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Objective: To estimate risks for all-cause mortality and for severe COVID-19 in multiple sclerosis patients and across relapsing-remitting multiple sclerosis patients exposed to disease-modifying therapies. Methods: We conducted a Swedish nationwide population-based multi-register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age-, sex-, and region-matched to five population-based controls (n = 86,176 in March 2020) during March 2020-June 2021. We compared annual all-cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID-19 in relation to disease-modifying therapy use, using Cox regression. Results: Absolute all-cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population-based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID-19 remained in line with those for all-cause hospitalization, intensive care admission, and mortality. Among relapsing-remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID-19 remained in the demographics-, socioeconomic status-, comorbidity-, and multiple sclerosis severity-adjusted model. Interpretation: Risks of severe COVID-19-related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non-COVID-19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre-pandemic years. The risk conveyed by disease-modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders. [ABSTRACT FROM AUTHOR]

Background and purpose: High levels of 25‐hydroxyvitamin D3 (25[OH]D3) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D3 is regulated by its main plasma carrier, vitamin D‐binding protein (DBP). Free 25(OH)D3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D3 and DBP as risk factors for MS. Methods: A nested case–control study was performed with presymptomatic serum samples identified through cross‐linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D3 was approximated as free vitamin D3 index: (25[OH]D3/DBP) × 103. MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs). Results: Serum samples from 660 pairs of matched cases and controls were included. At <20 years of age, high levels of free vitamin D3 index were associated with a lower risk of MS (highest vs. lowest quintile: OR = 0.37, 95% CI = 0.15–0.91, p for trend across quintiles = 0.04). At age 30–39 years, high levels of DBP were associated with a lower MS risk (highest vs. lowest quintile: OR = 0.36, 95% CI = 0.15–0.85, p for trend = 0.02). Conclusions: These findings support the hypothesis that high levels of free 25(OH)D3 at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology. The association of free vitamin D3 index, vitamin D‐binding protein, and the risk of developing multiple sclerosis was assessed in a case–control study of presymptomatically collected samples. High free vitamin D3 index before the age of 20 years was associated with a lower risk of developing multiple sclerosis later in life. High levels of vitamin D binding protein after the age of 30 years were associated with a lower risk of developing multiple sclerosis. [ABSTRACT FROM AUTHOR]

Axonal loss is the main cause of irreversible disability in multiple sclerosis (MS). Serum neurofilament light (sNfL) is a biomarker of axonal disintegration. In this nested case–control study, blood samples from 519 presymptomatic persons (age range 4–39 years) who later received an MS diagnosis showed higher sNfL concentrations than 519 matched controls (p < 0.0001), noticeable at least 10 years before clinical MS onset. Mean values for pre‐MS and control groups were 9.6 pg/mL versus 7.4 pg/mL 0–5 years before onset, and 6.4 pg/mL versus 5.8 pg/mL 5–10 years before onset. These results support that axonal injury occurs early in MS pathogenesis. [ABSTRACT FROM AUTHOR]

Background and purpose: Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV‐6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods: A nested case–control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV‐6A was determined using a bead‐based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV‐6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results: Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56–0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV‐6A (AP 0.34, 95% CI 0.06–0.61) and EBV antigen EBNA‐1 (amino acid 385–420) at age 20–39 years (AP 0.37, 95% CI 0.09–0.65). Conclusions: Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV‐6A seropositivity. [ABSTRACT FROM AUTHOR]

