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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. [ABSTRACT FROM AUTHOR]

Background: Treatment of neuromyelitis optica spectrum disorder (NMOSD) has so far been based on retrospective case series. The results of six randomized clinical trials including five different monoclonal antibodies targeting four molecules and three distinct pathophysiological pathways have recently been published. Methods: Literature search on clinical trials and case studies in NMOSD up to July 10. 2020. Results: We review mechanism of action, efficacy and side effects, and consequences for reproductive health from traditional immunosuppressants and monoclonal antibodies including rituximab, inebilizumab, eculizumab, tocilizumab and satralizumab. Conclusion: In NMOSD patients with antibodies against aquaporin 4, monoclonal antibodies that deplete B cells (rituximab and inebilizumab) or interfere with interleukin 6 signaling (tocilizumab and satralizumab) or complement activation (eculizumab) have superior efficacy compared to placebo. Tocilizumab and rituximab were also superior to azathioprine in head-to-head studies. Rituximab, tocilizumab and to some extent eculizumab have well-known safety profiles for other inflammatory diseases, and rituximab and azathioprine may be safe during pregnancy. [ABSTRACT FROM AUTHOR]

Objectives: The effect of vitamin D supplementation on the disease course of multiple sclerosis (MS) is not established. Neurofilament light chain (NFL) is a sensitive marker of axonal degeneration. The aim of this study was to establish whether high‐dose vitamin D supplementation reduces serum levels of NFL. Materials and Methods: We have performed a 96 weeks placebo‐controlled randomized study of weekly supplementation with 20 000 IU vitamin D3 in 71 patients with relapsing remitting MS (RRMS). Serum levels of NFL were measured at baseline, week 48 and week 96 with a single molecule (Simoa) assay in 69 of these patients. Results: Serum levels of 25‐hydroxyvitamin D more than doubled in the vitamin D group. Compared to placebo, vitamin D supplementation had no overall effect on the change in serum levels of NFL from baseline (P = 0.93 at week 48 and P = 0.56 at week 96). In the subgroup of patients not receiving disease‐modifying therapy, NFL decreased by 30.9% to week 48% and 32.6% to week 96 from baseline in the vitamin D group as compared to the placebo group (P = 0.06 for both time points). Conclusion: With a possible exception for patients not treated with disease‐modifying drugs, weekly supplementation with 20 000 IU vitamin D3 did not affect NFL levels in these RRMS patients. [ABSTRACT FROM AUTHOR]

The special nature of amyotrophic lateral sclerosis (ALS) and tracheostomy with invasive ventilation (TIV) leads to challenges that can be difficult in two senses: not only to handle well, but also to discuss with patients and other involved stakeholders. Because of the delicate nature of interpersonal relations and communication in ALS, some of the downsides to TIV may almost take on a nature of taboo, making them difficult to raise for open discussion. Yet these ethical challenges are important to be aware of, not only for health professionals and managers but, arguably, also for patients and next of kin. They are important also for a wider professional and societal debate about whether and to whom TIV should be offered. In this paper we highlight and examine ethical challenges in TIV for ALS, with a special emphasis on those that are hard to discuss openly and that therefore might fail to be addressed. The analysis is structured by the four core principles of healthcare ethics: beneficence, nonmaleficence, respect for patient autonomy, and justice. [ABSTRACT FROM AUTHOR]

