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Gunnarsson, Martin
Publications (10 of 79) Show all publications
Longinetti, E., Englund, S., Burman, J., Fink, K., Fogdell-Hahn, A., Gunnarsson, M., . . . Frisell, T. (2024). Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy. Journal of Neurology, Neurosurgery and Psychiatry, 95(2), 134-141
Open this publication in new window or tab >>Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy
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2024 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 95, no 2, p. 134-141Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2024
Keywords
Cognition, epidemiology, multiple sclerosis
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-107525 (URN)10.1136/jnnp-2023-331784 (DOI)001045834300001 ()37558400 (PubMedID)2-s2.0-85168293100 (Scopus ID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2020-0115Swedish Research Council, 2021-01418The Swedish Brain Foundation
Note

Funding agency:

Patient-Centered Outcomes Research Institute - PCORI MS- 1511-33196

Available from: 2023-08-11 Created: 2023-08-11 Last updated: 2024-01-12Bibliographically approved
Forsberg, L., Larsson, V., Hillert, J., Nilsson, P., Dahle, C., Svenningsson, A., . . . Olsson, T. (2023). A comparison of administration and discontinuation of Natalizuamb in Sweden over time for patients treated with either sucutaneous (SC) or intravenous (IV) administration methods since July 2021. Paper presented at 9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023. Multiple Sclerosis Journal, 29(Suppl. 3), 617-617, Article ID P716/2335.
Open this publication in new window or tab >>A comparison of administration and discontinuation of Natalizuamb in Sweden over time for patients treated with either sucutaneous (SC) or intravenous (IV) administration methods since July 2021
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2023 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 617-617, article id P716/2335Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing multiple sclerosis (RMS) originally launched as an intravenous (IV) therapy in Sweden in August 2006. A new subcutaneous (SC) administration method for NTZ was launched in April 2021.

Objectives/Aims: To investigate how the administration of NTZ has evolved in Sweden since the introduction of SC NTZ in 2021, and to explore potential differences in treatment discontinuation patterns between the SC or IV administration modalities.

Methods: Descriptive data will be presented from the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) study cohort. Data is collected from the nationwide Swedish Neuro Registry (NeuroReg). The drug survival is assessed using the Kaplan Meier one-year drug survival curve and Breslow Wilcoxon test of equality distribution.

Results: A total of 4011 NTZ participants were included in the IMSE 1 study from August 2006 until March 2023 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 49 months), including 295 since July 2021, of which 264 had available data on method of administration. In this cohort, 109 (41%) initiated IV NTZ, of which 16 (15%) later switched to SC administration, and 155 (59%) initiated treatment with SC NTZ. The distribution between administration methods altered over time, where IV was more common in Q3 2021 (70%) and then successively dropped to 31% in Q1 2023.The mean age at treatment start was 36 years (35 for IV and 37 for SC) and 69% (70% IV, 68% SC) were female.Out of 264 participants, 73 (28%) later discontinued treatment. Discontinuation was numerically more common in the IV group compared with the SC group, but differences in the one-year drug survival rate did not reach statistical significance.The most common reason for discontinuation in the IV group was “other reason; unspecified” followed by positive JC-virus serology (JCV+). In the SC group JCV+ was the most common reason for discontinuation. Four patients discontinued due to neutralizing NTZ antibodies; 2 in each group.

Conclusion: The SC administration has become the preferred administration method for NTZ since its launch in the spring of 2021, with 59% of NTZ treatment initiations being administered using SC method. We did not find significant differences in discontinuation rates between the two administration methods. Longer observation periods will be needed to assess possible differences in tolerability and treatment adherence between the two administration modalities.

Place, publisher, year, edition, pages
Sage Publications, 2023
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-110900 (URN)001091311304089 ()
Conference
9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-01-22Bibliographically approved
Larsson, V., Nilsson, P., Magdalena, L. A., Svenningsson, A., Gunnarsson, M., Ayad, A., . . . Fink, K. (2023). CLADCOMS- CLADribine tablets long-term Control Of MS - a post-marketing investigator driven study. Paper presented at 9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023. Multiple Sclerosis Journal, 29(Suppl. 3), 968-969, Article ID P1518/2240.
Open this publication in new window or tab >>CLADCOMS- CLADribine tablets long-term Control Of MS - a post-marketing investigator driven study
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2023 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 968-969, article id P1518/2240Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Cladribine is a deoxyadenosine analogue prodrug that induces immune reconstitution by selectively targeting B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. CLADCOMS (CLADribine tablets long-term Control Of MS) is a post-marketing investigator driven study. Here we report two year prospectively obtained data on the first 100 patients included in the study until April 2021.

