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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

Background: A challenge to implementation is management of the adaptation-fidelity dilemma or the balance between adopting an intervention with fidelity while assuring fit when transferred between contexts. A prior meta-analysis found that adapted interventions produce larger effects than novel and adopted interventions. This study attempts to replicate and expand previous findings. Methods: Meta-analysis was used to compare effects across a whole-population of Swedish outcome studies. Main and subcategories are explored. Results: The 523 studies included adapted (22%), adopted (33%), and novel (45%) interventions. The largest effect was found for adapted followed by novel and adopted interventions. Interventions in the mental health setting showed the highest effects, followed by somatic healthcare and social services. Conclusions: These results replicate and expand earlier findings. Results were stable across settings with the exception of social services. Consistent with a growing body of evidence results suggest that context is important when transferring interventions across settings.

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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

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: Baclofen is the first line drug choice for spasticity; a common MS feature influencing function and quality of life. Its prescription and discontinuation patterns among persons with MS (pwMS) are described incompletely. Objective & Aim: To characterize baclofen prescription patterns in a nationwide cohort study of people with prevalent (pMS) and incident (iMS) MS. Method: Data was linked from the Swedish MS register and national health registers for PwMS aged 18-65 years at diagnosis. Baclofen initiation was identified using the Prescription Drug Register excluding prescriptions from 1 July 2005—30 June 2006 (1st year of the register) and before MS diagnosis, to identify new prescriptions. Follow-up was from first dispensation until discontinuation, 31 Dec 2014 or death. Discontinuation was defined as no renewed prescription within gaps of 90, 150, or 180 days from last dispensation. Failure functions were plotted and Cox regression estimated hazard ratios. Results: A total of 188 (10%) of iMS (N=1826) and 628 (19%) of pMS (N=3519) received a new baclofen prescription. Discontinuation among iMS and pMS was similar using different time gaps: 49% (CI 0.42-0.57) iMS and 51% (CI 0.48-0.56) pMS discontinued within 150 days and approx. 90% discontinued overall. Approx. 65% of individuals discontinued within 1-year and 80% by 2-years. iMS with progressive course were treated for longer than relapsing course, and though similar among pMS differences between courses were less evident. Stratifying by EDSS (0-2.5, 3.0-5.5 and 6+) at baclofen initiation showed that PwMS with higher EDSS persisted longer than EDSS 0-2.5 but discontinuation was high among all groups. Cox regression showed EDSS associated with discontinuation, with iMS of EDSS 3-5.5 and 6+ 72% (CI 0.44-1.16) and 61% (CI 0.35-1.05); pMS 78% (CI 0.59-1.03) and 65% (CI 0.49-0.85) less likely to discontinue. No other MS characteristics (duration, age, course, sex, diagnosis/on

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 (

A natural hazard is a naturally occurring extreme event that has a negative effect on people and society or the environment. Natural hazards may have severe implications for human life and can potentially generate economic losses and damage ecosystems. A better understanding of their major causes, probability of occurrence, and consequences enables society to be better prepared to save human lives as well as to invest in adaptation options. Natural hazards related to climate change are identified as one of the Grand Challenges in the Baltic Sea region. Here, we summarize existing knowledge about extreme events in the Baltic Sea region with a focus on the past 200 years as well as on future climate scenarios. The events considered here are the major hydro-meteorological events in the region and include wind storms, extreme waves, high and low sea levels, ice ridging, heavy precipitation, sea-effect snowfall, river floods, heat waves, ice seasons, and drought. We also address some ecological extremes and the implications of extreme events for society (phytoplankton blooms, forest fires, coastal flooding, offshore infrastructure, and shipping). Significant knowledge gaps are identified, including the response of large-scale atmospheric circulation to climate change and also concerning specific events, for example, the occurrence of marine heat waves and small-scale variability in precipitation. Suggestions for future research include the further development of high-resolution Earth system models and the potential use of methodologies for data analysis (statistical methods and machine learning). With respect to the expected impacts of climate change, changes are expected for sea level, extreme precipitation, heat waves and phytoplankton blooms (increase), and cold spells and severe ice winters (decrease). For some extremes (drying, river flooding, and extreme waves), the change depends on the area and time period studied.