Genetic variants in SPAST are the most common cause of hereditary spastic paraplegia (HSP), entitled spastic paraplegia type 4 (SPG4). Inheritance is autosomal dominant, and age of onset can vary from childhood to adulthood. Pathogenic SPAST variants are often observed in isolated cases, likely due to reduced penetrance and clinical variability. We report an isolated case of SPG4 associated with a novel likely pathogenic variant in SPAST. A 38-year-old woman presented with an eight-year history of progressive difficulty walking. Neurological examination revealed spastic paraparesis in the absence of upper motor neuron dysfunction, sensory deficits, or intellectual disability. Magnetic resonance imaging (MRI) of the brain and spinal cord was normal. No family members had similar complaints. Genetic analysis revealed a novel heterozygous sequence variant in SPAST, c.1751A > G p.(Asp584Gly) (NM_014946.4). The affected amino acid is highly conserved among orthologue and paralogue species. Four other nucleotide substitutions predicted to affect the same amino acid, a "hot spot", have been reported previously in adult-onset HSP. This report describes a novel SPAST variant in a female with HSP without a known family history of the disorder. [ABSTRACT FROM AUTHOR]

Skogholt's disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt's disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ1––42, Aβ1–40, Aβx–38, Aβx–40, Aβx–42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ1/x–42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed. [ABSTRACT FROM AUTHOR]

Background: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare neurological condition with paraneoplastic etiology in about 20% of cases, usually presenting before or shortly after the oncological diagnosis is established. PERM associated with anti-glycine receptor antibodies is not previously reported in a patient with bladder cancer. Case presentation: A 72-years-old Caucasian male was admitted with acute onset of dysarthria, dysphagia and trismus three years after initial surgical treatment for bladder cancer. The condition was initially diagnosed as tetanus and treated accordingly, but the diagnosis was reconsidered because of progression despite adequate treatment. Diagnostic workup on readmission revealed lung and paraaortal metastases from bladder cancer and anti-glycine receptor (anti-GlyR) antibodies both in the cerebrospinal fluid and in serum, which supplemented with the clinical presentation led to the diagnosis of PERM, presumably related to bladder cancer. The patient showed improvement and stabilization after treatment with intravenous immunoglobulin and chemotherapy against metastatic bladder cancer. Conclusion: To the best of our knowledge, this is the first reported case of anti-GlyR antibody positive PERM related to urothelial carcinoma. The symptoms mimicked tetanus, and responded to chemotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: People with multiple sclerosis have high risk of osteoporosis and fractures. A poor vitamin D status is a risk factor for MS, and vitamin D supplementation has been recommended both to prevent MS progression and to maintain bone health.Methods: We assessed the effect of 20,000 IU vitamin D3 weekly compared to placebo on biochemical markers of bone metabolism in 68 persons with relapsing remitting multiple sclerosis.Results: Serum levels of 25-hydroxyvitamin D more than doubled in the vitamin D group, and parathyroid hormone decreased in the vitamin D group compared to the placebo group at week 48 and week 96. There was however no effect on bone formation as measured by procollagen type I N propeptide (PINP), or on bone resorption as measured by C-terminal cross-linking telopeptide of type I collagen (CTX1). Neither PINP nor CTX1 predicted bone loss from baseline to week 96.Conclusions: These findings corroborate the previously reported lack of effect of weekly high dose vitamin D supplementation on bone mass density in the same patients, and suggest that such vitamin D supplementation does not prevent bone loss in persons with MS who are not vitamin D deficient.Trial Registration: The trial was registered at ClinicalTrials.gov on April 4 2008, registration number NCT00785473 . [ABSTRACT FROM AUTHOR]

Background: Elevated antibody levels against Epstein–Barr virus (EBV) and a poor vitamin D status are environmental factors that may interact in relapsing-remitting multiple sclerosis (RRMS) aetiology. Objectives: To examine effects of high-dose oral vitamin D3 supplementation on antibody levels against EBV nuclear antigen 1 (EBNA1) in RRMS. Methods: Serum 25-hydroxyvitamin D3 (25(OH)D) and immunoglobulin G antibody levels against EBNA1 (whole protein and amino acid 385–420 fragment), EBV viral capsid antigen (VCA), cytomegalovirus (CMV) and varicella zoster virus (VZV) were measured in 68 RRMS patients enrolled in a 96-week randomised double-blinded placebo-controlled clinical trial of oral vitamin D3 supplementation (20,000 IU/week) (NCT00785473). Results: The mean 25(OH)D level more than doubled in the vitamin D group and was significantly higher than in the placebo group at study conclusion (123.2 versus 61.8 nmol/L, p < 0.001). Compared to the placebo group, both anti-EBNA1 protein and fragment antibody levels decreased in the vitamin D group from baseline to week 48 (p = 0.038 and p = 0.004, respectively), but not from baseline to week 96. Vitamin D3 supplementation did not affect antibodies against VCA, CMV or VZV. Conclusion: The results indicate that high-dose oral vitamin D3 supplementation can affect humoral immune responses against the latent EBV antigen EBNA1 in RRMS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

