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Background: The measurement of neurofilament light (NFL) in blood samples has been established as a sensitive measure of neuroaxonal damage in a wide range of diseases in the peripheral and central nervous system, including multiple sclerosis (MS). Previous studies have identified confounding factors that may influence the serum concentration of NFL., Aim: We aimed at investigating the relationship between known confounders (age, body mass index, blood volume) and risk factors for MS (smoking and human leukocyte antigen (HLA)) on serum concentrations of NFL in control subjects. In addition, we compared different methods for correction for confounders when applied to newly diagnosed patients with MS., Methods: We measured serum concentrations of NFL by single molecule array analysis in 1.101 control subjects without neurological disease from 4 different cohorts (including 906 healthy blood donors) and 72 patients with newly diagnosed relapsing-remitting MS. A questionnaire on smoking habits was distributed to the 906 healthy blood donors, and the HLA risk alleles HLA-DRB1*15:01 and HLA-A*02:01 were genotyped by TaqMan allelic-discrimination PCR analysis in these subjects., Results: We confirmed that serum concentrations of NFL increase with age, but we also found that sample storage conditions for the different cohorts of control subjects had a substantial effect. Prolonged storage time and storage at -20° were independently associated with lower serum concentrations of NFL than shorter storage time and storage at -80° In samples from the large cohort of blood donors, we confirmed an association between high BMI and high blood volume with lower serum concentrations of NFL and found that this association was marginally stronger for BMI than for blood volume. We found no association between smoking and HLA risk factors for MS with serum concentrations of NFL in the blood donor cohort. Finally, we found that a simple method for correcting for the effect of age on NFL performed as well as Z-scores, which consider the effect of both age and BMI. This was shown when discriminating between patients with MS and control subjects and between MS patients with and without Gd-enhancing MRI lesions., Conclusions: We confirm an association between serum concentrations of NFL, age, and BMI, but we also find that it may often be sufficient to correct for the effect of age alone. The effect of BMI should, however, be considered along with the effect of other confounding factors, including various comorbidities., Competing Interests: Declaration of competing interest Helle Bach Søndergaard, Anna Olsson, Cecilie Ammitzbøll, Lise Wegner Thørner, Erik Sørensen, Marie Krogh Nielsen, Josefine Britze, Signe Modvig, Poul Erik Hyldgaard Jensen, Torben Lykke Sørensen, Annette Bang Oturai have nothing to declare. Stefan Gustavsen has received support for congress participation from Merck and Sanofi. Finn Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

A significant proportion of multiple sclerosis (MS) patients treated with interferon beta-1a (Rebif™) develop anti-drug antibodies (ADA) with a negative impact on treatment efficacy. We hypothesized that high-throughput B-cell receptor (BCR) repertoire analysis could be used to predict and monitor ADA development. To study this we analyzed 228 peripheral blood samples from 68 longitudinally followed patients starting on interferon beta-1a. Our results show that whole blood BCR analysis does not reflect, and does not predict ADA development in MS patients treated with interferon beta-1a. We propose that BCR analysis of phenotypically selected cell subsets or tissues might be more informative., (Copyright © 2022. Published by Elsevier B.V.)

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations., Methods: We analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis., Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR) = 3.55 (95% confidence interval = 2.81-4.48), p = 2.1 × 10 -26 ) and rs28366299 in IFNβ-1b s.c.-treated patients (OR = 3.56 (2.69-4.72), p = 6.6 × 10 -19 ). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR = 2.88 (2.29-3.61), p = 7.4 × 10 -20 ) while DR3-DQ2 was protective (OR = 0.37 (0.27-0.52), p = 3.7 × 10 -09 ). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR = 7.35 (4.33-12.47), p = 1.5 × 10 -13 ). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFNβ-1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC = 0.91 (0.85-0.95), sensitivity = 0.78, and specificity = 0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR = 73.9 (11.8-463.6, p = 4.4 × 10 -6 ) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71-0.92), sensitivity = 0.80, specificity = 0.76, with an OR = 13.8 (3.0-63.3, p = 7.5 × 10 -4 )., Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.