Background and purpose Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. Methods In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). Conclusions This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]; Swedish Brain Foundation; KAW Foundation; Margaretha af Ugglas Foundation; Horizon 2020 MultipleMS [733161]; Multiple Sclerosis Society of Canada [EGID 3045]

Background and purpose Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. Methods In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). Conclusions This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]; Swedish Brain Foundation; KAW Foundation; Margaretha af Ugglas Foundation; Horizon 2020 MultipleMS [733161]; Multiple Sclerosis Society of Canada [EGID 3045]

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Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

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Background and purpose Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. Methods In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). Conclusions This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]; Swedish Brain Foundation; KAW Foundation; Margaretha af Ugglas Foundation; Horizon 2020 MultipleMS [733161]; Multiple Sclerosis Society of Canada [EGID 3045]

Background and purpose Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. Methods In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). Conclusions This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]; Swedish Brain Foundation; KAW Foundation; Margaretha af Ugglas Foundation; Horizon 2020 MultipleMS [733161]; Multiple Sclerosis Society of Canada [EGID 3045]

Introduction: Data on how processing speed of relapsing-remitting multiple sclerosis patients (RRMS) evolve over time and its association with disability progression is scarce. We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (CombatMS; NCT03193866), a nationwide observational drug trial in RRMS. Objectives: Identify trajectories of processing speed and disability and their connections after disease modulatory treatment (DMT) start within the RRMS population.Describe patient characteristics associated with trajectory groups. Aim: Model trajectories of processing speed and disability. Methods: We assessed trajectories of oral Symbol Digit Modalities Test (SDMT) and expanded disability status scale (EDSS) from first DMT start using a group-based modeling approach among 1,800 RRMS patients followed 2010-2021. We investigated predictors of trajectories using group membership assignments as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. Results: We identified four trajectories of processing speed: low SDMT score (mean starting values; MSV=36.7, standard deviation; SD=8.4)-stable (13%), medium score (MSV =50.8, SD=6.7)-minor decrease (52%), medium/high score (MSV=62.9, SD=8.6)-minor decrease (32%), and high score (MSV= 75.2, SD=9.7)-moderate decrease (3%), and four trajectories of disability: no disability-stable (23%), minimal signs-minor increase (45%), minimal disability-moderate increase (27%), and relatively severe disability-moderate increase (5%). Patients with natalizumab as first DMT were less likely to belong to the medium and high processing speed trajectories, relative to the low SDMT score-stable one. Sex, age at DMT start, and geographical region of treatment were associated with medium and high processing speed and with minimal signs and minimal dis-ability trajectories. There was 0% probability of belonging to the relatively severe disability-moderate increase EDSS tra

Background: Teriflunomide (TFM) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS) included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives: To assess the safety and effectiveness of TFM with focus on patients treated at least 48 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) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using Wilcoxon Signed Rank Test and drug survival using Kaplan-Meier curve. Results: 645 patients were included in the IMSE 4 study from March 2014 to April 2021, 70% were female, mean age at treatment start was 46 years and mean treatment duration was 31 months. The most common prior treatment was interferon beta or glatiramer acetate (34%) and 17% were treatment naïve. One- two- and three- year drug survival rates were 74%, 59% and 49% respectively. 340 patients (53%) have discontinued treatment with main reasons for discontinuation being AEs (41%) and lack of effect (40%). Of 68 reported AEs, 20 were serious. For both serious and non-serious AEs, skin and subcutaneous tissue disorders were the most common (25% and 21%, respectively). At the cut-off date, 168 patients had been treated for at least 48 months. This cohort had a mean age of 48 years at treatment start and a mean treatment duration of 65 months. The majority (64%) had switched from interferon or glatiramer acetate and 12% were treatment naïve. Significant improvement in mean values at 48 months of treatment compared to baseline were noted for SDMT in the 48-month cohort (49.1 ± 8.2 to 50.5 ± 10.0, n=35, p=0.049) while a minor worsening were noted for EDSS (2.2 ± 1.7 to 2.6 ± 2.0, n=37