During treatment with fingolimod, B cells are redistributed from blood to secondary lymphoid organs, where they are protected from the effect of anti-CD20 and other cell-depleting therapies.We describe a multiple sclerosis patient who had almost complete depletion of B cells in blood during and shortly after treatment with fingolimod. He developed severe disease activity resembling immune reconstitution syndrome after switching from fingolimod to rituximab, with first dose being six weeks after fingolimod cessation. Following recommendations from the Swedish MS Association, rituximab treatment was started as one single dose of 1000 mg. In patients treated with fingolimod, pathogenic B cells may still be sequestered in secondary lymph nodes if this dose is given early. To deplete such B cells as they egress from the lymph nodes, we propose that a second dose of rituximab a few weeks after the first dose should be considered. [ABSTRACT FROM AUTHOR]

Objective. Patients with multiple sclerosis (MS) are often suffering from neuropathic pain. Antiepileptic drugs (AEDs) and tricyclic antidepressants (TCAs) are commonly used and are susceptible to be involved in drug interactions. The aim of this retrospective study was to investigate the prevalence of use of antiepileptic and antidepressive drugs in MS patients and to discuss the theoretical potential for interactions. Methods. Review of the medical records from all patients treated at a dedicated MS rehabilitation centre in Norway between 2009 and 2012. Results. In total 1090 patients attended a rehabilitation stay during the study period. Of these, 342 (31%; 249 females) with mean age of 53 (±10) years and EDSS 4.8 (±1.7) used at least one AED (gabapentin 12.7%, pregabalin 7.7%, clonazepam 7.8%, and carbamazepine 2.6%) or amitriptyline (9.7%). Polypharmacy was widespread (mean 5.4 drugs) with 60% using additional CNS-active drugs with a propensity to be involved in interactions. Age, gender, and EDSS scores did not differ significantly between those using and not using AED/amitriptyline. Conclusion. One-third of MS patients attending a rehabilitation stay receive AED/amitriptyline treatment. The high prevalence of polypharmacy and use of CNS-active drugs calls for awareness of especially pharmacodynamic interactions and possible excessive adverse effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Autologous hematopoietic stem cell transplantation (HSCT) is a potent treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Objective: To evaluate long-term outcomes of HSCT in MS. Methods: National retrospective single-center observational study of patients with aggressive RRMS that underwent HSCT in Norway from January 2015 to January 2018. Criteria for receiving HSCT included at least two clinical relapses the last year while on disease modifying treatment (DMT). Results: In total, 29 patients, with a mean follow-up time of 70 months (standard deviation:14.3), were evaluated. Twenty patients (69%) had sustained no evidence of disease activity (NEDA-3) status, 24 (83%) were relapse-free, 23 (79%) free of magnetic resonance imaging (MRI) activity, and 26 (90%) free of progression. Number of patients working full-time increased from 1 (3%), before HSCT, to 10 (33%) after 2 years and 15 (52%) after 5 years. Conclusion: HSCT offers long-term disease-free survival with successively increasing work participation in patients with aggressive MS resistant to DMTs. [ABSTRACT FROM AUTHOR]

To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk. From Norwegian cardiovascular health surveys (1974–2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models. Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01–1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6–7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results. Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS. [ABSTRACT FROM AUTHOR]

