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BackgroundMultiple 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.MethodsWe 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.ResultsEBNA1 (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).ConclusionsSeroreactivity 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., Funding Agencies|Swedish Government [ALFGBG- 715986, 2017- 00915]; County Councils [ALFGBG- 772071, AF- 742881]; Research Foundation of the Gothenburg MS Society; Bjornsson Research Foundation; Gothenburg, Sweden; Gothenburg Society of Medicine; Visare Norr Fund; Northern County Councils Regional Federation; Research and Development Unit; Region Jaemtland Haerjedalen; Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden; Oskarfonden; NEURO Sweden; Swedish Research Council [ALFGBG- 772071]; European Research Council [ALFGBG- 715986, 2018- 02532]; Swedish State Support for Clinical Research [681712]; Alzheimer Drug Discovery Foundation-USA [101053962, 860197]; AD Strategic Fund and the Alzheimers Association [ALFGBG- 71320, 201809-2016862, RDAPB- 201809- 2016615]; Olav Thon Foundation; Erling- Persson Family Foundation; Stiftelsen foer Gamla Tjaenarinnor; Hjaernfonden-Sweden [ADSF- 21- 831376- C, UKDRI- 1003]; European Union [ADSF- 21- 831381- C]; European Union Joint Programme-Neurodegenerative Disease Research [ADSF- 21- 831377- C]; UK Dementia Research Institute at University College London [FO2019- 0228]; Swedish Research Council [FO2017- 0243]; Swedish Alzheimer Foundation [JPND2021- 00694]; European Union Joint Program for Neurodegenerative Disorders [JPND2019- 466- 236]; US National Institutes of Health [1R01AG068398- 01]; Alzheimers Association 2021 Zenith Award [ZEN- 21- 848495]; Swedish Brain Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; European Horizon [733161]; Swedish Research Foundation [2020- 01638]

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

BackgroundMultiple 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.MethodsWe 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.ResultsEBNA1 (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).ConclusionsSeroreactivity 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., Funding Agencies|Swedish Government [ALFGBG- 715986, 2017- 00915]; County Councils [ALFGBG- 772071, AF- 742881]; Research Foundation of the Gothenburg MS Society; Bjornsson Research Foundation; Gothenburg, Sweden; Gothenburg Society of Medicine; Visare Norr Fund; Northern County Councils Regional Federation; Research and Development Unit; Region Jaemtland Haerjedalen; Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden; Oskarfonden; NEURO Sweden; Swedish Research Council [ALFGBG- 772071]; European Research Council [ALFGBG- 715986, 2018- 02532]; Swedish State Support for Clinical Research [681712]; Alzheimer Drug Discovery Foundation-USA [101053962, 860197]; AD Strategic Fund and the Alzheimers Association [ALFGBG- 71320, 201809-2016862, RDAPB- 201809- 2016615]; Olav Thon Foundation; Erling- Persson Family Foundation; Stiftelsen foer Gamla Tjaenarinnor; Hjaernfonden-Sweden [ADSF- 21- 831376- C, UKDRI- 1003]; European Union [ADSF- 21- 831381- C]; European Union Joint Programme-Neurodegenerative Disease Research [ADSF- 21- 831377- C]; UK Dementia Research Institute at University College London [FO2019- 0228]; Swedish Research Council [FO2017- 0243]; Swedish Alzheimer Foundation [JPND2021- 00694]; European Union Joint Program for Neurodegenerative Disorders [JPND2019- 466- 236]; US National Institutes of Health [1R01AG068398- 01]; Alzheimers Association 2021 Zenith Award [ZEN- 21- 848495]; Swedish Brain Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; European Horizon [733161]; Swedish Research Foundation [2020- 01638]