Background: 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: To assess the effectiveness and safety of DMF with focus on patients treated at least 60 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) and Adverse Events (AEs) 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: 2466 DMF-treated patients were included between March 2014 and April 2021 with an overall drug survival rate of 41.2% and a mean treatment duration of 34 months. The main reasons for discontinuation were AEs (49%) and lack of effect (30%). 198 AEs were reported of which 62 were serious. For both serious and non-serious AEs reported, gastrointestinal disorders were the most common (19% and 27%, respectively). 588 patients had continuous treatment for at least 60 months. This cohort had a mean age of 42.1 years and a mean treatment duration of 72.4 months. The majority (63%) had switched from interferon or glatiramer acetate and 22% were treatment naïve. Significant improvements in mean values at 60 months of treatment compared to baseline were noted for MSSS in the 60-month cohort (p<0.001). MSIS-29 Psychological showed a tendency for improvement while all other tests remained stable after 5 years of treatment. Number of relapses per 1000 patients years were improved from 198.9 before DMF treatment start to 27.9 during treatment with DMF. 69 patients (12%) have discontinued DMF treatment in the 60 month cohort with a mean treatment duration of 67

Background: Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. Phase II and III studies have shown that PegIFN reduces relapse rate and disability progression. PegIFN were included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 6) due to the importance of studying the long-term safety and effectiveness. Objectives: To follow-up the long-term safety and effectiveness of PegIFN in a real-world setting. Methods: Data was obtained from the Swedish Neuro Registry (NeuroReg). All clinical measures; 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) were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve. Results: 393 patients (78% female; 86% RRMS) were included in IMSE 6 between June 2015 and April 2021. Mean age at treatment start was 42 years, mean treatment duration was 23 months. 25% were treatment naïve and 47% switched from other injectables prior PegIFN. The one- and two-year drug survival rate was 58% and 41% respectively, and 31% overall. In total, 271 patients discontinued their PegIFN treatment at some time point, mainly due to adverse events (51%) and lack of effect (26%). Most patients switched to rituximab (37%). During the entire treatment period 54% were relapse-free and 8% had only one relapse (36% missing data). In patients treated at least 24 months tendencies of improve-ments were seen for SDMT and EQ-5D. MSIS-PSYCH showed significantly worsened results (21.2 ± 18.6 to 24.3 ± 19.3, n=46). EDSS, MSSS, MSIS-PHYS and VAS scores remained stable. 25 adverse events (AEs) have been reported to Swedish Medical Product Agency (MPA). 6 of these were classified as serious where general disorders and administration site, and skin

Background: 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. The “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (August 2006). Objective: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting. Methods: IMSE 1 includes patients starting NTZ treatment. Data is collected from the nationwide Swedish Neuroregistry. Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT) are registered prospectively. Results: 3476 patients (75% female; 81% RRMS) were included from August 2006 until April 2021. Mean age at treatment start was 36 years and mean treatment duration was 51.3 months. 1190 patients were currently treated with NTZ at cut-off and 13% of these were JCV positive (JCV+) with a mean JCV index at 1.07 ± 0.97. 2470 patients (71%) discontinued their NTZ treatment at some time point where the main reason was JCV+ (40%). Most of these patients switched to rituximab (39%). The number of relapses per 1,000 patient years were reduced from 380 before treatment start to 73 during treatment (25% missing data). 61% were relapse-free and 12% had only one relapse during the entire treatment period. All clinical measures showed improvement in mean between baseline and 132 months. Improvements on MSSS, MSIS-29 and SDMT were statistically significant. 117 Serious AEs had been reported to the Swedish Medical Product Agency and included nine cases (2 fatal) of progressive multifocal leukoencephalopathy (PML). Eight of these nine cases had been reported between year 2008 and 2012, and one in 2018. 17 patients died within 6 mo