Objectives/Aims: To investigate number of patients free of disease activity until April 2023 among the first 100 RMS patients included.

Methods: CLADCOMS includes patients with RMS from eight academic neurology clinics of Sweden starting Cladribine treatment after 23rd of March 2018. Data was prospectively registered in the Swedish Neuroregistry using highly structured yearly follow-up routines. Descriptive data on relapses, MRI activity, and Patient Reported Outcome Measures from the first 100 patient included in the study were obtained from the registry.

Results: By April 2023, 206 patients were included in the CLADCOMS study. In April 2021 the first 100 patients had entered the study including 30% treatment naïve, 26% switched from natalizumab, 10% from dimethyl fumarate and 7% from rituximab. After the first two years after treatment initiation 87% were relapse free. MRI-activity during the first two years after treatment initiation will be analyzed.Analysis of CD19+ B-cells counts over time showed a significant drop from baseline before first dose (0.38x109/L ±0.68) to year one (0.15x109/L ±0.12) and year two (0.13x109/L ±0.09). The proportion of memory B-cells dropped from 11.8% ±9.33% at baseline to 3.0% ±2.8% after the first year and to 2.6% ±2.4% after the second year of treatment. The proportions of naïve B-cells raised over time from 61% ±18.3% at baseline to 76.8% ±18.7 year one and 78.6% ±12.3 after two years of treatment.

Conclusion: CladT treatment demonstrates clinical stability during the first two years after treatment initiation. The unique immune depletion helps to explain the durability of effects of Cladribine. However, continued follow-up is needed to assess the effectiveness and safety of treatment with Cladribine to investigate time to disease re-activation after full treatment.

Place, publisher, year, edition, pages
Sage Publications, 2023
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-110749 (URN)001091311306190 ()
Conference
9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023
Available from: 2024-01-19 Created: 2024-01-19 Last updated: 2024-01-19Bibliographically approved
Larsson, V., Forsberg, L., Hillert, J., Nilsson, P., Dahle, C., Svenningsson, A., . . . Olsson, T. (2023). Clinical Effectiveness and Safety of Cladribine Tablets for Patients Treated at least 24 Months in the Swedish post-market surveillance study "Immunomodulation and Multiple Sclerosis Epidemiology 10"(IMSE 10). Paper presented at 9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023. Multiple Sclerosis Journal, 29(Suppl. 3), 616-616, Article ID P715/1951.
Open this publication in new window or tab >>Clinical Effectiveness and Safety of Cladribine Tablets for Patients Treated at least 24 Months in the Swedish post-market surveillance study "Immunomodulation and Multiple Sclerosis Epidemiology 10"(IMSE 10)
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2023 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 616-616, article id P715/1951Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Cladribine is a deoxyadenosine analogue prodrug targeting proliferating B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with remitting multiple sclerosis (RMS). CladT is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology substudy 10” (IMSE 10).

Objectives/Aims: To assess safety and effectiveness of CladT with focus on 24 months treatment outcomes.

Methods: Data on Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life -5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) scores, and relapses and Adverse Events (AEs) were collected from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures and relapse rates were assessed using Wilcoxon Signed Rank Test.

Results: A total of 287 CladT exposed Persons with MS (PwMS) have been included in IMSE 10 since the launch of CladT in April 2018. In this cohort 90.6% remained with CladT while 27 patients (9%) discontinued treatment at any time after initiation. The most common reason for discontinuation was lack of effect (78%). A total of 24 AEs were reported to the Swedish Medical Products Agency, of which 10 were serious. The most common AE reported were infection and infestation.A total of 137 patients had CladT exposure for ⩾24 months of which 30 % being treatment naïve, 19% switched from Tysabri, 10 % from dimethyl fumarate and 7% from rituximab, prior CLadT treatment. In this cohort 91.9% remained with CladT. The ⩾24 months’ cohort demonstrated clinical stability with a non-significant trend for improvement in mean MSSS, SDMT, MSIS-29 Psychological/Physical scores compared with baseline. All other outcomes remained stable. The mean annual relapse rate (ARR) decreased significantly (p<0.05) during all treatment years compared to the ARR one-year prior treatment.Lymphocyte levels decreased from a mean of 1.9 x 109/L at treatment start to 1.11 x 109/L at 12 Months and 0.87 x 109/L at 24 months of treatment.

