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BACKGROUND: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens. METHODS: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury. RESULTS: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001).With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026). CONCLUSIONS: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS., DJ was supported by grants from the Swedish State under the ALF agreement between the Swedish Government and County Councils (ALFGBG- 772071), as well as by grants from the Research Foundation of the Gothenburg MS Society, Bjornsson Research Foundation, Gothenburg, Sweden, and The Gothenburg Society of Medicine. VG was supported by the Visare Norr Fund, Northern County Councils' Regional Federation, the Research and Development Unit, Region Jaemtland Haerjedalen, the Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden, Oskarfonden, and NEURO Sweden. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018- 02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG- 71320), the Alzheimer Drug Discovery Foundation-USA (#201809- 2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF- 21- 831376- C, #ADSF- 21- 831381- C and #ADSF- 21- 831377- C), the Olav Thon Foundation, the Erling- Persson Family Foundation, Stiftelsen foer Gamla Tjaenarinnor, Hjaernfonden-Sweden (#FO2019- 0228), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No. 860197 (MIRIADE), the European Union Joint Programme-Neurodegenerative Disease Research (JPND2021- 00694), and the UK Dementia Research Institute at University College London (UKDRI- 1003). KB is supported by the Swedish Research Council (#2017- 00915), the Alzheimer Drug Discovery Foundation-USA (#RDAPB- 201809- 2016615), the Swedish Alzheimer Foundation (#AF- 742881), Hjarnfonden, Sweden (#FO2017- 0243), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF agreement (#ALFGBG- 715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019- 466- 236), the US National Institutes of Health (grant EBV before MS- induced neuronal damage #1R01AG068398- 01), and the Alzh

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., Funding Agencies|Patient -Centered Outcomes Research Institute (PCORI) Award [MS- 1511-33196]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; Swedish Research Council [2021-01418]; Swedish Brain foundation

OBJECTIVE: To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS). METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

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.

Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing multiple sclerosis (RMS). Post-marketing surveillance is important to evaluate the long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon launch of NTZ in Sweden (Aug 2006). Objectives/Aims: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting. Methods: Adverse events (AEs), Serious AEs (SAEs), John Cunningham virus status (JCV) and clinical effectiveness measures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Scale (MSIS-29) data were collected from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test. Results: A total of 4011 NTZ patients were included in the IMSE 1 study from August 2006 until March 2023 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 52 months) and 249 had been treated for at least 132 months. Of the 132-month cohort, 75% were female, the mean age was 36 years, 88% had RRMS, and the mean treatment duration was 160 months. The majority were treated with interferons and glatiramer acetate prior to NTZ (68%), where 30% (74/249) discontinued NTZ treatment; 43% (32/74) due to being JCV positive (JCV+), with a mean JCV index of 1.1±0.9 (n=66). Annualized relapse rates dropped from 0.40 in the year before treatment start to 0.04 during treatment, where 68% were entirely free of relapses and 21% had only 1 relapse during the entire treatment period (17% missing data). All clinical effectiveness measures, except EDSS showed statistically significant improvement between baseline and 132 months (p<0.05).From the entire IMSE1 cohort (N=4011), 132 SAEs have been reported to the Swedish MPA, including 9 cases (2 fatal) of progressive mu