Background: Neurofilament light chain (NFL) and chitinase-3-like-1 (CHI3L1) concentrations in cerebrospinal fluid (CSF) may have prognostic value in clinically isolated syndromes (CIS) and relapsing-remitting multiple sclerosis (RRMS)., Objectives: To compare the prognostic value of CSF concentrations of NFL and CHI3L1 in newly diagnosed CIS and RRMS patients., Methods: NFL and CHI3L1 were measured in CSF in 177 newly diagnosed patients with CIS or RRMS who were followed clinically for a mean of 5.7 years., Results: At baseline CSF concentrations of NFL correlated with CSF concentrations of CHI3L1, relapses in the previous year, time from last relapse, and the Expanded Disability Status Scale (EDSS) score. CSF concentrations of NFL and CHI3L1 were both associated with increased relapse risk during the first 2 years in univariate analyses, but only the CSF concentration of NFL was independently associated with relapse risk in a multivariable analysis. There was no relationship between CSF concentrations of NFL or CHI3L1 and risk of conversion to secondary progressive MS or development of disability., Conclusion: CSF concentrations of NFL are associated with 2-year relapse risk but not with disease progression or clinical worsening in newly diagnosed CIS and RRMS patients. This may be due to confounding by the effect of disease-modifying therapies.

Objective: We evaluated the diagnostic value of cerebrospinal fluid oligoclonal bands in individuals less than 18 years of age., Methods: In a nationwide population-based setting, we retrieved data on 2055 children's oligoclonal band examination, including concordant cerebrospinal fluid biomarkers, during 1994 to 2017. Case ascertainment was by review of medical records and diagnostic codes. We used Fisher's exact test to explore distribution differences of oligoclonal band positivity in acquired demyelinating syndromes (ADS) before and after age 12 years and calculated the sensitivity, specificity, positive predictive value, and negative predictive value of oligoclonal bands to distinguish ADS from the other diagnostic groups., Results: Median age at oligoclonal band examination was 15.2 years (range = 1.8 to 18.0), and 10% had presence of cerebrospinal fluid oligoclonal bands. Oligoclonal band positivity was the highest in ADS (52%), but it was age dependent: 21% in children with ADS before age 12 years and 68% in children aged 12 through 17 years (P < 0.0001) owing to the higher incidence of multiple sclerosis in the latter. Cerebrospinal fluid oligoclonal bands were not predictive of ADS before age 12 years compared with the other diagnostic groups. However, cerebrospinal fluid oligoclonal bands in children aged 12 through 17 years were highly predictive of ADS compared with central nervous system infections and non-ADS immune-mediated central nervous system diseases (positive predictive value: 0.89; 95% confidence interval = 0.82 to 0.94; P < 0.0001), but negative oligoclonal bands were not discriminatory (negative predictive value: P = 0.17)., Conclusions: In a clinical setting, cerebrospinal fluid oligoclonal band examination may be of higher yield in children aged 12 through 17 years if there is clinical suspicion of multiple sclerosis, and in such circumstances a positive test supports a diagnosis of multiple sclerosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The incidence of pediatric neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease have not been reported previously. Our aim was to estimate the incidence of pediatric NMOSD and the occurrence of anti-MOG antibody-associated disease in Denmark during 2008-18, and to evaluate the diagnostic usefulness of antibodies against MOG and aquaporin-4 (AQP4) in children <18 years., Methods: We undertook a nationwide, population-based, multicenter cohort study using data from the Danish National Patient Register, the Danish Multiple Sclerosis Registry, and laboratories providing anti-AQP4 and anti-MOG antibody analyses. Diagnoses were confirmed by review of the medical records, including blinded MRI review in most children with acute disseminated encephalomyelitis (ADEM)., Results: In children with acquired demyelinating syndromes, anti-AQP4 antibodies were detected in 4% and anti-MOG antibodies in 18%, including in the two children with ADEM who relapsed. We identified four children with NMOSD, equivalent to an incidence of 0.031/100,000 (95% confidence interval = 0.011‒0.082). In anti-MOG antibody-positive children, 32% relapsed during follow-up., Conclusions: Pediatric NMOSD and MOG antibody-associated disease are rare, but one-third of anti-MOG-positive children relapsed. In pediatric ADEM, only anti-MOG antibody-positive children relapsed, but the overall risk of relapse after pediatric ADEM was low., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) can be found in different immune-mediated inflammatory CNS disorders. The full range of clinical manifestations may not have been fully discovered