Conclusion: Most PwMS exposed for ⩾24 months to CladT display clinical stability and a tendency for improvement compared with baseline in several of the investigated outcomes. Longer observation times will be needed to assess the effectiveness and safety of CladT beyond 24 month exposure.

Place, publisher, year, edition, pages
Sage Publications, 2023
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-110738 (URN)001091311304088 ()
Conference
9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023
Available from: 2024-01-19 Created: 2024-01-19 Last updated: 2024-01-19Bibliographically approved
Jons, D., Grut, V., Bergström, T., Zetterberg, H., Bistrom, M., Gunnarsson, M., . . . Andersen, O. A. (2023). Epstein-Barr virus seroreactivity, putative autoimmunity and axonal injury in pre-symptomatic multiple sclerosis. Paper presented at 9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023. Multiple Sclerosis Journal, 29(Suppl. 3), 39-40
Open this publication in new window or tab >>Epstein-Barr virus seroreactivity, putative autoimmunity and axonal injury in pre-symptomatic multiple sclerosis
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2023 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 39-40Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Multiple sclerosis (MS) and presymptomatic axonal injury appears to develop only after an Epstein-Barr virus (EBV) infection. Anoctamin2 (ANO2), a chloride channel expressed in glial cells and neurons, was identified as a possible MS autoantigen. We here examine serum neurofilament (sNfL), a comprehensive EBV seroreactivity and antibodies against ANO2 in pre-symptomatic MS.

Objectives/Aims: To study whether the appearance of EBV seroreactivity in the pre-symptomatic phase of MS precedes cumulating MS-induced neuroaxonal damage and whether it is associated with an incipient autoreactivity against a reported MS autoantigen (ANO2).

Methods: We performed a case-control study with presymptomatic serum samples identified through cross-linkage of the Swedish MS register and Swedish biobanks. We assayed serum antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18 (VCAp18), EBV glycoprotein 350 (gp350), anoctamin 2 (ANO2), and serum neurofilament light (sNfL) in 669 pre-MS cases and matched controls.

Results: EBNA1 seroreactivity increased in the pre-MS group from 20–15 years before MS onset, followed by gp350 seroreactivity (p=0.001–0.002, 15–10 years before onset). This appeared before the elevation of sNfL in EBV seropositive pre-MS cases (p=8⋅10-5, 10–5 years before onset). No significant sNfL increase was observed in the EBV seronegative group (p=0.95). Pre-MS cases with the highest sNfL levels cumulated in the EBV seropositive group (p=0.038). ANO2 seropositivity appeared virtually only in the EBNA1 seropositive group, in 16.7 % of EBNA1 seropositive pre-MS samples and in 10.0 % of corresponding controls (p=0.001). Combined EBNA1 and ANO2 seropositivity showed a higher association with subsequent MS than EBNA1 independent of ANO2 (p=0.002–0.028). In the EBNA1 seropositive stratum, ANO2 seropositivity was associated with 26% higher sNfL.

Conclusion: In presymptomatic MS an antibody response against EBV, associated with ANO2 autoimmunity, was detectable before elevated sNfL, which cumulated in the EBV seropositive group. ANO2 seropositivity was associated with higher sNfL. An increase in ANO2 seroreactivity did not appear until after EBV seroconversion, limited to a subgroup of the EBV seropositive stratum. Thus, this specific cross-reaction could contribute to MS pathogenesis in a subgroup. This further implicates EBV in the pathogenesis of MS.

Place, publisher, year, edition, pages
Sage Publications, 2023
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-110763 (URN)001091311300055 ()
Conference
9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023
Available from: 2024-01-17 Created: 2024-01-17 Last updated: 2024-01-17Bibliographically approved
Forsberg, L., Larsson, V., Hillert, J., Nilsson, P., Dahle, C., Svenningsson, A., . . . Olsson, T. (2023). Improved clinical outcomes in patients treated with Natalizumab for at least 11 years - Real-world data from a Swedish national post-marketing surveillance study (IMSE 1). Paper presented at 9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023. Multiple Sclerosis Journal, 29(Suppl. 3), 965-966, Article ID P1512/2294.
Open this publication in new window or tab >>Improved clinical outcomes in patients treated with Natalizumab for at least 11 years - Real-world data from a Swedish national post-marketing surveillance study (IMSE 1)
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2023 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 965-966, article id P1512/2294Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing multiple sclerosis (RMS). Post-marketing surveillance is important to evaluate the long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon launch of NTZ in Sweden (Aug 2006).