Introduction: Cladribine is a deoxyadenosine analogue prodrug that induces immune reconstitution by selectively targeting B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. CLADCOMS (CLADribine tablets long-term Control Of MS) is a post-marketing investigator driven study. Here we report two year prospectively obtained data on the first 100 patients included in the study until April 2021. Objectives/Aims: To investigate number of patients free of disease activity until April 2023 among the first 100 RMS patients included. Methods: CLADCOMS includes patients with RMS from eight academic neurology clinics of Sweden starting Cladribine treatment after 23rd of March 2018. Data was prospectively registered in the Swedish Neuroregistry using highly structured yearly follow-up routines. Descriptive data on relapses, MRI activity, and Patient Reported Outcome Measures from the first 100 patient included in the study were obtained from the registry. Results: By April 2023, 206 patients were included in the CLADCOMS study. In April 2021 the first 100 patients had entered the study including 30% treatment naïve, 26% switched from natalizumab, 10% from dimethyl fumarate and 7% from rituximab. After the first two years after treatment initiation 87% were relapse free. MRI-activity during the first two years after treatment initiation will be analyzed.Analysis of CD19+ B-cells counts over time showed a significant drop from baseline before first dose (0.38x109/L ±0.68) to year one (0.15x109/L ±0.12) and year two (0.13x109/L ±0.09). The proportion of memory B-cells dropped from 11.8% ±9.33% at baseline to 3.0% ±2.8% after the first year and to 2.6% ±2.4% after the second year of treatment. The proportions of naïve B-cells raised over time from 61% ±18.3% at baseli

Introduction: Multiple sclerosis (MS) and presymptomatic axonal injury appears to develop only after an Epstein-Barr virus (EBV) infection. Anoctamin2 (ANO2), a chloride channel expressed in glial cells and neurons, was identified as a possible MS autoantigen. We here examine serum neurofilament (sNfL), a comprehensive EBV seroreactivity and antibodies against ANO2 in pre-symptomatic MS. Objectives/Aims: To study whether the appearance of EBV seroreactivity in the pre-symptomatic phase of MS precedes cumulating MS-induced neuroaxonal damage and whether it is associated with an incipient autoreactivity against a reported MS autoantigen (ANO2). Methods: We performed a case-control study with presymptomatic serum samples identified through cross-linkage of the Swedish MS register and Swedish biobanks. We assayed serum antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18 (VCAp18), EBV glycoprotein 350 (gp350), anoctamin 2 (ANO2), and serum neurofilament light (sNfL) in 669 pre-MS cases and matched controls. Results: EBNA1 seroreactivity increased in the pre-MS group from 20–15 years before MS onset, followed by gp350 seroreactivity (p=0.001–0.002, 15–10 years before onset). This appeared before the elevation of sNfL in EBV seropositive pre-MS cases (p=8⋅10-5, 10–5 years before onset). No significant sNfL increase was observed in the EBV seronegative group (p=0.95). Pre-MS cases with the highest sNfL levels cumulated in the EBV seropositive group (p=0.038). ANO2 seropositivity appeared virtually only in the EBNA1 seropositive group, in 16.7 % of EBNA1 seropositive pre-MS samples and in 10.0 % of corresponding controls (p=0.001). Combined EBNA1 and ANO2 seropositivity showed a higher association with subsequent MS than EBNA1 independent of ANO2 (p=0.002–0.028). In the EBNA1 seropositive stratum, ANO2 seropositivity was associated with 26% higher sNfL. Conclusion: In presymptomatic MS an antibody response against EBV, associated with ANO2 autoimmunity

Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing multiple sclerosis (RMS) originally launched as an intravenous (IV) therapy in Sweden in August 2006. A new subcutaneous (SC) administration method for NTZ was launched in April 2021. Objectives/Aims: To investigate how the administration of NTZ has evolved in Sweden since the introduction of SC NTZ in 2021, and to explore potential differences in treatment discontinuation patterns between the SC or IV administration modalities. Methods: Descriptive data will be presented from the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) study cohort. Data is collected from the nationwide Swedish Neuro Registry (NeuroReg). The drug survival is assessed using the Kaplan Meier one-year drug survival curve and Breslow Wilcoxon test of equality distribution. Results: A total of 4011 NTZ participants were included in the IMSE 1 study from August 2006 until March 2023 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 49 months), including 295 since July 2021, of which 264 had available data on method of administration. In this cohort, 109 (41%) initiated IV NTZ, of which 16 (15%) later switched to SC administration, and 155 (59%) initiated treatment with SC NTZ. The distribution between administration methods altered over time, where IV was more common in Q3 2021 (70%) and then successively dropped to 31% in Q1 2023.The mean age at treatment start was 36 years (35 for IV and 37 for SC) and 69% (70% IV, 68% SC) were female.Out of 264 participants, 73 (28%) later discontinued treatment. Discontinuation was numerically more common in the IV group compared with the SC group, but differences in the one-year drug survival rate did not reach statistical significance.The most common reason for discontinuation in the IV group was “other reason; unspecified” followed by positive JC-virus serology (JCV+). In the SC group JCV+ was the most common reason for dis

Background: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens. Methods: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury. Results: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001). With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026). Conclusions: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.