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

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

BackgroundMultiple 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.MethodsWe 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.ResultsEBNA1 (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).ConclusionsSeroreactivity 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., Funding Agencies|Swedish Government [ALFGBG- 715986, 2017- 00915]; County Councils [ALFGBG- 772071, AF- 742881]; Research Foundation of the Gothenburg MS Society; Bjornsson Research Foundation; Gothenburg, Sweden; Gothenburg Society of Medicine; Visare Norr Fund; Northern County Councils Regional Federation; Research and Development Unit; Region Jaemtland Haerjedalen; Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden; Oskarfonden; NEURO Sweden; Swedish Research Council [ALFGBG- 772071]; European Research Council [ALFGBG- 715986, 2018- 02532]; Swedish State Support for Clinical Research [681712]; Alzheimer Drug Discovery Foundation-USA [101053962, 860197]; AD Strategic Fund and the Alzheimers Association [ALFGBG- 71320, 201809-2016862, RDAPB- 201809- 2016615]; Olav Thon Foundation; Erling- Persson Family Foundation; Stiftelsen foer Gamla Tjaenarinnor; Hjaernfonden-Sweden [ADSF- 21- 831376- C, UKDRI- 1003]; European Union [ADSF- 21- 831381- C]; European Union Joint Programme-Neurodegenerative Disease Research [ADSF- 21- 831377- C]; UK Dementia Research Institute at University College London [FO2019- 0228]; Swedish Research Council [FO2017- 0243]; Swedish Alzheimer Foundation [JPND2021- 00694]; European Union Joint Program for Neurodegenerative Disorders [JPND2019- 466- 236]; US National Institutes of Health [1R01AG068398- 01]; Alzheimers Association 2021 Zenith Award [ZEN- 21- 848495]; Swedish Brain Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; European Horizon [733161]; Swedish Research Foundation [2020- 01638]

BackgroundMultiple 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.MethodsWe 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.ResultsEBNA1 (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).ConclusionsSeroreactivity 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., Funding Agencies|Swedish Government [ALFGBG- 715986, 2017- 00915]; County Councils [ALFGBG- 772071, AF- 742881]; Research Foundation of the Gothenburg MS Society; Bjornsson Research Foundation; Gothenburg, Sweden; Gothenburg Society of Medicine; Visare Norr Fund; Northern County Councils Regional Federation; Research and Development Unit; Region Jaemtland Haerjedalen; Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden; Oskarfonden; NEURO Sweden; Swedish Research Council [ALFGBG- 772071]; European Research Council [ALFGBG- 715986, 2018- 02532]; Swedish State Support for Clinical Research [681712]; Alzheimer Drug Discovery Foundation-USA [101053962, 860197]; AD Strategic Fund and the Alzheimers Association [ALFGBG- 71320, 201809-2016862, RDAPB- 201809- 2016615]; Olav Thon Foundation; Erling- Persson Family Foundation; Stiftelsen foer Gamla Tjaenarinnor; Hjaernfonden-Sweden [ADSF- 21- 831376- C, UKDRI- 1003]; European Union [ADSF- 21- 831381- C]; European Union Joint Programme-Neurodegenerative Disease Research [ADSF- 21- 831377- C]; UK Dementia Research Institute at University College London [FO2019- 0228]; Swedish Research Council [FO2017- 0243]; Swedish Alzheimer Foundation [JPND2021- 00694]; European Union Joint Program for Neurodegenerative Disorders [JPND2019- 466- 236]; US National Institutes of Health [1R01AG068398- 01]; Alzheimers Association 2021 Zenith Award [ZEN- 21- 848495]; Swedish Brain Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; European Horizon [733161]; Swedish Research Foundation [2020- 01638]

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

BackgroundMultiple 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.MethodsWe 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.ResultsEBNA1 (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).ConclusionsSeroreactivity 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., Funding Agencies|Swedish Government [ALFGBG- 715986, 2017- 00915]; County Councils [ALFGBG- 772071, AF- 742881]; Research Foundation of the Gothenburg MS Society; Bjornsson Research Foundation; Gothenburg, Sweden; Gothenburg Society of Medicine; Visare Norr Fund; Northern County Councils Regional Federation; Research and Development Unit; Region Jaemtland Haerjedalen; Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden; Oskarfonden; NEURO Sweden; Swedish Research Council [ALFGBG- 772071]; European Research Council [ALFGBG- 715986, 2018- 02532]; Swedish State Support for Clinical Research [681712]; Alzheimer Drug Discovery Foundation-USA [101053962, 860197]; AD Strategic Fund and the Alzheimers Association [ALFGBG- 71320, 201809-2016862, RDAPB- 201809- 2016615]; Olav Thon Foundation; Erling- Persson Family Foundation; Stiftelsen foer Gamla Tjaenarinnor; Hjaernfonden-Sweden [ADSF- 21- 831376- C, UKDRI- 1003]; European Union [ADSF- 21- 831381- C]; European Union Joint Programme-Neurodegenerative Disease Research [ADSF- 21- 831377- C]; UK Dementia Research Institute at University College London [FO2019- 0228]; Swedish Research Council [FO2017- 0243]; Swedish Alzheimer Foundation [JPND2021- 00694]; European Union Joint Program for Neurodegenerative Disorders [JPND2019- 466- 236]; US National Institutes of Health [1R01AG068398- 01]; Alzheimers Association 2021 Zenith Award [ZEN- 21- 848495]; Swedish Brain Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; European Horizon [733161]; Swedish Research Foundation [2020- 01638]