Objectives/Aims: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting.

Methods: Adverse events (AEs), Serious AEs (SAEs), John Cunningham virus status (JCV) and clinical effectiveness measures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Scale (MSIS-29) data were collected from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test.

Results: A total of 4011 NTZ patients were included in the IMSE 1 study from August 2006 until March 2023 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 52 months) and 249 had been treated for at least 132 months. Of the 132-month cohort, 75% were female, the mean age was 36 years, 88% had RRMS, and the mean treatment duration was 160 months. The majority were treated with interferons and glatiramer acetate prior to NTZ (68%), where 30% (74/249) discontinued NTZ treatment; 43% (32/74) due to being JCV positive (JCV+), with a mean JCV index of 1.1±0.9 (n=66). Annualized relapse rates dropped from 0.40 in the year before treatment start to 0.04 during treatment, where 68% were entirely free of relapses and 21% had only 1 relapse during the entire treatment period (17% missing data). All clinical effectiveness measures, except EDSS showed statistically significant improvement between baseline and 132 months (p<0.05).From the entire IMSE1 cohort (N=4011), 132 SAEs have been reported to the Swedish MPA, including 9 cases (2 fatal) of progressive multifocal leukoencephalopathy (PML) of which 8 occurred between 2008 and 2012, and one in 2018.

Conclusion: NTZ is generally well tolerated and displays sustained effectiveness regarding cognitive, physical and psychological measures, as well as relapse-control. Introduction of JCV testing has led to fewer treated JCV+ patients, likely explaining a drastically reduced incidence of PML.

Place, publisher, year, edition, pages
Sage Publications, 2023
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-110735 (URN)001091311306184 ()
Conference
9th Joint ECTRIMS-ACTRIMS meeting, Milan, Italy, October 11-13, 2023
Available from: 2024-01-19 Created: 2024-01-19 Last updated: 2024-01-19Bibliographically approved
Englund, S., Kierkegaard, M., Burman, J., Fink, K., Fogdell-Hahn, A., Gunnarsson, M., . . . Piehl, F. (2023). Predictors of patient-reported fatigue symptom severity in a nationwide multiple sclerosis cohort. Multiple Sclerosis and Related Disorders, 70, Article ID 104481.
Open this publication in new window or tab >>Predictors of patient-reported fatigue symptom severity in a nationwide multiple sclerosis cohort
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2023 (English)In: Multiple Sclerosis and Related Disorders, ISSN 2211-0348, E-ISSN 2211-0356, Vol. 70, article id 104481Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Cohort studies, Comorbidity, Fatigue, Health-related quality of life, Multiple sclerosis, Quality of life
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-103138 (URN)10.1016/j.msard.2022.104481 (DOI)000918422400001 ()36603296 (PubMedID)2-s2.0-85146029879 (Scopus ID)
Funder
Swedish Research Council, 2020-02700 TF 2016-01355Forte, Swedish Research Council for Health, Working Life and Welfare, 2020-0115
Note

Funding agency:

NEURO Sweden

Available from: 2023-01-16 Created: 2023-01-16 Last updated: 2023-02-14Bibliographically approved
Jons, D., Grut, V., Bergström, T., Zetterberg, H., Biström, M., Gunnarsson, M., . . . Andersen, O. (2023). Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage. Journal of Neurology, Neurosurgery and Psychiatry, Article ID jnnp-2023-331868.
Open this publication in new window or tab >>Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage
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2023 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, article id jnnp-2023-331868Article in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens.

METHODS: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury.

RESULTS: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001).With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026).

CONCLUSIONS: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2023
Keywords
MULTIPLE SCLEROSIS, VIROLOGY
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-108881 (URN)001085444600001 ()37802637 (PubMedID)
Funder
Region Jämtland HärjedalenSwedish Research Council, 2018-02532 2017-00915 2020-01638Stiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, FO2019-0228 FO2017- 0243EU, Horizon 2020, 860197 733161Alzheimerfonden, 742881Knut and Alice Wallenberg Foundation
Note