During the last decades, more and more devices have been connected to the Internet.Today, there are more devices connected to the Internet than humans.An increasingly more common type of devices are cyber-physical devices.A device that interacts with its environment is called a cyber-physical device.Sensors that measure their environment and actuators that alter the physical environment are both cyber-physical devices.Devices connected to the Internet risk being compromised by threat actors such as hackers.Cyber-physical devices have become a preferred target for threat actors since the consequence of an intrusion disrupting or destroying a cyber-physical system can be severe.Cyber attacks against power and energy infrastructure have caused significant disruptions in recent years.Many cyber-physical devices are categorized as constrained devices.A constrained device is characterized by one or more of the following limitations: limited memory, a less powerful CPU, or a limited communication interface.Many constrained devices are also powered by a battery or energy harvesting, which limits the available energy budget.Devices must be efficient to make the most of the limited resources.Mitigating cyber attacks is a complex task, requiring technical and organizational measures.Constrained cyber-physical devices require efficient security mechanisms to avoid overloading the systems limited resources.In this thesis, we present research on efficient security protocols for constrained cyber-physical devices.We have implemented and evaluated two state-of-the-art protocols, OSCORE and Group OSCORE.These protocols allow end-to-end protection of CoAP messages in the presence of untrusted proxies.Next, we have performed a formal protocol verification of WirelessHART, a protocol for communications in an industrial control systems setting.In our work, we present a novel attack against the protocol.We have developed a novel architecture for industrial control systems utilizing the D

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., Funding Agencies|Swedish Government [ALFGBG-772071, ALFGBG-715986]; Swedish County Councils [ALFGBG-772071]; Research Foundation of the Gothenburg MS Society; Bjornsson Research Foundation, Gothenburg, Sweden; Gothenburg Society of Medicine; Swedish Research Council [2018-02532, 2017-00915]; European Research Council [681712]; Swedish State Support for Clinical Research [ALFGBG-720931]; Alzheimer Drug Discovery Foundation (ADDF), USA [201809-2016862, RDAPB-201809-2016615]; AD Strategic Fund; Alzheimers Association [ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C]; Olav Thon Foundation; Erling-Persson Family Foundation; Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden [FO2019-0228]; European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [860197]; European Union Joint Program for Neurodegenerative Disorders [JPND2021-00694, JPND2019-466-236]; UK Dementia Research Institute at UCL; Swedish Alzheimer Foundation [AF-742881]; Hjarnfonden, Sweden [FO2017-0243]; Swedish County Councils, the ALFagreement [ALFGBG-715986]; National Institutes of Health (NIH), USA [1R01AG068398-01]; Alzheimers Association 2021 Zenith Award [ZEN-21-848495]

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.

The Constrained Application Protocol (CoAP) is a major application-layer protocol for the Internet of Things (IoT). The recently standardized security protocol Object Security for Constrained RESTful Environments (OSCORE) efficiently provides end-to-end security of CoAP messages at the application layer, also in the presence of untrusted intermediaries. At the same time, CoAP supports one-to-many communication, targeting use cases such as smart lighting and building automation, firmware update, or emergency broadcast. Securing group communication for CoAP has additional challenges. It can be done using the novel Group Object Security for Constrained RESTful Environments (Group OSCORE) security protocol, which fulfills the same security requirements of OSCORE in group communication environments. While evaluations of OSCORE are available, no studies exist on the performance of Group OSCORE on resource-constrained IoT devices. This article presents the results of our extensive performance evaluation of Group OSCORE over two popular constrained IoT platforms, namely Zolertia Zoul and TI Simplelink. We have implemented Group OSCORE for the Contiki-NG operating system and made our implementation available as open source software. We compared Group OSCORE against unprotected CoAP as well as OSCORE. To the best of our knowledge, this is the first comprehensive and experimental evaluation of Group OSCORE over real constrained IoT devices.