Background. In patients with multiple sclerosis (MS), there is a decline in muscle strength and physical capacity due to demyelination and axonal loss in the central nervous system. In patients with advanced MS or in a later stage of the disease, also respiratory impairment may occur. The degree of pulmonary dysfunction in the earlier stages of MS has not been thoroughly described. Therefore, the primary aims of this study are to describe pulmonary function and respiratory muscle strength in patients with a moderate disease course and to identify associations between respiratory muscle strength and functional capacity. Methods. A sample of 48 patients with a diagnosis of MS and mean age 56 ± 11 years was studied using a descriptive cross-sectional design. The patients had a disease duration of 24 ± 11 years and a median Expanded Disability Status Scale (EDSS) score of 4.5 (interquartile range 4.0-6.5). Pulmonary function assessed by spirometry, respiratory muscle strength, peak cough flow and peripheral oxygen saturation, subjective breathing and coughing ability, and physical capacity measured using the 6MWT were evaluated. Results. The patients had normal pulmonary function with no significant abnormalities in dynamic spirometry (vital capacity 103 ± 16 % predicted, forced expiratory volume in 1 second 95 ± 15 % predicted). Peak expiratory flow rate 89 ± 17 % predicted was in the lower limit of normal. Respiratory muscle strength, determined by maximal inspiratory (MIP) and expiratory (MEP) static pressures, was normal but with large differences between individuals. MIP ranged from 26 to 143 cmH2O (98 ± 31 % predicted); the MEP values ranged from 43 to 166 cmH2O (104 ± 29 % predicted), with two patients having values below the lower limit of normal. Significant positive associations between MIP as well as MEP were found in several pulmonary function variables. A significant negative association was found between EDSS score and MEP (r = − 0.312 , p = 0.031). Mean peak cough flow was 389 ± 70 L/min, which is comparable with the values reported for healthy adults. The patients did not experience a severely decreased ability to take deep breaths or cough. There was a moderate correlation between MEP and physical capacity, as assessed by the 6MWT (r = 0.399 , p = 0.010) and between peak expiratory flow (PEF) and the 6MWT (r = 0.311 , p = 0.048). Conclusion. Respiratory muscle strength, pulmonary function assessed by spirometry, and peak cough flow were normal in patients with mild to moderate MS; however, there were large individual differences demonstrating low respiratory muscle strength in some patients. Significant associations between MEP and functional capacity and between MEP and disease severity were found, indicating that patients with impaired respiratory muscle strength have lower functional capacity and more severe disease. [ABSTRACT FROM AUTHOR]

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing–remitting multiple sclerosis (RRMS). Methods: In this nested case–control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z -scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z -score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1–1.9) and in all men (OR = 1.4, 95% CI = 1.0–2.0). In contrast, for women aged 30–39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54–1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals. [ABSTRACT FROM AUTHOR]

Background: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited. Objective: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden. Methods: We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF (n = 641) or interferons/glatiramer acetate (IFN/GA; n = 555) as the initial therapy, or DMF (n = 703) or fingolimod (FGL; n = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016. Results: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37–0.58, p < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08–2.09, p < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03–0.06 vs 0.10, CI: 0.07–0.13; p < 0.05), but not FGL (0.03, CI: 0.02–0.05 vs 0.02, CI: 0.01–0.04; p = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy (p < 0.05 and p = 0.20, respectively). Conclusion: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes. [ABSTRACT FROM AUTHOR]

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer.Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84).Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. ANN NEUROL 2020;87:688-699. [ABSTRACT FROM AUTHOR]

The digital twin is a rather new industrial control and automation systems concept. While the approach so far has gained interest mainly due to capabilities to make advanced simulations and optimizations, recently the possibilities for enhanced security have got attention within the research community. In this article, we discuss how a digital twin replication model and corresponding security architecture can be used to allow data sharing and control of security-critical processes. We identify design-driving security requirements for digital twin based data sharing and control. We show that the proposed state synchronization design meets the expected digital twin synchronization requirements and give a high-level design and evaluation of other security components of the architecture. We also make performance evaluations of a proof of concept for protected software upgrade using the proposed digital twin design. Our new security framework provides a foundation for future research work in this promising new area. [ABSTRACT FROM AUTHOR]