Background: Alemtuzumab (ALZ) is a modulatory drug for patients with relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important to assess the long-term safety and effectiveness in a real-world setting where ALZ was included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology Study 3” (IMSE 3) upon launch in Sweden (March 2014). Objective: To follow up the effectiveness and long-term safety of ALZ in a real-world setting. Methods: Swedish MS patients are registered in the nationwide Swedish Neuro Registry (NeuroReg). IMSE 3 includes patients starting ALZ treatment with annual clinical measures obtained from NeuroReg; 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 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS). The Wilcoxon signed-rank test was used to assess changes in effectiveness. Results: 118 patients (59% female; 95% RRMS) have been included in IMSE 3 between March 2014 and April 2021. Mean age at treatment start was 34 years. At cut-off date 85 patients had been treated with ALZ with at least 48 months of follow-up. Mean values at baseline compared to 48 months showed significant improvements for MSSS and SDMT while EQ-5D, EDSS, MSIS-29 and VAS scores showed tendencies of improvement. The largest proportion of the entire cohort switched from natalizumab (39%) or were treatment naïve (14%) prior ALZ. The number of relapses per 1,000 patient years decreased from 441 before ALZ initiation to 84 during ALZ treatment (16% missing data). 36 adverse events (AEs) were reported to the Swedish Medical Products Agency. 23 were classified as serious and the most common AEs categories were infections and infestations and blood and lymphatic system disorders (23% respectively). For non-serious events endocrine disorders (43%) was the most common c

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). CladT are included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objective: To assess the safety and effectiveness of CladT with focus on patients treated at least 12 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), relapses and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and relapse rates were tested using the paired samples T-test. Results: 140 patients were included in the IMSE 10 study since the Swedish market launch in April 2018 with a one year drug survival rate of 96.5%. 6 patients discontinued treatment, of which 2 later restarted. 18 AEs were reported of which 5 were serious. The most common AE reported were infection and infestation (8 reports). 22% of the patients was treated with CladT as their first MS drug. 18% were treated with natalizumab and 11% with dimethyl fumarate prior to CladT. 83 patients were treated for at least 12 months. Relapse data was available for 47 of 83 patients in the 12-month cohort. The number of relapses decreased significantly from 249.6 per 1,000 patient years before treatment start to 53.5 during treatment. Only 5 patients in this cohort experienced a relapse during treatment.Significant improvements in mean values at 12 months of treatment compared to baseline were noted for MSSS (p=0.007) and VAS (p=0.029) for the 12-month cohort. All other tests remai

Background and purpose Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. Methods In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). Conclusions This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]; Swedish Brain Foundation; KAW Foundation; Margaretha af Ugglas Foundation; Horizon 2020 MultipleMS [733161]; Multiple Sclerosis Society of Canada [EGID 3045]

At many storage rings for synchrotron light production there is demand for serving both high-flux and timing users simultaneously. Today this is most commonly achieved by operating inhomogeneous fill patterns, but this is not preferable for rings that employ passive harmonic cavities to damp instabilities and increase Touschek lifetime. For these rings, inhomogeneous fill patterns could severely reduce the effect of the harmonic cavities. It is therefore of interest to develop methods to serve high-flux and timing users simultaneously without requiring gaps in the fill pattern. One such method is pseudo-single-bunch (PSB), where one bunch in the bunch train is kicked onto another orbit by a fast stripline kicker. The light emitted from the kicked bunch can then be separated by an aperture in the beamline. Due to recent developments in fast kicker design, PSB operation in multibunch mode is within reach for rings that operate with a 100 MHz RF system, such as the MAX IV and Solaris storage rings. This paper describes machine requirements and resulting performance for such a mode at the MAX IV 1.5 GeV storage ring. A solution for serving all beamlines is discussed as well as the consequences of beamline design and operation in the soft X-ray energy range.

At many storage rings for synchrotron light production there is demand for serving both high-flux and timing users simultaneously. Today this is most commonly achieved by operating inhomogeneous fill patterns, but this is not preferable for rings that employ passive harmonic cavities to damp instabilities and increase Touschek lifetime. For these rings, inhomogeneous fill patterns could severely reduce the effect of the harmonic cavities. It is therefore of interest to develop methods to serve high-flux and timing users simultaneously without requiring gaps in the fill pattern. One such method is pseudo-single-bunch (PSB), where one bunch in the bunch train is kicked onto another orbit by a fast stripline kicker. The light emitted from the kicked bunch can then be separated by an aperture in the beamline. Due to recent developments in fast kicker design, PSB operation in multibunch mode is within reach for rings that operate with a 100 MHz RF system, such as the MAX IV and Solaris storage rings. This paper describes machine requirements and resulting performance for such a mode at the MAX IV 1.5 GeV storage ring. A solution for serving all beamlines is discussed as well as the consequences of beamline design and operation in the soft X-ray energy range.