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.

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.

Introduction: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives/Aims: To assess the effectiveness and safety of DMF with focus on patients treated at least 72 months. Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS), Adverse Events (AEs) and Serious AEs (SAEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve. Results: 2565 DMF-treated patients were included between March 2014 and March 2022 with an overall drug survival rate of 38.7% and a mean treatment duration of 37 months. The main reasons for discontinuation were AEs (47%) and lack of effect (30%). 199 AEs were reported of which 63 were serious. For both serious and non-serious AEs reported, gastrointestinal disorders were the most common (19% and 27%, respectively).509 patients had continuous treatment for at least 72 months. This cohort had a mean age of 42 years and a mean treatment duration of 84 months. The majority (51%) had switched from interferon or glatiramer acetate and 24% were treatment naïve.Significant improvements in mean values at 72 months of treatment compared to baseline were noted for MSSS, MSIS-29 Psychological, and EQ-5D (p<0.05). All other tests remained stable after 6 years of treatment. Number of relapses per 1000 patient years were improved from 199.6 before DMF treatment start to 23.0 during treatment with DMF.49 patients (10%) have discontinued DMF treatment in the 72 month cohort with a mean treatment duration of 84 months (range 70-97 months). The

Background: Cladribine is a deoxyadenosine analogue prodrug that selectively induces immune reconstitution by targeting B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. CLADCOMS (CLADribine tablets long-term Control Of MS) is a post-marketing investigator driven study. Here we report one year follow-up data on the first 100 patients included in the study in April 2021. Objective: 1) To investigate for how long a full dose treatment with Cladribine 10 mg tablets (3.5 mg/kg over two years) offers freedom of disease activity in relapsing MS patients.2) To collect complete data on safety and effectiveness with the help of the Swedish Neuroregistry to enable future assessment on effectiveness and safety in comparison with other in Sweden commonly used disease modifying treatments. Methods: CLADCOMS includes patients with relapsing MS from the eight academic clinics starting Cladribine treatment after 23rd of March 2018. Data is collected in the Swedish Neuroregistry using highly structured yearly follow-up routines. Descriptive data on relapses, MRI activity, Patient Reported Outcome Measures and Serious Adverse events (SAEs) from the first 100 patient included in the study are obtained from the registry. Results: Up to April 2022 1XX patients were included in the study. In April 2021 the first 100 patient entered the study. 40% of patients included were treatment naïve, 29% switched from natalizumab and 13% from rituximab. By April 2022, 5 patients experienced a relapse during the treatment initiation and showed MRT activity with contrast enhancing (CEL)lesions more than six months after initiation of treatment, of which 2 patients showed CEL more

Introduction: Epstein-Barr virus (EBV) infection may be a pre-condition for the development of multiple sclerosis (MS). EBV antibodies, predominantly anti-EBNA1, develop in the presymp-tomatic phase of virtually all MS patients. Using material from a serum repository, studies in advance of MS onset indicated that EBV seropositivity preceded the first expression of incipient axonal lesions, serum Neurofilament Light (sNFL) . Objectives: To determine the onset and individual order of appearance of EBV seroreactivity and the serum neuroaxonal injury marker neurofilament light (sNfL) in a wide age spectrum of presymptomatic MS patients. Aims: To characterize the presymptomatic appearance of anti-bodies against an intranuclear (EBNA1) and a surface EBV anti-gen (gp350) and sNfL.Methods: A nested case-control study in 669 pre-symptomati-cally acquired blood samples from persons who later received an MS diagnosis, and from 1:1 matched control persons. Serum lev-els of EBNA1, VCA and gp350 IgG antibodies and sNFL (n=519) were measured in individual presymptomatic samples and expressed as delta scores with matched controls in relation to time until MS onset. Results: Serum levels expressed as delta scores for anti EBV and NfL IgG showed an incipient increase for anti EBNA1 and gp350 from 15-20 years before MS debut. Significant (p=0.001 and p=0.002) from 10-15 years, with consistent delta-scores succes-sively closer to MS onset. These findings contrasted to the level of sNfL which increasingly diverged from matched controls from 5-10 years before the onset of MS. None of the individual sam-ples negative for both EBNA1 and VCA IgG antibodies in the pre-MS group (n = 36) showed any elevation of the sNfL level. Conclusions: In a pre-MS material, the seroreactivity against EBNA1 was followed by VCA and gp350, before increased sNFL appeared, indicating incipient axonal injury. Togeth

Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (Aug 2006). Objectives/Aims: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting. Methods: Adverse events (AEs), Serious AEs (SAEs), John Cunningham virus status (JCV) and clinical effectiveness measures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Scale (MSIS-29) data is collected from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test. Results: A total of 3622 NTZ patients were included in the IMSE 1 study from August 2006 until March 2022 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 49 months) and 186 had been treated for at east 132 months. Of the 132-month cohort, 73% were female, the mean age was 36 years, 88% had RRMS, and the mean treatment duration was 155 months. The majority were treated with interferons and glatiramer acetate prior NTZ (64%). 25% (47/186) discontinued NTZ treatment of which 47% (n=22) discontinued due to JCV positive (JCV+). In total, 30% (55/186) of these patients were JCV+ with a mean JCV index of 1.2±1.0 (2% missing data). Relapses before treatment were reduced from 380/1000 patient years to 43/1000 during treatment, 71% were relapse-free and 18% had 1 relapse during the entire treatment period (15% missing data). Most clinical effectiveness measures, MSSS, MSIS-29 and SDMT showed statistically significant improvement between baseline and 132

Introduction: Cladribine is a deoxyadenosine analogue prodrug that selectively induces immune reconstitution by targeting B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). CladT are included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology”(IMSE). Objectives: To assess the safety and effectiveness of CladT with focus on patients treated at least 12 months. Methods: Data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS), relapses and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using Wilcoxon Signed Rank Test and relapse rates were tested using paired samples T-test. Results: 208 patients were included in the IMSE 10 study since the Swedish market launch in April 2018 with an overall drug survival rate of 94.2%. 12 patients discontinued treatment, of which 1 later restarted. The most common reason for discontinuation was lack of effect (83%). 21 AEs were reported of which 7 were serious. The most common AE reported were infection and infestation (8 reports).139 patients were treated for at least 12 months. 29 % of the patients was treated with CladT as their first MS drug. 19 % were treated with natalizumab and 10 % with dimethyl fumarate prior to CladT. The number of relapses decreased significantly from 249 per 1,000 patient years before treatment start to 73 during treatment. 12 patients in this cohort have experienced a relapse during treatment. Significant improvements in mean values at 12 months of tre

Introduction: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with blunted humoral vaccination responses, but relevance for SARS-CoV-2 infection is unclear. Objectives: To determine SARS-CoV-2 exposure rates and formation of antibody memory among participants of the COMparison Between All immunoTherapies for MS (COMBAT-MS; NCT03193866) and the Immunomodulation and MS Epidemiology (IMSE) studies. Aim: To determine SARS-CoV2 serological response of people living with MS (pwMS). Methods: Using a multiplex bead-based assay we determined SARS-CoV-2 spike and nucleocapsid antibody levels in 3,723 pwMS in paired serum samples (n=7,157) donated prior (

BACKGROUND: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. METHODS: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. RESULTS: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. CONCLUSION: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS inc, Funding agencies:Swedish MS SocietySanofi-Aventis Genzyme Corporation Merck KGaA UCB Pharma SA DMC Parexel Biogen Novartis