Byline: Ylva Nilsson, Lars Eriksson, Martin Gunnarsson Fuel optimal control of a variable compression engine is studied and it is shown that a crucial component is the model for the engine torque. A model for the produced work that captures the important effects of ignition and compression ratio is proposed and investigated. The main task for the model is to be a mean for determining the fuel optimal control signals, for each requested engine torque and speed. The contribution is a model suitable for finding this optimal combination. This model consists of well-known components, and the novelty lies in the compilation and validation of the control-oriented efficiency model for a variable compression engine. The modelling and validation is performed on a multicylinder variable compression engine using two fuels with different octane rating. Despite the models simplicity, it describes the indicated work with good accuracy, and suits its purpose of finding optimal control signals. In the evaluation, it is shown that a fuel optimal controller based on the proposed model captures the optimal IMEP to within 1.2%. This corresponds to a loss in engine efficiency that is in the range of 0.5% units or less.

Background: High 25-hydroxyvitamin D concentrations have been associated with a reduced risk of multiple sclerosis, with indications of a stronger effect among young individuals. Objective: Investigate the 25-hydroxyvitamin D association with multiple sclerosis and test if this association is age dependent. Methods: Prospectively drawn blood samples from individuals later developing relapsing-remitting multiple sclerosis and controls matched for biobank, sex, age and date of sampling, were analysed with liquid chromatography tandem mass spectrometry. Results: High levels of 25-hydroxyvitamin D (top quintile) were associated with a reduced multiple sclerosis risk (odds ratio 0.68, 95% confidence interval 0.50-0.93). Conclusion: These findings further support a role for vitamin D in MS aetiology. [ABSTRACT FROM AUTHOR]

Objective: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease‐modifying treatments in multiple sclerosis. Materials and methods: Seventy‐five patients with clinically stable relapsing‐remitting multiple sclerosis (RRMS) participating in the clinical trial "Switch‐To RItuXimab in MS" (STRIX‐MS) were switched to rituximab from first‐line injectable therapy and then followed up for 2 years. Thirty patients from the extension trial (STRIX‐MS extension), accepting repeated lumbar punctures, were followed up for an additional 3 years. Plasma and CSF samples were collected yearly during the follow‐up. NFL concentration in plasma was measured by an in‐house NF‐light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA. Results: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF‐NFL was 25% during the first year of follow‐up (from a mean of 471 [SD 393] to 354 [SD 174] pg/mL; P = 0.006) and was statistically significant. The corresponding reduction in plasma NFL was 18% (from 9.73 [SD 7.04] to 7.94 [SD 3.10] pg/mL; P = 0.055) and did not reach statistical significance. Conclusion: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimize the use in clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC). Method: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis. Results: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab. Conclusion: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS. [ABSTRACT FROM AUTHOR]

Background: Imbalance leading to falls is common in people with multiple sclerosis (PwMS). Objective: To evaluate the effects of a balance group exercise programme (CoDuSe) on balance and walking in PwMS (Expanded Disability Status Scale, 4.0–7.5). Methods: A multi-centre, randomized, controlled single-blinded pilot study with random allocation to early or late start of exercise, with the latter group serving as control group for the physical function measures. In total, 14 supervised 60-minute exercise sessions were delivered over 7 weeks. Pretest–posttest analyses were conducted for self-reported near falls and falls in the group starting late. Primary outcome was Berg Balance Scale (BBS). A total of 51 participants were initially enrolled; three were lost to follow-up. Results: Post-intervention, the exercise group showed statistically significant improvement (p = 0.015) in BBS and borderline significant improvement in MS Walking Scale (p = 0.051), both with large effect sizes (3.66; −2.89). No other significant differences were found between groups. In the group starting late, numbers of falls and near falls were statistically significantly reduced after exercise compared to before (p < 0.001; p < 0.004). Conclusion: This pilot study suggests that the CoDuSe exercise improved balance and reduced perceived walking limitations, compared to no exercise. The intervention reduced falls and near falls frequency. [ABSTRACT FROM AUTHOR]