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

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing-remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS >= 6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Research Council [2020-02700, TF 2016-01355]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; NEURO Sweden

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing-remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS >= 6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Research Council [2020-02700, TF 2016-01355]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; NEURO Sweden

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing-remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS >= 6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Research Council [2020-02700, TF 2016-01355]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; NEURO Sweden

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing-remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS >= 6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Research Council [2020-02700, TF 2016-01355]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; NEURO Sweden

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing-remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS >= 6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Research Council [2020-02700, TF 2016-01355]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; NEURO Sweden

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., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish MRC [2020-02700]; Swedish Research Council [2021-01418]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; Knut and Alice Wallenbergs foundation [KAW 2020.0299_VC-2020-0040/VC-2021-0018]

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., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish MRC [2020-02700]; Swedish Research Council [2021-01418]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; Knut and Alice Wallenbergs foundation [KAW 2020.0299_VC-2020-0040/VC-2021-0018]

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., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish MRC [2020-02700]; Swedish Research Council [2021-01418]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; Knut and Alice Wallenbergs foundation [KAW 2020.0299_VC-2020-0040/VC-2021-0018]

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]

Background B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines. Methods RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744. Findings Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment grou, Funding Agencies|Swedish Research Council [2016-00398]

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., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish MRC [2020-02700]; Swedish Research Council [2021-01418]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; Knut and Alice Wallenbergs foundation [KAW 2020.0299_VC-2020-0040/VC-2021-0018]

Background and purpose High levels of 25-hydroxyvitamin D-3 (25[OH]D-3) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D-3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D-3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D-3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D-3 and DBP as risk factors for MS. Methods A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D-3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D-3 was approximated as free vitamin D-3 index: (25[OH]D-3/DBP) x 10(3). MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs). Results Serum samples from 660 pairs of matched cases and controls were included. At <20 years of age, high levels of free vitamin D-3 index were associated with a lower risk of MS (highest vs. lowest quintile: OR = 0.37, 95% CI = 0.15-0.91, p for trend across quintiles = 0.04). At age 30-39 years, high levels of DBP were associated with a lower MS risk (highest vs. lowest quintile: OR = 0.36, 95% CI = 0.15-0.85, p for trend = 0.02). Conclusions These findings support the hypothesis that high levels of free 25(OH)D-3 at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology., Funding Agencies|Margaretha af Ugglas stiftelse; NEURO Sweden; Research and Development Unit, Region Jamtland Harjedalen [JLL-939768]; Swedish Neuro Foundation; Visare Norr Fund; Northern County Councils Regional Federation [940405]; Vetenskapsradet [2015-02419]; MS Research fund

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., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish MRC [2020-02700]; Swedish Research Council [2021-01418]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; Knut and Alice Wallenbergs foundation [KAW 2020.0299_VC-2020-0040/VC-2021-0018]

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]

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS). Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS). Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]

Background and Objectives To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. Methods In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores. Results A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state. Discussion In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options., Funding Agencies|Swedish medical association; Karolinska Institutet research funds; Ake Wiberg Foundation; Tore Nilsson Foundation

Background and Objectives To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. Methods In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores. Results A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state. Discussion In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options., Funding Agencies|Swedish medical association; Karolinska Institutet research funds; Ake Wiberg Foundation; Tore Nilsson Foundation

Background and purpose Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65). Conclusions Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity., Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2015-02419, 2018-03918]; Visare Norr Fund, Northern County Councils Regional Federation [940405]; Research and Development Unit, Region Jamtland Harjedalen [JLL-939768]; Margaretha af Ugglas stiftelse; Swedish Neuro Foundation; MS Research fund; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Brain Foundation; Horizon 2020 MultipleMS Grant [733161]