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.

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.

Background: Alemtuzumab (ALZ) is an approved disease-modi-fying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important to assess the long-term safety and effectiveness in a real-world setting. ALZ has therefore been included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE) upon launch in Sweden (March 2014). Objectives: To track effectiveness and long-term safety of ALZ in a real-world setting, with focus on patients treated with ALZ for at least 36 months. Methods: Swedish MS patients are registered into the nationwide Swedish MS Registry (NeuroReg). IMSE 3 includes all patients starting ALZ treatment with annual clinical measures obtained from NeuroReg; 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 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS). Results: A total of 118 patients (59% female; 95% RRMS) were included in IMSE 3 between March 2014 and June 2020. Out of 118 patients, 93 had been treated for at least 36 months (62% female), of which 10 patients had switched to another DMT. Mean age at treatment start for patients treated ⩾ 36 months was 34 years and mean treatment duration was 54 months. Mean number of drugs prior ALZ initiation was 2.4. Most of the patients (40%, n=37) switched to ALZ from natalizumab or were treatment naïve (13%, n=12) prior ALZ. The mean num-ber of relapses was reduced from 0.72 one year before ALZ initiation to 0.10 during the first treatment year, followed by 0.08 the second treatment year and 0.06 the third year of ALZ treatment (n=79, 15% missing data). In patients treated ⩾ 36 months significant improvements in mean baseline compared to 36 months were seen for MSSS (3.3 ± 2.7 to 2.3 ± 2.3, n=44) and EQ-5D (0.7 ± 0.3 to 0.8 ± 0.3, n=50), while SDMT showed signific

Background: Teriflunomid (TFM) is an oral therapy for relaps-ing-remitting multiple sclerosis (RRMS), which has been included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives: To assess the long-term safety and effectiveness of TFM for patients treated in a real-world setting over time. Methods: A large majority of MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). The IMSE 4 study obtains descriptive data of adverse events (AEs), 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 - Five Dimensions Test (EQ-5D) and Visual Analog Scale (VAS) from NeuroReg. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve. Results: 609 TFM-treated patients had been included in the IMSE 4 study from March 2014 to June 2020, 70% were female and mean age at treatment start was 46 years. Mean treatment duration was 27 months and 89% of the patients had RRMS. The most common prior treatment was interferon beta or glatiramer acetate (39%) and 17% of the patients were treatment naïve. The overall one- two- and three- year drug survival rates were 73%, 59% and 48% respectively. 307 (50%) patients had discontinued treatment at some point, of which 34% started rituximab treatment (36% had no new treatment registered). The most common rea-sons for discontinuation were AEs (42%) and lack of effect (40%). 204 patients had been continuously treated with TFM for ⩾36 months and significant changes in mean baseline values compared to values at 36 months were noted only for EDSS (2.0 ± 1.6 to 2.3 ± 1.8, n=49). All other clinical measures were stable. A total of 68 AEs were reported of which 20 events were classified as serious (S). The most common AE category was skin and subcutaneous tissue disord

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.

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.

Aim: This cross-sectional study investigates the psychometric properties of the Swedish edition of the Adolescent Drug Abuse Diagnosis (ADAD), and specifically examines the internal consistency and construct validity of five life domains reported by female adolescents in special residential care in Sweden (N = 780; Mage = 16 years old). Methods: Principal component analysis and entropy-based analysis were used to test construct validity. Conclusion: Results indicate that ADAD may be able to reliably distinguish between areas that are important targets for intervention.