Objective: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. Results: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment. [ABSTRACT FROM AUTHOR]

In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • Serum levels of leptin were lower and serum levels of adiponectin were higher during IFNB-treatment compared to before. • There was no association between serum levels of leptin or adiponectin and MRI- or clinical activity. • Serum levels of leptin and adiponectin could not predict clinical relapses or treatment-response. • Fewer of the overweight patients obtained NEDA-status, but this was not explained by serum levels of adipokines. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis ( MS) and IgG levels in the cerebrospinal fluid ( CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease-specific mechanism involved in B-cell establishment within the central nervous system in MS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Obesity is a possible risk factor of multiple sclerosis (MS), but the association between obesity and MS disease activity has not been explored. In a cohort of 86 MS patients, 80% of overweight or obese patients (BMI ≥ 25 kg/m 2 ) had MRI activity compared to 48% of the normal-weight patients (BMI < 25 kg/m 2 ) (p = 0.001) during interferon-beta treatment. NEDA-status (no evidence of disease activity) was defined as a composite that consisted of absence of any relapses, sustained disability-progression and MRI-activity. Among normal-weight patients 26% obtained NEDA-status compared to only 13% of patients with BMI > 25 (p = 0.05). This may indicate that BMI affects interferon-beta treatment response. [ABSTRACT FROM AUTHOR]

The article examines the reflection of Epstein-Barr virus (EBV) antibody levels in magnetic resonance imaging (MRI) disease activity in multiple sclerosis and as EBV treatment response biomarkers. The study indicates the relation of higher anti-EBNA-1 immunoglobulin G levels to increased MRI activity.

Introduction: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017.Methods: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017.Results: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017.Conclusion: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study.ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs.At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion.ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions.Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017. [ABSTRACT FROM AUTHOR]

In multiple sclerosis (MS), B cells are trafficking across the blood-brain barrier, but it is not known how this relates to the synthesis of oligoclonal IgG. We used quantitative mass spectrometry of oligoclonal bands and high-throughput sequencing of immunoglobulin heavy-chain variable transcripts to study the longitudinal B cell response in the cerebrospinal fluid (CSF) and blood of two MS patients. Twenty of 22 (91%) and 25 of 28 (89%) of oligoclonal band peptides persisted in samples collected 18 months apart, in spite of a dynamic exchange across the blood-CSF barrier of B lineage cells connecting to oligoclonal IgG. Unlabelled Image • Intrathecally synthesized oligoclonal IgG persist over time in multiple sclerosis. • Clusters of B cell clones connecting to oligoclonal IgG persist over time. • Oligoclonal IgG persists in spite of a dynamic B cell response. [ABSTRACT FROM AUTHOR]

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 D3 (cholecalciferol) per day with placebo for 48 weeks in 232 randomized patients, whereas CHOLINE compared vitamin D3 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We have previously shown that plasmablasts of the G1m1 allotype of IgG1 are selectively enriched in the cerebrospinal fluid of G1m1/G1m3 heterozygous patients with multiple sclerosis, whereas both allotypes are equally used in neuroborreliosis. Here, we demonstrate a strong preference for the G1m1 allotype in the intrathecal humoral immune responses against measles, rubella, and varicella zoster virus in G1m1/G1m3 heterozygous multiple sclerosis patients. Conversely, intrathecally synthesized varicella zoster virus‐specific IgG1 in varicella zoster virus meningoencephalitis comprised both allotypes. This implies that G1m1 B cells are selected to the central nervous system of multiple sclerosis patients regardless of specificity and suggests that an antigen‐independent mechanism could drive the intrathecal humoral immune response. [ABSTRACT FROM AUTHOR]