Objective: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab. Method: A total of 75 patients with clinically stable relapsing–remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period. Results: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1–7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment (p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression. Conclusion: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy. [ABSTRACT FROM AUTHOR]

Introduction Breathing exercises with positive expiratory pressure are often recommended to patients with advanced neurological deficits, but the potential benefit in multiple sclerosis ( MS) patients with mild and moderate symptoms has not yet been investigated in randomized controlled trials. Objectives To study the effects of 2 months of home-based breathing exercises for patients with mild to moderate MS on respiratory muscle strength, lung function, and subjective breathing and health status outcomes. Methods Forty-eight patients with MS according to the revised McDonald criteria were enrolled in a randomized controlled trial. Patients performing breathing exercises ( n = 23) were compared with a control group ( n = 25) performing no breathing exercises. The breathing exercises were performed with a positive expiratory pressure device (10-15 cm H2O) and consisted of 30 slow deep breaths performed twice a day for 2 months. Respiratory muscle strength (maximal inspiratory and expiratory pressure at the mouth), spirometry, oxygenation, thoracic excursion, subjective perceptions of breathing and self-reported health status were evaluated before and after the intervention period. Results Following the intervention, there was a significant difference between the breathing group and the control group regarding the relative change in lung function, favoring the breathing group (vital capacity: P < 0.043; forced vital capacity: P < 0.025). There were no other significant differences between the groups. Conclusion Breathing exercises may be beneficial in patients with mild to moderate stages of MS. However, the clinical significance needs to be clarified, and it remains to be seen whether a sustainable effect in delaying the development of respiratory dysfunction in MS can be obtained. [ABSTRACT FROM AUTHOR]

Background and Purpose People with multiple sclerosis (PwMS) experience falls, usually when walking and transferring. The aim was to investigate if walking distance and patient overestimate of walking distance are predictors of falls in PwMS. Methods A prospective study was conducted, with a single test occasion followed by prospective registration of falls for 3 months. All PwMS in Region Örebro County with a previously registered Expanded Disability Status Scale score between 3.0 and 7.0 in the Swedish MS Registry were invited to participate ( n = 149). Altogether, data from 49 PwMS being relapse free for at least 3 months and with a confirmed Expanded Disability Status Scale between 1.5 and 7.0 upon study entry were analysed. Results Twenty-two PwMS (45%) fell during the study period, providing information of 66 falls. Walking distance or overestimate of one's walking distance, as compared with test results, did not predict falls in this MS sample. Discussion Walking and standing activities are associated with numerous falls in PwMS. Our data do not clearly support routine measurements of walking distance in assessing individual fall risk. © 2015 The Authors. Physiotherapy Research International published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the effect on cerebrospinal fluid (CSF) biomarkers of axonal damage, astrogliosis, and B-cell regulation following immunosuppressive therapy with mitoxantrone or rituximab in progressive multiple sclerosis (PMS). The study included 35 patients with MS, five with primary progressive (PP) MS and 30 with SPMS. The study concluded that some patients with active PMS may have plausible beneficial effects from potent immunosuppressive regimens.

The human α2-macroglobulin gene is approximately 48 kb in size and consists of 36 exons, which encode the 180 kDa subunit of this large tetrameric protein. In this investigation, a procedure of sequencing human α2-macroglobulin mRNA, using mRNA from lipopolysaccharide-stimulated peripheral blood mononuclear cells as template in RT-PCR, was developed. Incubation of peripheral blood mononuclear cell populations with lipopolysaccharide induced α2-macroglobulin mRNA expression reaching levels detectable by RT-PCR. Extracted human α2-macroglobulin mRNA was used to determine the nucleotide sequence of a 500 bp DNA segment encoding the most C-terminal, receptor-binding part of the protein, using α2-macroglobulin specific primers. The sequence obtained matched the earlier published sequence of human α2-macroglobulin , except for three point mutations, i.e., cytosine for guanine, cytosine for thymidine and thymidine for adenine substitutions at positions 4369, 4423, and 4511, respectively. None of these alterations, however, affect the amino acid sequence of the protein. In conclusion, we demonstrate a new, improved, approach to sequence human α2-macroglobulin mRNA by overexpressing the protein in peripheral blood mononuclear cells. This procedure may be useful in the search for mutations in α2-macroglobulin, examining its role in the pathogenesis of human diseases. [Copyright &y& Elsevier]