Background and Objectives To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. Methods In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores. Results A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state. Discussion In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options., Funding Agencies|Swedish medical association; Karolinska Institutet research funds; Ake Wiberg Foundation; Tore Nilsson Foundation

Background and purpose Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65). Conclusions Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity., Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2015-02419, 2018-03918]; Visare Norr Fund, Northern County Councils Regional Federation [940405]; Research and Development Unit, Region Jamtland Harjedalen [JLL-939768]; Margaretha af Ugglas stiftelse; Swedish Neuro Foundation; MS Research fund; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Brain Foundation; Horizon 2020 MultipleMS Grant [733161]

Background and purpose Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65). Conclusions Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity., Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2015-02419, 2018-03918]; Visare Norr Fund, Northern County Councils Regional Federation [940405]; Research and Development Unit, Region Jamtland Harjedalen [JLL-939768]; Margaretha af Ugglas stiftelse; Swedish Neuro Foundation; MS Research fund; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Brain Foundation; Horizon 2020 MultipleMS Grant [733161]

Background and Objectives To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. Methods In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores. Results A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state. Discussion In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options., Funding Agencies|Swedish medical association; Karolinska Institutet research funds; Ake Wiberg Foundation; Tore Nilsson Foundation

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS). Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]

Background and Objectives To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. Methods In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores. Results A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state. Discussion In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options., Funding Agencies|Swedish medical association; Karolinska Institutet research funds; Ake Wiberg Foundation; Tore Nilsson Foundation

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS). Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]

Background and purpose Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65). Conclusions Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity., Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2015-02419, 2018-03918]; Visare Norr Fund, Northern County Councils Regional Federation [940405]; Research and Development Unit, Region Jamtland Harjedalen [JLL-939768]; Margaretha af Ugglas stiftelse; Swedish Neuro Foundation; MS Research fund; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Brain Foundation; Horizon 2020 MultipleMS Grant [733161]

Background and purpose Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65). Conclusions Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity., Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2015-02419, 2018-03918]; Visare Norr Fund, Northern County Councils Regional Federation [940405]; Research and Development Unit, Region Jamtland Harjedalen [JLL-939768]; Margaretha af Ugglas stiftelse; Swedish Neuro Foundation; MS Research fund; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Brain Foundation; Horizon 2020 MultipleMS Grant [733161]

Background and Objectives To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. Methods In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores. Results A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state. Discussion In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options., Funding Agencies|Swedish medical association; Karolinska Institutet research funds; Ake Wiberg Foundation; Tore Nilsson Foundation

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS). Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]

Question What is the risk of infections in association with different disease-modifying treatments for multiple sclerosis? Findings This nationwide cohort study found that patients with multiple sclerosis are at a generally increased risk of infections, and this risk is partly dependent on the choice of treatment. The rate of infections was lowest with injectable therapies; among newer treatments, use of rituximab was associated with the highest rate of serious infections but less use of herpes antiviral medications compared with fingolimod and natalizumab. Meaning Per the results of this study, physicians and patients should be aware of infection risks associated with newer multiple sclerosis treatments and perhaps particularly anti-CD20 therapies. This registry-based cohort study examines the risk of serious infections associated with disease-modifying treatments for multiple sclerosis in Sweden. Importance Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden. Objective To examine the risk of serious infections associated with disease-modifying treatments for MS. Design, Setting, and Participants This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included. Exposures Treatment wi, Funding Agencies|Patient-Centered Outcomes Research Institute AwardPatient-Centered Outcomes Research Institute - PCORI [MS-1511-33196]; Swedish Foundation for MS Research

The Swedish Multiple Sclerosis Register is a national register monitoring treatment and clinical course for all Swedish multiple sclerosis (MS) patients, with high coverage and close integration with the clinic. Despite its great value for epidemiologic research, it has not previously been validated. In this brief report, we summarize a large validation of amp;gt;3,000 patients in the register using clinical chart review in the context of the COMBAT-MS study. While further improving the data quality for a central cohort of patients available for future epidemiologic research, this study also allowed us to estimate the accuracy and completeness of the register data., Funding Agencies|Patient-Centered Outcomes Research Institute (PCORI) Award [MS-1511-33196]; Swedish Foundation for MS Research; Biogen; Roche; Biogen Idec; Genzyme; Novartis