Objective: In Norway, diagnoses from specialist health care visits, drug prescriptions, and causes of deaths are registered in compulsory health registers. We aimed to determine amyotrophic lateral sclerosis (ALS) prevalence from 2009 to 2015 by combining these registers. Methods: We validated the Norwegian Patient Registry (NPR) through hospital files, and linked it with the Norwegian Cause of Death Registry and the Norwegian Prescription Database. Poisson regression models were fitted for estimating gender ratios, time trends and possible interactions. Similar models were used for mortality data subtracted from the dataset. Results: Eleven percent of patients with at least one ALS-related entry in NPR did not have ALS. ALS prevalence could nevertheless be reliably estimated through ascertaining cases identified in two separate registers, or with at least two entries in NPR with first entry within four years prior to prevalence date. ALS prevalence remained stable, and was 7.6/100,000 (95% CI 6.9-8.4) at 31st December 2015. Mean male:female ratio was higher for prevalence (1.8; 95% CI 1.6-2.0) than for mortality (1.5; 95% CI 1.2-1.8) (p = 0.04). There were also significant regional differences in prevalence (p < 0.01) but not in mortality. Conclusions: Norwegian compulsory health registers provide reliable tools for ALS surveillance, and suggest gender and regional differences in survival after diagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele.In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recent studies suggest that the incidence and mortality of amyotrophic lateral sclerosis (ALS) are increasing. Changing environmental factors could influence disease risk differently throughout life span, and also between genders, birth cohorts, and seasons of birth. We aimed at describing long-term ALS mortality trends in Norway between 1951 and 2014 using age-period-cohort analysis. The Norwegian Cause of Death Registry provided ALS mortality data that were age- and sex-adjusted through direct standardization. Poisson regression analyses were used for identification of mortality trends and potential month of birth effects. We identified 5345 ALS cases, of which 54.7 % were men. ALS mortality increased throughout the whole period ( p < 0.001), with a mean annual increase of 1.14 %. The increase was confined to those older than 60 years, but rates consistently dropped amongst the absolute oldest. The increase was mainly driven by birth cohort effects that increased from 1860 until 1934 ( p < 0.001). No month of birth effect or change in sex ratio was found. The continuous increase in ALS mortality since 1951 is best explained by the long-term changes in exposure to risk factors or in case ascertainment, affecting men and women equally in the generations born since 1860 and at least into 1934. [ABSTRACT FROM AUTHOR]

T cells and B cells are crucial in the initiation and maintenance of multiple sclerosis (MS), and the activation of these cells is believed to be mediated through specific recognition of antigens by the T- and B-cell receptors. The antigen receptors are highly polymorphic due to recombination (T- and B-cell receptors) and mutation (B-cell receptors) of the encoding genes, which can therefore be used as fingerprints to track individual T- and B-cell clones. Such studies can shed light on mechanisms driving the immune responses and provide new insights into the pathogenesis. Here, we summarize studies that have explored the T- and B-cell receptor repertoires using earlier methodological approaches, and we focus on how high-throughput sequencing has provided new knowledge by surveying the immune repertoires in MS in even greater detail and with unprecedented depth. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Observational studies have suggested that vitamin D may reduce inflammation in relapsing-remitting multiple sclerosis (RRMS), but this has not been clearly confirmed in randomized controlled trials. To further explore the possible anti-inflammatory effects of vitamin D in RRMS, we examined the effect of high-dose oral vitamin D on eleven markers of systemic inflammation in 68 RRMS patients enrolled in a double-blinded randomized placebo-controlled trial of vitamin D supplementation (20,000 IU/week) (NCT00785473). Serum inflammation markers and 25-hydroxyvitamin D (25(OH)D) were measured at baseline and week 96, and no restrictions were set on additional standard immunomodulatory treatment for RRMS. The mean 25(OH)D level rose from 56 ± 29 to 123 ± 34 nmol/L among patients receiving vitamin D supplementation, whereas only a minor increase from 57 ± 22 to 63 ± 24 nmol/L was seen in the placebo group. However, no significant differences appeared between the vitamin D group and the placebo group for any of the inflammation markers. Patients on immunomodulatory therapy had significantly higher levels of interleukin-1 receptor antagonist and chemokine (C-X-C motif) ligand 16 than patients without immunomodulatory treatment, but there were no clear synergistic effects between immunomodulatory therapy and vitamin D supplementation on any of the inflammation markers. The rise in 25(OH)D levels after vitamin D supplementation was unaffected by immunomodulatory treatment. We conclude that in this study of RRMS patients, high-dose oral vitamin D supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation, while a more anti-inflammatory phenotype was found among patients on immunomodulatory treatment. [ABSTRACT FROM AUTHOR]