Background: Infectious agents in MS etiology have been previously investigated. Theories of pathogenic mechanisms include molecular mimicry or activation of macrophages and natural killer cells with subsequent infiltration of the blood brain barrier. Epstein-Barr virus (EBV) infection often signaled by infectious mononucleosis (IM) is a notable MS risk factors, but other infections including Chlamydia pneumoniae, among others, are also associated with MS. Adolescence is a potentially critical period for susceptibility MS and asso-ciations with exposures in adolescence such as concussion, pneumonia, BMI, and EBV/IM have been found. No studies to our knowledge have examined CNS infection as a risk factor for MS. Objectives: To determine if CNS infection in childhood (age 0-11 years) or adolescence (age 11-20) is associated with MS risk after age 20 years. Methods: A cohort born in Sweden between 1970-1994 followed until 31 December 2014, was identified using the Total Population Register, excluding those diagnosed with MS before age 20 years (y) (N=2,422,969). ICD codes from the National Patient Register identified diagnoses of MS after age 20y (n=4,022) (two or more diagnoses), and CNS infection (bacterial and viral) before age 20y. Diagnoses of IM, pneumonia, and other bacterial or viral infections were identified. Infections were classified as present/absent at 0-10y or 11-20y. Cox regression was used to determine associations of CNS infection with MS, with follow-up from age 20y to first MS diagnosis, adjusting for gastrointestinal, genitourinary, respiratory, skin, other infections, sex and parental socioeconomic position. Results: CNS infection before age 11y was not associated with MS. CNS infection in adolescence was statistically significantly associated with increased MS risk producing an adjusted hazard ratio of 2.80 (95%CI 1.90-4.12). Excluding encephalomyelitis (as this includes acute disseminated encephalitis, often a precursor of MS) the estimate was 1.

Background: Cladribine is a deoxyadenosine analogue prodrug. Cladribine tablets (CT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). CT are included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives: To assess the safety and effectiveness of CT in a real-world setting with focus on patients treated at least 12 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), relapses and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and relapse rates were tested using the paired samples T-test. Results: 85 patients were included in the IMSE 10 study since CT were introduced on the Swedish market in April 2018. 42 patients were treated for at least 12 months. Five AEs were reported since the study start, four were classified as infections and infestations. 25 % of the entire cohort was treated with CT as their first MS drug. 13 % were treated with natalizumab and 12 % with dimethyl fumarate prior to CT. Five AEs were reported since the study start, four were classified as infections and infestations. Relapse data was available for 27/42 patients in the 12-month cohort. The number of reported relapses decreased significantly from 208.6 per 1,000 patient years before treatment start to 83.6 during treatment. Only three patients in this cohort experienced a relapse during treatment of which two were during the first treatment year. Significant improvements in mean values at 12 months of treatment compared to baseline were noted for MSSS for the 12-month cohort (n=17). All other tests remained stable but significantly uncha

Background: Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. The clinical trial program showed that PegIFN reduced the relapse rate and proportion with disability progression compared to placebo. At its launch in Sweden, PegIFN was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 6), providing possibilities to track long-term effectiveness and safety in a population-based setting. Objectives: To follow-up the long-term effectiveness and safety of PegIFN treatment in Swedish patients in a real-world context. Methods: Data was obtained from the nationwide Swedish Neuro Registry (NeuroReg) between June 2015 and May 2020. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve. Results: A total of 364 patients (78% female; 87% RRMS; mean age at treatments start 43 years) were followed up to 57 months (mean 20 months), of which 200 (55%) patients had been treated for at least 12 months. The majority of the patients had switched from other injectables (164 patients, 45%) or were treatment naïve (90 patients, 25%) prior to treatment with PegIFN. Over the dura-tion of the follow-up, 68% (247/364) patients discontinued their PegIFN treatment for various reasons (60% adverse events, 24% lack of effect) and switched mainly to rituximab (105 patients, 43%). The overall drug survival was 32%, 40% for men and 30% for women. The one- and two-year drug survival rate was 57% and 40%, respectively. The mean number of relapses were reduced from 0.35 one year before treatment start to 0.11 one year after (35% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5-Dimension test (EQ-5D), Visual Analogue Score (VAS) and Symbol Digit Modalities Test (SDMT)) remai