Human α2-macroglobulin displays extensive conformational changes when induced to transform into new quaternary structures, which are eliminated from the systemic circulation by receptor-mediated endocytosis. One major region involved in these conformational changes is located in a segment of 30 amino acids from Glu1314 to Ser1343 (-Glu-Glu-Phe-Pro-Phe-Ala-Leu-Gly-Val-Gln-Thr-Leu-Pro-Gln-Thr-Cys-Asp-Glu-Pro-Lys-Ala-His-Thr-Ser-Phe-Gln-Ile-Ser-Leu-Ser-), which we term the ‘switch region’ of α2-macroglobulin, as deduced by immunochemical techniques. Monoclonal antibodies were generated using either native, methylamine-treated or the 18-kDa C-terminal receptor-binding fragment as the immunogen. From an extensive number of obtained hybridomas, 11 mAbs were selected because of their capacity to bind to the C-terminal fragment. Irrespective of the original configuration of the antigen used for immunization, seven of the antibodies were shown to be reactive with a set of overlapping epitopes, closely positioned within the ‘switch region’, as confirmed by the use of synthetic peptides covering the entire C-terminal fragment. The specificities of the seven individual antibodies, as determined by ELISA and BIAcore technologies, revealed a pronounced conformational pleomorphism in the ‘switch region’. The results indicate that the ‘switch region’ may be involved in the exposure of the receptor recognition site and can be used as an indicator region for different conformational states of α2-macroglobulin. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation To assess comparative effectiveness, safety, and tolerability of off‐label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS).A Swedish cohort study of persons with relapsing–remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low‐dose rituximab was compared with MS‐approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale‐29 (MSIS‐29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention‐to‐treat approach and were adjusted for demographics, MS features, and health characteristics.We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS‐approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS‐29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease‐modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital‐treated infections was higher with rituximab after a therapy switch, but not as a first therapy.This population‐based real‐world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS‐approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start., Methods: Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories., Results: We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories., Conclusions: In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start., Competing Interests: Competing interests: AF-H has received unrestricted funding from Biogen Idec, Pfizer, Orion Pharma and Celltrion, speaking honoraria from Merck and consulting fee from Roche and AstraZeneca. KF has received honoraria for serving on advisory boards for Biogen and Merck KGaA, and speaker’s fees from Biogen, Novartis and Merck KGaA. JH has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis and Sandoz, and speaker’s fees from Biogen, Novartis, Merck, KGaA, Teva and Sanofi-Genzyme, and he has served as PI for projects, or received unrestricted research support from, Biogen, Celgene, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. AML-G receives grant support and awards from the Patient Centered Outcomes Research Institute and the National MS Society; she currently serves as a voting member on the California Technology Assessment Forum, a core program of the Institute for Clinical and Economic Review (ICER); she has received sponsored and reimbursed travel from ICER and the National Institutes of Health. PN has received travel support from Bayer Schering Pharma, Merck Serono, Biogen and Genzyme a Sanofi Company, honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis and Roche, lectures for Biogen and has received unrestricted grants from Biogen. JL has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, BMS, Celgene, Janssen and Sanofi Genzyme; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis, Merck, Roche, Sanofi Genzyme and BMS; serves on the editorial board of the Acta Neurologica Scandinavica; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator-initiated study. JS has received consultancy fees paid to the institution by Mabion S.A. FP has received research grants from Janssen, Merck KGaA and UCB, and fees for serving as Chair of DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of witness statement for Novartis. TO has received compensation for advisory boards/lectures and unrestricted MS research grants from Biogen, Merck, Novartis and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: C-reactive protein (CRP) is a marker of systemic inflammation. Increased levels of CRP in young persons have been suggested to decrease the risk of multiple sclerosis (MS)., Objectives: To assess CRP as a risk factor for MS., Methods: Levels of CRP were measured with a high-sensitive immunoassay in biobank samples from 837 individuals who later developed MS and 984 matched controls. The risk of developing MS was analysed by conditional logistic regression on z -scored CRP values., Results: Levels of CRP were not associated with MS risk., Conclusions: We found no association between CRP levels and risk of MS development., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: MB has received a speaker fee from Biogen. JS has received material research support from Synapsys and Interacoustics, and institutional consultancy fees from Mabion S.A. VG, PSt, AL, LAM, OA, DJ, MG, MV, JH and PSu report no disclosures., (© The Author(s), 2022.)

