activity the next month, but this was not significant after Bonferroni correction. In agreement with previously reported MRI and clinical results, ω-3 fatty acid treatment did not induce any change in the inflammation markers., Conclusions: Serum levels of CXCL16, MMP-9, and osteoprotegerin reflect disease activity in MS, but are not affected by ω-3 fatty acid treatment. CXCL16 could be a novel biomarker and potential predictor of disease activity in MS.

Objective: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient., Methods: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose., Results: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98-1.24), in Middle Norway 1.11 (0.97-1.27) and in Northern Norway 1.28 (1.0-1.63) compared with the other months., Conclusions: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71 °N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway, and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 (p < 0.001). In patients with relapsing remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.

Background: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease. It is thought to be mediated by CD4(+) Th1/Th17 cells. More recently, cells of the innate immune system such as dendritic cells (DCs) and natural killer (NK) cells have been in focus. Glatiramer acetate (GA) is an approved drug for treating MS patients., Methodology/principal Findings: In the current study we examined the activities of NK and DCs in nine relapsing remitting MS patients for up to one year after initiation of GA treatment. We observed that NK cells isolated from most of these patients have increased cytotoxic activity against K562 cells. Further analysis showed that the same NK cells lysed both autologous immature (i) and mature (m) DCs. In most patients this increased activity was correlated with increased NK cell activating cytotoxicity receptors such as NKp30, NKp44, NKp46 and NKG2D, and reduced expression of the inhibitory molecule CD158 on the surface of these NK cells. The expression of HLA-DR was increased on iDCs and mDCs in the majority of the patients, but no consistency was observed for the expression of HLA-I or HLA-E. Also, the co-stimulatory receptors CD80, CD83 or CD86 expression was down-regulated on iDCs and mDCs in most cases. Further, the expression of CCR6 was increased on mDCs at later time points of therapy (between 32-48 weeks)., Conclusions/significance: Our results are the first showing the effects of GA treatment on NK cells in MS patients, which may impact future use of this and other drugs to treat this disease.

Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if so, by which mechanisms the virus may contribute. In this review, we discuss possible viral and immunological mechanisms that might explain associations between EBV and autoimmune diseases and whether these associations represent causes or effects of inflammation and autoimmunity.

Epidemiological and experimental evidence suggest that a poor vitamin D status is associated with an increased risk of developing multiple sclerosis (MS), and also an unfavorable disease course. Vitamin D may exert relevant effects both on the immune system and on resident cells within the CNS. The data from clinical trials is, however, restricted, and does not allow any conclusion on the effect of high-dose vitamin D supplementation on disease course. The results from sufficiently powered studies will not be available for at least 2 years. MS patients are, however, prone to develop osteoporosis and have increased risk of fractures. Therefore, the authors advise that the serum concentration of 25-hydroxyvitamin D is monitored in order to prevent bone deficit, and that a serum level of 75-125 nmol/l is targeted. This level is sufficient for maintenance of bone health, is not known to be associated with adverse events, and is in the range that has been associated with low risk of developing MS and low disease activity.