DJ was supported by grants from the Swedish State under the ALF agreement between the Swedish Government and County Councils (ALFGBG- 772071), as well as by grants from the Research Foundation of the Gothenburg MS Society, Bjornsson Research Foundation, Gothenburg, Sweden, and The Gothenburg Society of Medicine. VG was supported by the Visare Norr Fund, Northern County Councils' Regional Federation, the Research and Development Unit, Region Jaemtland Haerjedalen, the Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden, Oskarfonden, and NEURO Sweden. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018- 02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG- 71320), the Alzheimer Drug Discovery Foundation-USA (#201809- 2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF- 21- 831376- C, #ADSF- 21- 831381- C and #ADSF- 21- 831377- C), the Olav Thon Foundation, the Erling- Persson Family Foundation, Stiftelsen foer Gamla Tjaenarinnor, Hjaernfonden-Sweden (#FO2019- 0228), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No. 860197 (MIRIADE), the European Union Joint Programme-Neurodegenerative Disease Research (JPND2021- 00694), and the UK Dementia Research Institute at University College London (UKDRI- 1003). KB is supported by the Swedish Research Council (#2017- 00915), the Alzheimer Drug Discovery Foundation-USA (#RDAPB- 201809- 2016615), the Swedish Alzheimer Foundation (#AF- 742881), Hjarnfonden, Sweden (#FO2017- 0243), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF agreement (#ALFGBG- 715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019- 466- 236), the US National Institutes of Health (grant EBV before MS- induced neuronal damage #1R01AG068398- 01), and the Alzheimer's Association 2021 Zenith Award (ZEN- 21- 848495). TO has received grants from the Swedish Research Council, the Swedish Brain Foundation, Knut and Alice Wallenberg Foundation, and Margaretha af Ugglas Foundation. IK was supported by a European Horizon 2020 grant (MultipleMS, project nr 733161), the Swedish Research Foundation (grant no. 2020- 01638), and the Swedish Brain Foundation.

Available from: 2023-10-11 Created: 2023-10-11 Last updated: 2024-01-29Bibliographically approved
Petersson, M., Jons, D., Feresiadou, A., Ilinca, A., Lundin, F., Johansson, R., . . . Brauner, S. (2023). Smoking and alcohol associated to the risk of developing Myasthenia gravis in a Swedish nationwide prevalent cohort. Paper presented at 9th Congress of the European Academy of Neurology, Budapest, Hungary, July 1-4, 2023. European Journal of Neurology, 30(Suppl. 1), 54-55, Article ID OPR-015.
Open this publication in new window or tab >>Smoking and alcohol associated to the risk of developing Myasthenia gravis in a Swedish nationwide prevalent cohort
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2023 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 30, no Suppl. 1, p. 54-55, article id OPR-015Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2023
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-109403 (URN)001058307000071 ()
Conference
9th Congress of the European Academy of Neurology, Budapest, Hungary, July 1-4, 2023
Available from: 2023-10-25 Created: 2023-10-25 Last updated: 2023-10-25Bibliographically approved
Jons, D., Zetterberg, H., Biström, M., Alonso-Magdalena, L., Gunnarsson, M., Vrethem, M., . . . Andersen, O. (2022). Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis. Annals of Clinical and Translational Neurology, 9(6), 882-887
Open this publication in new window or tab >>Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis
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2022 (English)In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 9, no 6, p. 882-887Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Neurosciences
Identifiers
urn:nbn:se:oru:diva-98852 (URN)10.1002/acn3.51568 (DOI)000789844900001 ()35502756 (PubMedID)2-s2.0-85129266300 (Scopus ID)
Funder
Swedish Research Council, 2018-02532 2017-00915EU, European Research Council, 681712Stiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, FO2019-0228 FO2017-0243Alzheimerfonden, AF-742881
Note

Funding agencies:

Swedish Government ALFGBG-772071 ALFGBG-715986 

Research Foundation of the Gothenburg MS Society

Bjornsson Research Foundation, Gothenburg, Sweden

Gothenburg Society of Medicine

Swedish State Support for Clinical Research ALFGBG-720931

Alzheimer Drug Discovery Foundation (ADDF), USA 201809-2016862 RDAPB-201809-2016615 

AD Strategic Fund

Alzheimer's Association ADSF-21-831376-C ADSF-21-831381-C  ADSF-21-831377-C 

Olav Thon Foundation

Erling-Persson Family Foundation

SKA South Africa 860197  

European Union Joint Program for Neurodegenerative Disorders JPND2021-00694 JPND2019-466-236 

UK Dementia Research Institute at UCL

Swedish County Councils, the ALFagreement ALFGBG-715986

United States Department of Health & Human Services National Institutes of Health (NIH) - USA 1R01AG068398-01  

Alzheimer's Association 2021 Zenith Award ZEN-21-848495

Available from: 2022-05-04 Created: 2022-05-04 Last updated: 2023-12-08Bibliographically approved
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