The mechanisms driving the intrathecal synthesis of IgG in multiple sclerosis (MS) are unknown. We combined high-throughput sequencing of transcribed immunoglobulin heavy-chain variable (IGHV) genes and mass spectrometry to chart the diversity and compartmentalization of IgG-producing B cells in the cerebrospinal fluid (CSF) of MS patients and controls with other neuroinflammatory diseases. In both groups, a few clones dominated the intrathecal IGHV transcriptome. In most MS patients and some controls, dominant transcripts matched the CSF IgG. The IGHV transcripts in CSF of MS patients frequently carried IGHV4 genes and had more replacement mutations compared to controls. In both groups, dominant IGHV transcripts were identified within clusters of clonally related B cells that had identical or related IGHV transcripts in the blood. These findings suggest more pronounced affinity maturation, but an equal degree of diversity and compartmentalization of the intrathecal B-cell response in MS compared to other neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

The article presents research which examines if body size influences the risk of multiple sclerosis (MS) in a population-based, case control study in Norway and Italy. It notes the definition of body size-related MS risk by odds ratios (ORs) in logistic regression analyses adjusting for age, smoking and outdoor activity. It reveals the possibility of obesity from childhood until young adulthood to be a risk factor for MS with a seemingly stronger effect in countries mentioned.

To explore if vitamin D modulates interferon-β1a treatment effects in relapsing-remitting multiple sclerosis, we examined relationships between serum vitamin D and magnetic resonance imaging (MRI) activity and ten systemic inflammation markers in 88 patients, before and during treatment. Odds ratios for all MRI parameters were negatively associated with vitamin D levels before therapy, but converged to equally low values irrespective of vitamin D status during treatment. During therapy, similar alterations of MRI activity and inflammation markers were found across patients categorized by mean vitamin D values. This suggests that vitamin D status has no major influence on interferon-β1a treatment effects. [ABSTRACT FROM AUTHOR]

The article examines the association between multiple sclerosis (MS) and measures of sun exposure in specific age periods in Norway and Italy. The multinational case-control study (EnvIMS) study included 1660 MS patients and 3050 controls from Italy and Norway. It found converging evidence that underlines the beneficial effect of sun exposure on MS risk.

Cysteine cathepsins are critical components of the adaptive immune system involved in the generation of epitopes for presentation on human leukocyte antigen (HLA) molecules and have been implicated in degradation of autoantigens. Immunoglobulin variable regions with somatic mutations and random complementarity region 3 amino acid composition are inherently immunogenic. T cell reactivity towards immunoglobulin variable regions has been investigated in relation to specific diseases, as well as reactivity to therapeutic monoclonal antibodies. Yet, how the immunoglobulins, or the B cell receptors, are processed in endolysosomal compartments of professional antigen presenting cells has not been described in detail. Here we present in silico and in vitro experimental evidence suggesting that cysteine cathepsins S, L and B may have important roles in generating peptides fitting HLA class II molecules, capable of being presented to T cells, from monoclonal antibodies as well as from central nervous system proteins including a well described autoantigen. By combining neural net models with in vitro proteomics experiments, we further suggest how such degradation can be predicted, how it fits with available cellular models, and that it is immunoglobulin heavy chain variable family dependent. These findings are relevant for biotherapeutic drug design as well as to understand disease development. We also suggest how these tools can be improved, including improved machine learning methodology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]