Background: 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: To assess the effectiveness and safety of DMF with focus on patients treated at least 36 months in the IMSE study. 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) and Adverse Events (AEs) 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: 2349 DMF-treated patients were included between March 2014 and June 2020 with an overall drug survival rate of 45%. The main reasons for discontinuation were AEs (50%) and lack of effect (30%). 186 AEs were reported to the Swedish Medical Products Agency, of which 59 were serious. A total of 8 patients have died during DMF treatment or within 6 months of treatment discontinuation. 36 month cohort: 940 patients had con-tinuous treatment for at least 36 months. This cohort had a mean age of 42 years and a mean treatment duration of 56 months. The majority (50%) had switched from interferon or glatiramer ace-tate, and (24%) were treatment naïve (TN). Significant improve-ments in mean values at 36 months of treatment compared to baseline for the 36-month cohort were noted for MSSS, SDMT, MSIS-29 Psychological, EQ-5D and VAS. When TN patients were solely assessed (n=230) improvements were noted for all above mentioned measures as well as MSIS-29 Psychological. The remaining patients in the cohort; treatment experienced patients (n=710) displayed significant improvements only for MSSS, MSIS-29 Psychological and EQ-5D. TN patients had a

Background: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evalua-tion 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 (August 2006). Objectives: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting, with focus on patients treated at least 10 years. Methods: IMSE 1 includes patients starting NTZ treatment and data is collected from the nationwide Swedish Neuro Registry (NeuroReg). Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures are registered in NeuroReg pro-spectively. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test. Results: A total of 3291 patients were included in the IMSE 1 study from August 2006 until June 2020 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 50 months). 171/3291 patients (5%) had been treated for at least 120 months (73% female; men age 36 years; 87% RRMS; mean treatment duration 139 months). A total of 64% (110/171) were treated with interferons or glatiramer acetate prior to NTZ treatment. Over the duration of follow-up discontinued 21% (35/171) their NTZ treat-ment of which 46% (16/35) discontinued due to JCV positive (JCV+). In total, 27% (46/171) of these patients were JCV+ with a mean JCV index of 1.2±1.0 (4% missing data). The mean num-ber of relapses were reduced from 0.84 one year before NTZ treat-ment start to 0.00 during the first treatment year (12% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT)) showed improvement in mean between baseline and 120 months. However, only MSSS, MSIS-29 psy-chological and SDMT

Background: Fingolimod (FGL) is an oral disease-modifying therapy (DMT) for patients with relapsing-remitting multiple sclerosis, introduced in Sweden 2011. Already from launch, FGL was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE) in order to enable long-term surveillance of effectiveness and safety aspects in a large population-based cohort. Objectives: To assess the relation between Expanded Disability Status Scale (EDSS) and patient-reported outcome measurements (PROMS) in patients treated with FGL. Methods: Swedish MS patients are registered into the nation-wide Swedish MS Registry. Demographic data, EDSS and the Multiple Sclerosis Impact Scale (MSIS-29), Symbol Digit Modalities Test (SDMT), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) were collected for FGL patients who agreed to participate in the IMSE 2 study. Spearman rank correlation were used to determine associations between EDSS and PROMS. Results: From September 2011 until June 2020, 1670 MS patients (68% female) were included in IMSE 2. Mean age at treatment start was 39 years and mean treatment duration in the entire cohort was 44 months (M). Out of 1670 patients, 560 (63% female) had been treated with FGL for at least 60 M. Mean age was 40 years and mean treatment duration 81 M. Significant (p<0.05) correla-tions was found between EDSS and all PROMs. The strongest correlation was found between the physical component of MSIS-29 for both baseline (r=0.60, n=778) and 60 M (r=0.64, n=109). Also, for both EQ-5D and VAS, Spearman coefficient indicates a moderate correlation for baseline (EQ-5D; r=-0.48, n=744 and VAS; -0.43, n=706) and 60 M (EQ-5D; r=-0.47, n=102 and VAS; -0.48, n=102) respectively. The correlation between EDSS and SDMT and the psychological component of MSIS-29, both indi-cated a weak correlation for baseline (SDMT; r=-0.28, n=771 and MSIS-29 psychological; r=0.28, n=778). For 60 M the correla-tions were

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.

Supplement: 2 Special Issue: SI Meeting Abstract: 222