Background and Purpose: High levels of 25-hydroxyvitamin D 3 (25[OH]D 3 ) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D 3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D 3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D 3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D 3 and DBP as risk factors for MS., Methods: A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D 3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D 3 was approximated as free vitamin D 3 index: (25[OH]D 3 /DBP) × 10 3 . MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs)., Results: Serum samples from 660 pairs of matched cases and controls were included. At <20 years of age, high levels of free vitamin D 3 index were associated with a lower risk of MS (highest vs. lowest quintile: OR = 0.37, 95% CI = 0.15-0.91, p for trend across quintiles = 0.04). At age 30-39 years, high levels of DBP were associated with a lower MS risk (highest vs. lowest quintile: OR = 0.36, 95% CI = 0.15-0.85, p for trend = 0.02)., Conclusions: These findings support the hypothesis that high levels of free 25(OH)D 3 at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection., Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS)., Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z -scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs)., Results: A 1-unit leptin z -score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels., Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.

Background: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited., Objective: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden., Methods: We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF ( n  = 641) or interferons/glatiramer acetate (IFN/GA; n  = 555) as the initial therapy, or DMF ( n  = 703) or fingolimod (FGL; n  = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016., Results: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58, p  < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09, p  < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13; p  < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04; p  = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy ( p  < 0.05 and p  = 0.20, respectively)., Conclusion: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date., Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions., Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC., Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex., Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept., Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses., Results: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes., Conclusions and Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

Background: Imbalance leading to falls is common in people with multiple sclerosis (PwMS)., Objective: To evaluate the effects of a balance group exercise programme (CoDuSe) on balance and walking in PwMS (Expanded Disability Status Scale, 4.0-7.5)., Methods: A multi-centre, randomized, controlled single-blinded pilot study with random allocation to early or late start of exercise, with the latter group serving as control group for the physical function measures. In total, 14 supervised 60-minute exercise sessions were delivered over 7 weeks. Pretest-posttest analyses were conducted for self-reported near falls and falls in the group starting late. Primary outcome was Berg Balance Scale (BBS). A total of 51 participants were initially enrolled; three were lost to follow-up., Results: Post-intervention, the exercise group showed statistically significant improvement ( p = 0.015) in BBS and borderline significant improvement in MS Walking Scale ( p = 0.051), both with large effect sizes (3.66; -2.89). No other significant differences were found between groups. In the group starting late, numbers of falls and near falls were statistically significantly reduced after exercise compared to before ( p < 0.001; p < 0.004)., Conclusion: This pilot study suggests that the CoDuSe exercise improved balance and reduced perceived walking limitations, compared to no exercise. The intervention reduced falls and near falls frequency.

Objective: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab., Method: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period., Results: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment ( p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression., Conclusion: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.

Background: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression., Objective: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13)., Methods: CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays., Results: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline., Conclusions: Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.