yet., Methods: In a cross-sectional study 184 adults (age ≥ 16) were tested for anti-MOG antibody (Ab) with a cell-based assay. To define the relevant target population for anti-MOG antibody testing in a neurology clinic, we divided the entire study population based on the presenting symptoms and classified cases followed for multiple sclerosis (MS) according to the clinical features and response to disease-modifying therapy., Results: We identified eight (4.4%) MOG-Ab positive cases in the whole cohort. All eight cases had first manifestations suggestive of neuromyelitis optica spectrum disorder (NMOSD), but had highly variable disease courses and responses to therapy. This included a patient with chronic relapsing inflammatory optic neuropathy (CRION) responding only to therapy with infliximab. Four (3%) out of 134 cases followed for MS who tested positive for anti-MOG Ab showed atypical features and had poor response to therapy., Conclusion: A broad range of clinical and radiological features of anti-MOG associated disorder was observed in a single centre. MOG-Ab testing should be considered in patients with an NMOSD phenotype and in MS patients presenting atypical features. The potential use of infliximab therapy for MOG-Ab disease should be further investigated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Although immunosuppressants in the treatment of myasthenia have been available for several decades, population-based studies describing drug utilization in myasthenia patients are scarce. We aimed in this study to describe the treatment of myasthenia in Denmark in more recent years with emphasis on use of oral immunosuppressant agents. We identified a nationwide cohort of incident myasthenia patients in Denmark from 1996 to 2013 and tracked their use of drugs over the entire period using data from nationwide registers. Patients with myasthenia were classified according to utilization of specific immunosuppressants (e.g. prednisolone) as 'never user' or 'ever user'. We used Kaplan-Meier (K-M) and proportion of patients covered (PPC) curves to describe treatment onset and termination. We identified 928 patients (52% female) with incident myasthenia in the study period. Overall, 638 (69%) were treated with prednisolone and 506 (55%) with azathioprine. Treatment with prednisolone and azathioprine within 2 years of myasthenia diagnosis was initiated in 462 (56%) and 366 (45%). Only one of four myasthenia patients (n = 231) did not receive oral immunosuppressive treatment at any time in the study period. Prednisolone was stopped in most patients, whereas treatment with azathioprine was often continued throughout follow-up. In conclusion, we found that treatment of myasthenia in Denmark in recent years corresponded well to the expected clinical course of myasthenia and that most patients underwent long-term immunosuppression., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Chitinase 3-like 1 (CHI3L1), neurofilament light chain (NFL) and oligoclonal bands (OCB) in cerebrospinal fluid are associated with central nervous system demyelination in adults. CHI3L1 and OCB are markers of central nervous system inflammation, whereas NFL is a marker of white-matter axonal injury. The aim was to examine whether CHI3L1 and NFL in cerebrospinal fluid are associated with acquired demyelinating syndromes at disease onset in a pediatric population., Methods: Children (<18 years) referred to hospital for possible neuroinflammatory disease were retrospectively included from 2010 to 2016. Case ascertainment was by review of medical records. NFL and CHI3L1 were measured by enzyme-linked immunosorbent assays. Endpoints were differences in concentrations of cerebrospinal fluid NFL and CHI3L1., Results: We included 193 children who all underwent cerebrospinal fluid OCB examination as part of their diagnostic work-up and classified these children into 5 groups: acquired demyelinating syndromes (n = 33), normal diagnostic work-up (n = 36), inflammatory neurological disease (n = 50), other neurological disease (n = 55), and systemic inflammatory diseases (n = 19). NFL and CHI3L1 in cerebrospinal fluid differed significantly between the five groups (p = 0.0001). CHI3L1 was significantly higher in acquired demyelinating syndromes than in all other groups, and NFL was significantly higher in acquired demyelinating syndromes than in the other groups except systemic inflammatory disease. Children with acute disseminated encephalomyelitis had significantly higher concentrations of CHI3L1 than did children with multiple sclerosis., Conclusion: We provide class II evidence that CHI3L1 and NFL are associated with pediatric acquired demyelinating syndromes. CHI3L1 may help distinguishing between acute disseminated encephalomyelitis and multiple sclerosis, but this needs further confirmation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS; however, up to 30% of IFN-β-treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration.