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  • 1.
    Alping, P.
    et al.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; Karolinska Institutet, Clinical Epidemiology Division, Department of Medicine Solna, Stockholm, Sweden.
    Burman, J.
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Fink, K.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; Stockholm Health Services, Academic Specialist Centre, Stockholm, Sweden.
    Fogdell-Hahn, A.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Hillert, J.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; Karolinska University Hospital, Department of Neurology, Stockholm, Sweden.
    Langer-Gould, A.
    Kaiser Permanente, Clinical and Translational Neuroscience, Southern California Permanente Medical Group, Pasadena, United States.
    Lycke, J.
    University of Gothenburg, Department of Clinical Neuroscience, Gothenburg, Sweden.
    Nilsson, P.
    Lund University, Department of Clinical Sciences/Neurology, Lund, Sweden.
    Olsson, T.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; Stockholm Health Services, Academic Specialist Centre, Stockholm, Sweden.
    Salzer, J.
    Department of Clinical ScienUmeå University, Department of Pharmacology and Clinical Neuroscience, Umeå, Sweden.
    Svenningsson, A.
    Karolinska Institutet, Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Vrethem, M.
    Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden.
    Frisell, T.
    Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden.
    Piehl, F.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Effectiveness of initial MS treatments in the COMBAT-MS trial: injectables, dimethyl fumarate, natalizumab and rituximab2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no Suppl. 2, p. 21-22Article in journal (Other academic)
    Abstract [en]

    Introduction: Direct comparisons across multiple disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) are valuable in clinical decision making. COMBAT-MS (NCT03193866) is an observational drug trial capturing data on clinical relapses, lesions on magnetic resonance imaging (MRI), Expanded Disability Status Scale (EDSS), and drug survival, at all Swedish university clinics.

    Objective: Compare the effectiveness of the most common initial MS therapies in Sweden.

    Methods: All first-ever MS treatments with injectables (INJ, interferon-β/glatiramer acetate), dimethyl fumarate (DMF), natalizumab (NTZ), and rituximab (RTX), started 2011-01-01 to 2020-12-14, were identified with prospectively recorded outcome data in the Swedish MS Register. Follow-up continued even if the therapy ended. Missing data were imputed using multiple imputation and potential confounding was adjusted for using stabilized inverse probability of treatment weighting with baseline variables: age, sex, MS duration, geographical region, EDSS, and relapses. All comparisons are made against RTX.

    Results: We included 1936 first-ever therapy episodes: 856 INJ, 341 DMF, 270 NTZ, and 469 RTX. Baseline characteristics differed by DMT, with natalizumab having the youngest patients, shortest MS duration, and the most previous relapses.After adjustment, the hazard ratio (HR) for first relapse vs RTX was for INJ 5.9 (95% confidence interval 3.7; 9.5), DMF 2.8 (1.7; 4.8), and NTZ 1.8 (1.0; 3.3). Similarly, the relative three-year lesion rate was for INJ 6.06 (3.75; 9.80), DMF 3.52 (2.01; 6.17), and NTZ 2.03 (1.14; 3.64). EDSS differences at three years were only marginally different: INJ 0.25 (0.06; 0.44), DMF 0.05 (-0.16; 0.26), and NTZ 0.00 (-0.23; 0.24). In contrast, HR for treatment discontinuation was marked: INJ 32.5 (19.0; 55.7), DMF 20.2 (11.5; 35.4), and NTZ 16.2 (8.9; 29.5).

    Conclusions: In treatment-naïve patients, RTX was associated with the lowest risk of relapses and MRI lesions, and by far the lowest probability of switching to a second therapy. In contrast, EDSS at 3 years was similar for RTX, DMF, and NTZ, and only slightly higher for INJ. The apparent difference in effectiveness between NTZ and RTX could possibly be explained by the vulnerable period after switching from NTZ, mainly due to JC virus positivity. These findings underscore the importance of tracking long-term outcomes from first DMT start, while considering subsequent therapy switches.

  • 2.
    Alping, Peter
    et al.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Askling, Johan
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Burman, Joachim
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Fink, Katharina
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Fogdell-Hahn, Anna
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Hillert, Jan
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Langer-Gould, Annette
    Clinical and Translational Neuroscience, Southern California Permanente Medical Group, Kaiser Permanente, Pasadena, CA, USA.
    Lycke, Jan
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Petra
    Department of Clinical Sciences/Neurology, Lund University, Lund, Sweden.
    Salzer, Jonatan
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Vrethem, Magnus
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
    Frisell, Thomas
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients2020In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 87, no 5, p. 688-699Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.

    METHODS: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer.

    RESULTS: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84).

    INTERPRETATION: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.

  • 3.
    Alping, Peter
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Langer-Gould, Annette
    Clinical and Translational Neuroscience, Southern Clinical and Translational Neuroscience, Southern California Permanente Medical Group, Kaiser Permanente, Pasadena CA, USA.
    Frisell, Thomas
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Burman, Joachim
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Fink, Katharina
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fogdell-Hahn, Anna
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Center for Health and Medical Psychology.
    Hillert, Jan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kockum, Ingrid
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Lycke, Jan
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Petra
    Department of Clinical Sciences/Neurology, Lund University, Lund, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Salzer, Jonatan
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå.
    Svenningsson, Anders
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Virtanen, Suvi
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Vrethem, Magnus
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Validation of the Swedish Multiple Sclerosis Register Further Improving a Resource for Pharmacoepidemiologic Evaluations2019In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 30, no 2, p. 230-233Article in journal (Refereed)
    Abstract [en]

    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 >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.

  • 4.
    Axelsson, Markus
    et al.
    University of Gothenburg, Gothenburg, Sweden .
    Malmeström, Clas
    University of Gothenburg, Gothenburg, Sweden .
    Gunnarsson, Martin
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Zetterberg, Henrik
    University of Gothenburg, Mölndal, Sweden; Institute of Neurology, The University College London (UCL), London, UK.
    Sundstrom, Peter
    Umeå University, Umeå, Sweden .
    Lycke, Jan
    University of Gothenburg, Gothenburg, Sweden .
    Svenningsson, Anders
    Umeå University, Umeå, Sweden .
    Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis2014In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    Background: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression.

    Objective: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13).

    Methods: CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays.

    Results: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline.

    Conclusions: Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.

  • 5.
    Biström, M.
    et al.
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Andersen, O.
    Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Alonso-Magdalena, L.
    Department of Neurology, Skåne University Hospital, Malmö, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Vrethem, M.
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hultdin, J.
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    Sundström, P.
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    High serum concentrations of vitamin D may protect against multiple sclerosis2018In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, no Suppl. 2, p. 1001-1002Article in journal (Other academic)
  • 6.
    Biström, M.
    et al.
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Hultdin, J.
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    Andersen, O.
    Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Alonso-Magdalena, L.
    Department of Neurology, Skåne University Hospital, Malmö, sweden.
    Jons, D.
    Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Vrethem, M.
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Sundström, P.
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Leptin levels are associated with multiple sclerosis risk2019In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, no Suppl. 2, p. 904-904Article in journal (Other academic)
    Abstract [en]

    Introduction: One environmental factor that in the last decade repeatedly has been linked to increased risk of developing multiple sclerosis (MS) is overweight, including obesity, early in life. The incidence of both MS and overweight are increasing, making elucidation of this connection important. The adipokine leptin is strongly correlated to both body mass index and total fat mass and the peptide hormone insulin is associated with obesity and type 2 diabetes, making leptin and insulin suitable biomarkers to investigate the connection between overweight and MS.

    Objectives: To determine if leptin or insulin are risk factors for developing relapsing MS.

    Aims: To further the understanding of how overweight influence MS risk.

    Methods: In this case-control study, we compared concentrations of leptin and insulin in 649 individuals that later developed relapsing-remitting MS with 649 matched controls. Cases were matched for biobank, sex, date of sampling and age with decreasing priority. Only prospectively collected samples from individuals below the age of 40 were included in the study. Conditional logistic regression was performed on log10 transformed and z-scored values for the entire group, separately for men and women and divided into age groups.

    Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals below 20 years of age (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1–1.9) and for 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. No statistically significant association was found between insulin levels and MS risk.

    Conclusions: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals. The age dependent relationship between leptin and MS risk in women - for whom leptin levels are several-fold higher than in men - suggests a possible role for leptin as being the link between MS risk and being overweight early in life.

  • 7.
    Biström, Martin
    et al.
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Hultdin, Johan
    Clinical Chemistry, Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Alonso-Magdalena, Lucia
    Department of Neurology, Skåne University Hospital, Malmö, Sweden/Lund and Institution of Clinical Sciences, Neurology, Lund University, Malmö, Sweden.
    Jons, Daniel
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Vrethem, Magnus
    Division of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Sundström, Peter
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Leptin levels are associated with multiple sclerosis risk2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no 1, p. 19-27Article in journal (Refereed)
    Abstract [en]

    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: -scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

    RESULTS: -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.

  • 8.
    Biström, Martin
    et al.
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Jons, Daniel
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Engdahl, Elin
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
    Gustafsson, Rasmus
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
    Huang, Jesse
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
    Brenner, Nicole
    Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany.
    Butt, Julia
    Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany.
    Alonso-Magdalena, Lucia
    Department of Neurology, Skåne University Hospital in Malmö/Lund, Institution of Clinical Sciences, Neurology, Lund University, Lund, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Vrethem, Magnus
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Bender, Noemi
    Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany.
    Waterboer, Tim
    Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany.
    Granåsen, Gabriel
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
    Kockum, Ingrid
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Fogdell-Hahn, Anna
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
    Sundström, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Epstein-Barr virus infection after adolescence and Human herpesvirus 6A as risk factors for multiple sclerosis2021In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 28, no 2, p. 579-586Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Infections with human herpesvirus 6A (HHV-6A) and Epstein–Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS.

    Methods: In this nested case–control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals.

    Results: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20–29 and 30–39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6–2.7).

    Conclusions: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

  • 9.
    Bridel, Claire
    et al.
    Neurochemistry Laboratory, Department of Clinical Chemistry, VU University Medical Centre, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Weiss, Edward J.
    UCL Institute of Neurology, London, England.
    Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis2019In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 76, no 9, p. 1035-1048Article, review/survey (Refereed)
    Abstract [en]

    Key Points: QuestionHow do levels of neurofilament light in cerebrospinal fluid (cNfL) compare between neurological conditions and with healthy controls?

    Findings: Among 10 059 individuals in this systematic review and meta-analysis, cNfL was elevated in most neurological conditions compared with healthy controls, and the magnitude of the increase varies extensively. Although cNfL overlaps between most clinically similar conditions, its distribution did not overlap in frontotemporal dementia and other dementias or in Parkinson disease and atypical parkinsonian syndromes.

    Meaning: The cNfL is a marker of neuronal damage and may be useful to differentiate some clinically similar conditions, such as frontotemporal dementia from Alzheimer disease and Parkinson disease from atypical parkinsonian syndromes.

    This systematic review and meta-analysis assesses the associations of age, sex, and diagnosis with neurofilament light in cerebrospinal fluid and evaluates its potential in discriminating clinically similar conditions.

    Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

    Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

    Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

    Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

    Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

    Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses.

    Results: Data were collected for 10059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n=2795), dementias and predementia stages (n=4284), parkinsonian disorders (n=984), and HC (n=1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

    Conclusions and Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.

  • 10.
    Burman, Joachim
    et al.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden; Department of Neurology, Uppsala University Hospital, Uppsala, Sweden .
    Iacobaeus, Ellen
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute Solna, Center for Molecular Medicine, Stockholm, Sweden.
    Svenningsson, Anders
    Department of Pharmacology and Clinical Neuroscience, Umeå University and University Hospital of Northern Sweden, Umeå, Sweden .
    Lycke, Jan
    Department of Neurology, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Neurology, Örebro University Hospital, Örebro, Sweden .
    Nilsson, Petra
    Department of Neurology, Skåne University Hospital Lund, Lund, Sweden.
    Vrethem, Magnus
    Neurology and Clinical Neurophysiology, Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Neurology and Neurophysiology, County Council of Östergötland, Linköping, Sweden .
    Fredrikson, Sten
    Department of Clinical Neuroscience, Karolinska Institute Huddinge, Stockholm, Sweden .
    Martin, Claes
    Neurology Unit, Division of Internal Medicine, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden .
    Sandstedt, Anna
    Department of Hematology, Linköping University Hospital, Linköping, Sweden .
    Uggla, Bertil
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Division of Hematology, Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Lenhoff, Stig
    Department of Hematology and Coagulation, Skåne University Hospital, Lund, Sweden .
    Johansson, Jan-Erik
    Department of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Isaksson, Cecilia
    Department of Radiosciences, Umeå University, Umeå, Sweden .
    Hägglund, Hans
    Division of Hematology, Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden.
    Carlson, Kristina
    Division of Hematology, Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden.
    Fagius, Jan
    Department of Neuroscience, Uppsala University, Uppsala, Sweden; Department of Neurology, Uppsala University Hospital, Uppsala, Sweden .
    Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience2014In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 10, p. 1116-1121Article in journal (Refereed)
    Abstract [en]

    Background: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS.

    Methods: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

    Results: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

    Conclusions: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

  • 11.
    Carling, Anna
    et al.
    Örebro University, School of Medical Sciences. University Healthcare Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Physiotherapy, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Forsberg, Anette
    Örebro University, School of Health Sciences. University Healthcare Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Nilsagård, Ylva
    Örebro University, School of Health Sciences. Örebro University Hospital. University Healthcare Research Centre.
    CoDuSe group exercise programme improves balance and reduces falls in people with multiple sclerosis: A multi-centre, randomized, controlled pilot study2017In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 10, p. 1394-1404Article in journal (Refereed)
    Abstract [en]

    Background: Imbalance leading to falls is common in people with multiple sclerosis (PwMS).

    Objective: To evaluate the effects of a balance group exercise programme (CoDuSe) on balance and walking in PwMS (Expanded Disability Status Scale, 4.0-7.5).

    Methods: A multi-centre, randomized, controlled single-blinded pilot study with random allocation to early or late start of exercise, with the latter group serving as control group for the physical function measures. In total, 14 supervised 60-minute exercise sessions were delivered over 7 weeks. Pretest-posttest analyses were conducted for self-reported near falls and falls in the group starting late. Primary outcome was Berg Balance Scale (BBS). A total of 51 participants were initially enrolled; three were lost to follow-up.

    Results: Post-intervention, the exercise group showed statistically significant improvement (p = 0.015) in BBS and borderline significant improvement in MS Walking Scale (p = 0.051), both with large effect sizes (3.66; -2.89). No other significant differences were found between groups. In the group starting late, numbers of falls and near falls were statistically significantly reduced after exercise compared to before (p < 0.001; p < 0.004).

    Conclusion: This pilot study suggests that the CoDuSe exercise improved balance and reduced perceived walking limitations, compared to no exercise. The intervention reduced falls and near falls frequency.

  • 12.
    de Flon, Pierre
    et al.
    Department of Pharmacology and Clinical Neuroscience, Unit of Neurology, Östersund, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Laurell, Katarina
    Department of Pharmacology and Clinical Neuroscience, Unit of Neurology, Östersund, Umeå University, Umeå, Sweden.
    Söderström, Lars
    Unit of Research, Education and Development, Region Jämtland Härjedalen, Sweden.
    Birgander, Richard
    Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden.
    Lindqvist, Thomas
    Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden.
    Krauss, Wolfgang
    Örebro University, School of Medical Sciences. Department of Radiology.
    Dring, Ann
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Bergman, Joakim
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Sundström, Peter
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Svenningsson, Anders
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden; Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab2016In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 87, no 2, p. 141-147Article in journal (Refereed)
    Abstract [en]

    Objective: To describe the effects of switching treatment from ongoing first-line injectable therapies to rituximab on inflammatory activity measured by MRI and levels of CSF neurofilament light chain (CSF-NFL) in a cohort of patients with clinically stable relapsing-remitting multiple sclerosis (RRMS).

    Method: Seventy-five patients with clinically stable RRMS treated with the first-line injectables interferon-β (IFN-β) and glatiramer acetate (GA) at 3 Swedish centers were switched to rituximab in this open-label phase II multicenter study. After a run-in period of 3 months, 2 IV doses of 1,000 mg rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months.

    Results: The mean cumulated number of gadolinium-enhancing lesions per patient at months 3 and 6 after treatment shift to rituximab was reduced compared to the run-in period (0.028 vs 0.36, p = 0.029). During the first year after treatment shift, the mean number of new or enlarged T2 lesions per patient was reduced (0.01 vs 0.28, p = 0.004) and mean CSF-NFL levels were reduced by 21% (p = 0.01).

    Conclusions: For patients with RRMS, a treatment switch from IFN or GA to rituximab is associated with reduced inflammatory activity measured by MRI and CSF-NFL.

    Classification of evidence: This study provides Class IV evidence that rituximab has an equal or superior effect in reducing inflammatory activity in RRMS measured by MRI and CSF-NFL compared to first-line injectables during the first year after treatment shift.

  • 13.
    de Flon, Pierre
    et al.
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Laurell, Katarina
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Sundström, Peter
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Söderström, Lars
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Svenningsson, Anders
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden; Department of Clinical Sciences, Karolinska Institute Danderyd Hospital, Stockholm, Sweden.
    Comparison of plasma and cerebrospinal fluid neurofilament light in a multiple sclerosis trial2019In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 139, no 5, p. 462-468Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis.

    MATERIALS & METHODS: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial "Switch-To RItuXimab in MS" (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed for two years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed for an additional three years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA.

    RESULTS: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL was 25% during the first year of follow-up (from a mean of 471 (SD 393) to 354 (SD 174) pg/mL; p=0.006) and was statistically significant. The corresponding reduction in plasma-NFL was 18% (from 9.73 (SD 7.04) to 7.94 (SD 3.10) pg/mL; p=0.055) and did not reach statistical significance.

    CONCLUSION: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimise the use in clinical trials.

  • 14.
    de Flon, Pierre
    et al.
    Department of Neurology, Östersund Hospital, Östersund, Sweden; Neurology Unit, Department of Pharmacology and Clinical Neuroscience, Umeå University, Östersund, Sweden.
    Laurell, Katarina
    Neurology Unit, Department of Pharmacology and Clinical Neuroscience, Umeå University, Östersund, Sweden.
    Söderström, Lars
    Unit of Research, Education and Development, Östersund Hospital, Region Jämtland Härjedalen, Östersund, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Svenningsson, Anders
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden; Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS2017In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 9, p. 1249-1257Article in journal (Refereed)
    Abstract [en]

    Objective: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab.

    Method: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period.

    Results: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment (p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression.

    Conclusion: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.

  • 15.
    de Flon, Pierre
    et al.
    Dept of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden.
    Söderström, Lars
    Unit of Research, Education and Development, Östersund Hospital, Region Jaämtland Härjedalen, Östersund, Sweden.
    Laurell, Katarina
    Dept of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden.
    Dring, Ann
    Dept of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden.
    Sundström, Peter
    Dept of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Dept of Neurology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Svenningsson, Anders
    Dept of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden; Dept of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 2, article id e0192516Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC).

    Method: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis.

    Results: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab.

    Conclusion: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.

  • 16.
    Demirbüker, S. Safer
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fält, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Berglund, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Martin, C.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of dimethyl fumarate (IMSE 5)2018In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, no Suppl. 2, p. 701-702Article in journal (Other academic)
    Abstract [en]

    Background: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS), which has been included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology 5” (IMSE 5) in order to monitor and determine the long-term safety and effectiveness in a real-world setting.

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

    Methods: MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg) in Sweden. The IMSE 5 study obtains descriptive data of adverse events (AEs), Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - Five Dimensions Test (EQ-5D) and Visual Analog Scale (VAS) from NeuroReg. Drug survival was measured using the Kaplan-Meier curve and effectiveness measures were assessed using the Wilcoxon Signed Rank Test.

    Results: 2010 DMF-treated patients have been included in the IMSE 5 study between March 2014 and April 2018. 73 % were female and the mean age at treatment start was 40.6 years. The mean treatment duration was 22.3 months. 92 % of the patients had RRMS with 2 % missing data on MS phenotype. Most patients switched from interferon and glaimer acetat (41 %) and 24 % of the patients were treatment naïve (13 % were missing data on prior treatment). The overall one year drug survival was 74 % and 889 patients terminated their treatment at some point. Most patients (39 %) switched to rituximab (15 % have no new treatment registered). The most common reason for discontinuation was AEs (53 %) and lack of effect (29 %). 227 (11 %) patients have continued treatment for ≥36 months. In patients treated with DMF continuously for ≥24 months (n=918), significant improvements in mean values at 24 months of treatment compared to mean baseline values have been noted for EDSS (1.9 ± 1.6 to 1.6 ± 1.6, n=196); MSSS (2.5 ± 2.4 to 2.0 ± 2.0, n=145); SDMT (52.6 ± 11.0 to 53.8 ± 11.7, n=315); MSIS-29 Psychological Subscale (26.3 ± 22.8 to 21.8 ± 20.6, n=337); and EQ-5D (0.76 ± 0.23 to 0.81 ± 0.20, n=284).

    Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. A longer follow-up period is needed to assess the real-world effectiveness and safety of DMF.

  • 17.
    Demirbüker, S. Safer
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fält, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Martin, C.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological study of the long-term safety and effectiveness of teriflunomid (IMSE 4)2018In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, no Suppl. 2, p. 922-923Article in journal (Other academic)
    Abstract [en]

    Background: Teriflunomid (TFM) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS), which has been included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology 4” (IMSE 4) in order to surveille and determine the long-term safety and effectiveness in a real-world setting.

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

    Methods: MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg) in Sweden. The IMSE 4 study obtains descriptive data of adverse events (AEs), Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - Five Dimensions Test (EQ-5D) and Visual Analog Scale (VAS) from NeuroReg. Drug survival was measured using the Kaplan-Meier curve.

    Results: 481 TFM-treated patients have been included in the IMSE 4 study between March 2014 and April 2018. 70 % were female and the mean age at treatment start was 45.8 years. The mean treatment duration was 20.5 months. 89 % of the patients had RRMS with 3 % missing data on MS phenotype. Most patients switched from interferon and glatimer acetat (37 %) and 14 % of the patients were treatment naïve before starting TFM. The overall one year drug survival rate was 81 % and the overall two year drug survival rate was 41 %. 168 (35 %) patients terminated their treatment at some point, of which 33 % started rituximab treatment and 22 % have no new treatment registered. The most common reasons for discontinuation were AEs (49 %) and lack of effect (40 %). 318 patients have been continuously treated with TFM for ≥12 months and mean baseline values compared to val-ues at 12 months have been noted for EDSS (2.0 ± 1.5 to 2.2 ± 1.5, n=141); MSSS (2.6 ± 2.2 to 2.9 ± 2.3, n=126); SDMT (50.8 ± 10.5 to 50.8 ± 10.7, n=165); MSIS-29 Physiological subscale (20.2 ± 19.3 to 19.7 ± 20.0, n=181); MSIS-29 Psychological subscale (28.1 ± 22.2 to 23.7 ± 21.7, n=181); EQ-5D (0.74 ± 0.24 to 0.73 ± 0.26, n=154); and VAS (70.0 ± 20.8 to 70.8 ± 19.6, n=150).

    Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. However, a longer follow-up period is needed to assess the real-world effectiveness and safety of TMF.

  • 18.
    Ekström, E.
    et al.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Rosengren, V.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Kågström, S.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Forsberg, L.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Berglund, A.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Hillert, J.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Nilsson, P.
    Lund University, Department of Neurology, Lund, Sweden.
    Dahle, C.
    Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Lycke, J.
    University of Gothenburg, Department of Clinical Neuroscience, Göteborg, Sweden.
    Landtblom, A. -M
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Sundström, P.
    Umeå University, Clinical Science, Neurosciences, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Piehl, F.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Olsson, T.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Real-world longitudinal data of peginterferon beta-1a from the Swedish national post-marketing surveillance study (IMSE 6) - effectiveness and safety profile2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no Suppl. 2, p. 626-627Article in journal (Other academic)
    Abstract [en]

    Background: Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. Phase II and III studies have shown that PegIFN reduces relapse rate and disability progression. PegIFN were included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 6) due to the importance of studying the long-term safety and effectiveness.

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

    Methods: Data was obtained from the Swedish Neuro Registry (NeuroReg). All clinical measures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

    Results: 393 patients (78% female; 86% RRMS) were included in IMSE 6 between June 2015 and April 2021. Mean age at treatment start was 42 years, mean treatment duration was 23 months. 25% were treatment naïve and 47% switched from other injectables prior PegIFN. The one- and two-year drug survival rate was 58% and 41% respectively, and 31% overall. In total, 271 patients discontinued their PegIFN treatment at some time point, mainly due to adverse events (51%) and lack of effect (26%). Most patients switched to rituximab (37%). During the entire treatment period 54% were relapse-free and 8% had only one relapse (36% missing data). In patients treated at least 24 months tendencies of improve-ments were seen for SDMT and EQ-5D. MSIS-PSYCH showed significantly worsened results (21.2 ± 18.6 to 24.3 ± 19.3, n=46). EDSS, MSSS, MSIS-PHYS and VAS scores remained stable. 25 adverse events (AEs) have been reported to Swedish Medical Product Agency (MPA). 6 of these were classified as serious where general disorders and administration site, and skin (33% respectively) were the most common categories. General disorders and administration site were also the most common for non-serious AEs (68%).

    Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform. All clinical effectiveness measures, except MSIS-PHYS, remained stable in patients treated for at least 24 months in this nationwide population-based real-world study. Longer follow up is needed to address the long-term effectiveness.

  • 19.
    Ekström, E.
    et al.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Rosengren, V.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Kågström, S.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Forsberg, L.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Berglund, A.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Hillert, J.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Nilsson, P.
    Lund University, Department of Neurology, Lund, Sweden.
    Dahle, C.
    Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Lycke, J.
    University of Gothenburg, Department of Clinical Neuroscience, Göteborg, Sweden.
    Landtblom, A. -M
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Sundström, P.
    Umeå University, Clinical Science, Neurosciences, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Piehl, F.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Olsson, T.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    The long-term safety and effectiveness of natalizumab (IMSE 1) - Real-world data from a Swedish nationwide pharmaco-epidemiological study2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no Suppl. 2, p. 618-619Article in journal (Other academic)
    Abstract [en]

    Background: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. The “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (August 2006).

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

    Methods: IMSE 1 includes patients starting NTZ treatment. Data is collected from the nationwide Swedish Neuroregistry. Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT) are registered prospectively.

    Results: 3476 patients (75% female; 81% RRMS) were included from August 2006 until April 2021. Mean age at treatment start was 36 years and mean treatment duration was 51.3 months. 1190 patients were currently treated with NTZ at cut-off and 13% of these were JCV positive (JCV+) with a mean JCV index at 1.07 ± 0.97. 2470 patients (71%) discontinued their NTZ treatment at some time point where the main reason was JCV+ (40%). Most of these patients switched to rituximab (39%). The number of relapses per 1,000 patient years were reduced from 380 before treatment start to 73 during treatment (25% missing data). 61% were relapse-free and 12% had only one relapse during the entire treatment period. All clinical measures showed improvement in mean between baseline and 132 months. Improvements on MSSS, MSIS-29 and SDMT were statistically significant. 117 Serious AEs had been reported to the Swedish Medical Product Agency and included nine cases (2 fatal) of progressive multifocal leukoencephalopathy (PML). Eight of these nine cases had been reported between year 2008 and 2012, and one in 2018. 17 patients died within 6 months of last NTZ infusion. The most common category for non-serious AEs was infections and infestations (21%). For serious AEs neoplasms benign, malignant and unspecified were the most common (16%).

    Conclusions: NTZ is generally well tolerated with sustained effectiveness regarding clinical cognitive, physical and psychological measures.

  • 20.
    Ekström, E.
    et al.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Rosengren, V.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Kågström, S.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Forsberg, L.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Hillert, J.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Nilsson, P.
    Lund University, Department of Neurology, Lund, Sweden.
    Dahle, C.
    Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden..
    Lycke, J.
    University of Gothenburg, Department of Clinical Neuroscience, Göteborg, Sweden.
    Landtblom, A. -M
    Uppsala University, Department of Neuroscience, Uppsala, Sweden,.
    Burman, J.
    Uppsala University, Department of Neuroscience, Uppsala, Sweden,.
    Martin, C.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden..
    Sundström, P.
    Umeå University, Clinical Science, Neurosciences, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Piehl, F.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Olsson, T.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological study of the long-term safety and effectiveness of alemtuzumab (IMSE 3)2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no Suppl. 2, p. 616-617Article in journal (Other academic)
    Abstract [en]

    Background: Alemtuzumab (ALZ) is a modulatory drug for patients with relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important to assess the long-term safety and effectiveness in a real-world setting where ALZ was included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology Study 3” (IMSE 3) upon launch in Sweden (March 2014).

    Objective: To follow up the effectiveness and long-term safety of ALZ in a real-world setting.

    Methods: Swedish MS patients are registered in the nationwide Swedish Neuro Registry (NeuroReg).

    IMSE 3 includes patients starting ALZ treatment with annual clinical measures obtained from NeuroReg; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS). The Wilcoxon signed-rank test was used to assess changes in effectiveness.

    Results: 118 patients (59% female; 95% RRMS) have been included in IMSE 3 between March 2014 and April 2021. Mean age at treatment start was 34 years. At cut-off date 85 patients had been treated with ALZ with at least 48 months of follow-up. Mean values at baseline compared to 48 months showed significant improvements for MSSS and SDMT while EQ-5D, EDSS, MSIS-29 and VAS scores showed tendencies of improvement.

    The largest proportion of the entire cohort switched from natalizumab (39%) or were treatment naïve (14%) prior ALZ. The number of relapses per 1,000 patient years decreased from 441 before ALZ initiation to 84 during ALZ treatment (16% missing data). 36 adverse events (AEs) were reported to the Swedish Medical Products Agency. 23 were classified as serious and the most common AEs categories were infections and infestations and blood and lymphatic system disorders (23% respectively). For non-serious events endocrine disorders (43%) was the most common category. Two patients died during ALZ treatment, one of which was associated to ALZ treatment, and died in association with the first ALZ treatment cycle due to fulminant viral hepatitis.

    Conclusions: Patients treated with ALZ for at least 48 months improved or remained stable across all effectiveness measures. Continued follow-up is needed to evaluate the real-world effectiveness and safety of ALZ.

  • 21.
    Englund, Simon
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: simon.englund@ki.se.
    Kierkegaard, Marie
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Burman, Joachim
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Fink, Katharina
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fogdell-Hahn, Anna
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Hillert, Jan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Langer-Gould, Annette
    Clinical and Translational Neuroscience, Southern California Permanente Medical Group, Kaiser Permanente, Pasadena, United States.
    Lycke, Jan
    Department of Clinical Neuroscience, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Petra
    Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden.
    Salzer, Jonatan
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Svenningsson, Anders
    Clinical Sciences, Danderyd Hospital Stockholm, Stockholm, Sweden.
    Mellergård, Johan
    Department of Biomedical and Clinical Sciences, Division of Neurobiology, Linköping University, Linköping, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Longinetti, Elisa
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Frisell, Thomas
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Predictors of patient-reported fatigue symptom severity in a nationwide multiple sclerosis cohort2023In: Multiple Sclerosis and Related Disorders, ISSN 2211-0348, E-ISSN 2211-0356, Vol. 70, article id 104481Article in journal (Refereed)
    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.

  • 22.
    Fink, K.
    et al.
    Academic Specialist Center, Centrum for Neurology, Stockholm, Sweden; Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Nilsson, P.
    Lund University, Department of Neurology, Lund, Sweden.
    Alonso, L.
    Lund University, Department of Neurology, Lund, Sweden.
    Sveningsson, A.
    Danderyd Hospital, Department of Clinical Science, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Lange, Niclas
    Örebro University, School of Medical Sciences. Department of Neurology.
    Ayad, A.
    Capio S:t Göran Hospital, Neurologiska kliniken, Stockholm, Sweden.
    Vrethem, M.
    Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden.
    Burman, J.
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Lycke, J.
    University of Gothenburg, Department of Clinical Neuroscience, Gothenburg, Sweden.
    Piehl, F.
    Academic Specialist Center, Centrum for Neurology, Stockholm, Sweden; Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    CLADCOMS - CLADribine tablets long-term Control Of MS - a post-marketing investigator driven study2022In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 28, no Suppl. 3, p. 847-848, article id EP1060Article in journal (Other academic)
    Abstract [en]

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

    Objective: 1) To  investigate for how long a full dose treatment with Cladribine 10 mg tablets (3.5 mg/kg over two years) offers freedom of disease activity in relapsing MS patients.2) To collect complete data on safety and effectiveness with the help of the Swedish Neuroregistry to enable future assessment on effectiveness and safety in comparison with other in Sweden commonly used disease modifying treatments.

    Methods: CLADCOMS  includes  patients  with  relapsing  MS  from  the  eight academic  clinics  starting  Cladribine  treatment  after  23rd  of  March  2018. Data  is  collected  in  the  Swedish  Neuroregistry  using  highly  structured  yearly follow-up  routines.   Descriptive   data   on   relapses,   MRI   activity,   Patient   Reported   Outcome   Measures   and   Serious   Adverse   events   (SAEs)  from the  first  100  patient  included  in  the  study  are  obtained from the registry.

    Results: Up  to  April  2022  1XX  patients  were  included  in  the  study. In April 2021 the first 100 patient entered the study. 40% of patients included were treatment naïve, 29% switched from natalizumab and 13% from rituximab. By April 2022, 5 patients experienced a relapse during the treatment initiation and showed MRT activity with contrast enhancing (CEL)lesions more than six months after initiation of treatment, of which 2 patients showed CEL more than six months after the second treatment course year two. 20% of the patients showed new lesions on the first MRI performed up to 18 months after treatment initiation. Two patients reported SEAs. Analysis of CD19   and   CD27-   B-cells   counts   over   time   will   be   performed.

    Conclusions: Cladribine treatment demonstrates clinical stability in patients treated ⩾ 12 months. However, continued follow-up is needed to assess the effectiveness and safety of treatment with Cladribine over a longer time to investigate time to disease reactivation after the second treatment course year two has been administered.

  • 23.
    Forsberg, L.
    et al.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Ekström, E.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Hillert, J.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Nilsson, P.
    Lund University, Department of Neurology, Lund, Sweden.
    Dahle, C.
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Lycke, J.
    University of Gothenburg, Department of Clinical Neuroscience, Göteborg, Sweden.
    Landtblom, A. -M
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Sundström, P.
    Umeå University, Department of Clinical Neuroscience, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Piehl, F.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Olsson, T.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    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)2022In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 28, no Suppl. 3, p. 352-353, article id P324Article in journal (Other academic)
    Abstract [en]

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

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

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

    Results: A total of 3622 NTZ patients were included in the IMSE 1 study from August 2006 until March 2022 (72% female; mean age  36  years;  80%  RRMS; mean  treatment  duration  49  months)  and  186  had  been  treated  for  at  east  132  months.  Of  the  132-month cohort, 73% were female, the mean age was 36 years, 88% had  RRMS,  and  the  mean  treatment  duration  was  155 months.  The majority were treated with interferons and glatiramer acetate prior NTZ  (64%).  25%  (47/186)  discontinued  NTZ  treatment  of  which 47% (n=22) discontinued due to JCV positive (JCV+). In total,  30%  (55/186)  of  these patients  were  JCV+  with  a  mean  JCV index of 1.2±1.0 (2% missing data). Relapses before treatment were reduced from 380/1000 patient years to 43/1000 during treatment,  71%  were  relapse-free  and  18%  had  1  relapse  during  the entire  treatment  period  (15%  missing  data).  Most  clinical  effectiveness measures, MSSS, MSIS-29 and SDMT showed statistically  significant  improvement between  baseline  and  132  months (p<0.05). Over the entire observation time, 125 SAEs had 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.

    Conclusions: NTZ  is  generally  well  tolerated  with  sustained  effectiveness regarding  cognitive,  physical  and  psychological  measures, as well as relapse-control. Introduction of JCV testing has  led  to  fewer  treated  JCV+  patients, which  likely  explains  a  drastic drop in number of reported cases of PML.

  • 24.
    Forsberg, L.
    et al.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Ekström, E.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Hillert, J.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Nilsson, P.
    Lund University, Department of Neurology, Lund, Sweden.
    Dahle, C.
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden.
    Lycke, J.
    University of Gothenburg, Department of Clinical Neuroscience, Göteborg, Sweden.
    Lantblom, A. -M
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden,.
    Sundström, P.
    Umeå University, Department of Clinical Neuroscience, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Piehl, F.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Olsson, T.
    Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
    Clinical effectiveness and safety of dimethyl fumarate for patients treated at least 6 years in the swedish post-market surveillance study "immunomodulation and multiple sclerosis epidemiology 5" (IMSE 5)2022In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 28, no Suppl. 3, p. 858-859, article id EP1078Article in journal (Other academic)
    Abstract [en]

    Introduction: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

    Objectives/Aims: To assess the effectiveness and safety of DMF with focus on patients treated at least 72 months.

    Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS), Adverse Events (AEs) and Serious AEs (SAEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

    Results: 2565 DMF-treated patients were included between March 2014 and March 2022 with an overall drug survival rate of 38.7% and a mean treatment duration of 37 months. The main reasons for discontinuation were AEs (47%) and lack of effect (30%). 199 AEs were reported of which 63 were serious. For both serious and non-serious AEs reported, gastrointestinal disorders were the most common (19% and 27%, respectively).509 patients had continuous treatment for at least 72 months. This cohort had a mean age of 42 years and a mean treatment duration of 84 months. The majority (51%) had switched from interferon or glatiramer acetate and 24% were treatment naïve.Significant improvements in mean values at 72 months of treatment compared to baseline were noted for MSSS, MSIS-29 Psychological, and EQ-5D (p<0.05). All other tests remained stable after 6 years of treatment. Number of relapses per 1000 patient years were improved from 199.6 before DMF treatment start to 23.0 during treatment with DMF.49 patients (10%) have discontinued DMF treatment in the 72 month cohort with a mean treatment duration of 84 months (range 70-97 months). The main reasons for discontinuation were other reasons (33%), lack of effect (29%), stable condition (14%), and AEs (12%).

    Conclusions: DMF demonstrates partly clinical improvements in patients treated 72 months. However; due to the high discontinuation rate there is an unavoidable selection bias. Continued follow up is needed to assess the effectiveness and safety of DMF over longer time periods in a real world setting.

  • 25.
    Forsberg, L.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fält, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Berglund, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Svenningsson, A.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Clinical effectiveness of dimethyl fumarate with focus on patients treated at least 36 months - a Swedish nationwide study of the long-term effectiveness and safety of dimethyl fumarate (IMSE5)2019In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, no Suppl. 2, p. 316-317Article in journal (Other academic)
    Abstract [en]

    Background: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

    Objective: To assess the effectiveness and safety of DMF with focus on patients treated at least 36 months in the IMSE study.

    Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

    Results: 2229 DMF-treated patients were included since March 2014 with a one- and two-year drug survival rate of 73% and 59%. The main reasons for discontinuation were AEs (51%) and lack of effect (29%). 77 AEs were reported to the Swedish Medical Products Agency of which 20 were serious. There were 6 fatal cases of which 4 were confirmed as unrelated to DMF and 2 were still under investigation.865 patients had continuous treatment for at least 36 months. This cohort had a mean age of 42 years and a mean treatment duration of 44 months. The majority had switched from interferon and glatiramer acetate (IFN&GA) (50%) or were treatment naïve (TN) (22%). Significant improvements in mean values at 36 months of treatment compared to baseline were noted for EDSS, MSSS, SDMT, MSIS-29 Psychological and EQ-5D. When TN patients were solely assessed improvements were noted for EDSS, MSSS, SDMT, MSIS-29 Physical and Psychological and EQ-5D. Treatment experienced patients displayed significant improvements only for MSSS and EQ-5D. Patients previously treated with IFN&GA also improved only in MSSS and EQ-5D. TN patients had a mean duration from diagnosis to treatment start of 6 months compared to 83 months for IFN&GA patients and 105 months for the remaining cohort.

    Conclusions: DMF demonstrates clinical improvements in patients treated ⩾ 36 months, most pronounced in TN patients. However; the tolerability of DMF was reduced since 41% interrupted treatment during the first 24 months of therapy. Continued follow up is needed to assess the effectiveness and safety of DMF over longer time periods in a real world setting.

  • 26.
    Forsberg, L.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fält, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A Swedish Nationwide study of the long-term effectiveness and safety of teriflunomid based on data from the Swedish "Immunomodulation and Multiple Sclerosis Epidemiology" Study (IMSE 4)2019In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, no Suppl. 2, p. 316-316Article in journal (Other academic)
    Abstract [en]

    Background: Teriflunomid (TFM) is a newly approved oral therapy for relapsing-remitting multiple sclerosis (RRMS), which has been included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE) in order to track the long-term safety and effectiveness in a real-world setting.

    Objectives: To track the long-term safety and effectiveness of TFM in a real-world setting.

    Methods: A large majority of MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). The IMSE 4 study obtains descriptive data of adverse events (AEs), Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - Five Dimensions Test (EQ-5D) and Visual Analog Scale (VAS) from NeuroReg. Drug survival was measured using the Kaplan-Meier curve.

    Results: A total of 559 TFM-treated patients had been included in the IMSE 4 study from March 2014 to March 2019. 71 % were female and the mean age at treatment start was 46 years. The mean treatment duration was 23 months and 89 % of the patients had RRMS (9 % missing data on MS phenotype). Most patients switched from interferon/glatiramer acetate (36 %) and 16 % of the patients were treatment naïve before starting TFM. The overall one-year drug survival rate was 74 % and the overall two-year drug survival rate was 58 %. 232 (42 %) patients had terminated their treatment at some point, of which 46 % started rituximab treatment and 12 % had no new treatment registered. The most common reasons for discontinuation were AEs (41 %) and lack of effect (39 %). 229 patients had been continuously treated with TFM for ⩾24 months and significant changes in mean baseline values compared to values at 24 months were noted for EDSS (1.9 ± 1.5 to 2.1 ± 1.6, n=66) and SDMT (50.3 ± 10.5 to 52.3 ± 13.0, n=88). A total of 34 AEs were reported to the Swedish Medical Products Agency of which 9 events were classified as serious, none fatal.

    Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. Patients starting TMF are older at treat-ment start than most other DMTs, which may explain the lack of improvement in EDSS scores. Still, a relatively high proportion switched due to lack of effect. A longer follow-up period is needed to assess the real-world effectiveness and safety of TMF.

  • 27.
    Forsberg, L.
    et al.
    Karolinska Institutet, Solna, Sweden.
    Kågström, S.
    Karolinska Institutet, Solna, Sweden.
    Leandersson, Å.
    Karolinska Institutet, Solna, Sweden.
    Berglund, A.
    Karolinska Institutet, Solna, Sweden.
    Hillert, J.
    Karolinska Institutet, Solna, Sweden.
    Nilsson, P.
    Lund University, Lund, Sweden.
    Dahle, C.
    Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Institute of Neuroscience and Physiology, Gothenburg, Sweden.
    Landtblom, A. -M
    Uppsala University, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Danderyd, Sweden.
    Sundström, P.
    Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Piehl, F.
    Karolinska Institutet, Solna, Sweden.
    Olsson, T.
    Karolinska Institutet, Stockholm, Sweden.
    A swedish post-market surveillance study: long-term effectiveness and safety of dimethyl fumarate (imse 5) for patients treated at least 36 months: on-demand eposters p0001-p02862020In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 26, no 3 Suppl., p. 254-255Article in journal (Other academic)
    Abstract [en]

    Background: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

    Objectives: To assess the effectiveness and safety of DMF with focus on patients treated at least 36 months in the IMSE study.

    Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

    Results: 2349 DMF-treated patients were included between March 2014 and June 2020 with an overall drug survival rate of 45%. The main reasons for discontinuation were AEs (50%) and lack of effect (30%). 186 AEs were reported to the Swedish Medical Products Agency, of which 59 were serious. A total of 8 patients have died during DMF treatment or within 6 months of treatment discontinuation. 36 month cohort: 940 patients had con-tinuous treatment for at least 36 months. This cohort had a mean age of 42 years and a mean treatment duration of 56 months. The majority (50%) had switched from interferon or glatiramer ace-tate, and (24%) were treatment naïve (TN). Significant improve-ments in mean values at 36 months of treatment compared to baseline for the 36-month cohort were noted for MSSS, SDMT, MSIS-29 Psychological, EQ-5D and VAS. When TN patients were solely assessed (n=230) improvements were noted for all above mentioned measures as well as MSIS-29 Psychological. The remaining patients in the cohort; treatment experienced patients (n=710) displayed significant improvements only for MSSS, MSIS-29 Psychological and EQ-5D. TN patients had a mean duration from diagnosis to treatment start of 5 months com-pared to 91 months for the remaining cohort. TN were also younger than the remaining cohort (37 years vs 43 years).Conclusions: DMF demonstrates clinical improvements in patients treated 36 months, more pronounced in TN patients. However; due to the high discontinuation rate there is an unavoidable selection bias. Continued follow up is needed to assess the effectiveness and safety of DMF over longer time periods in a real world setting.

  • 28.
    Forsberg, L.
    et al.
    Karolinska Instituet, Solna, Sweden.
    Kågström, S.
    Karolinska Instituet, Solna, Sweden.
    Leandersson, Å.
    Karolinska Instituet, Solna, Sweden.
    Hillert, J.
    Karolinska Instituet, Solna, Sweden.
    Nilsson, P.
    Lund University, Lund, Sweden.
    Dahle, C.
    Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Institute of Neuroscience and Physiology, Gothenburg, Sweden.
    Landtblom, A. -M
    Uppsala University, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Danderyd, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Piehl, F.
    Karolinska Instituet, Solna, Sweden.
    Olsson, T.
    Karolinska Institutet, Stockholm, Sweden.
    A swedish post-market surveillance study of the long-term effectiveness and safety of teriflunomid (IMSE 4) for patients treated at least 36 months2020In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 26, no 3 Suppl., p. 253-254Article in journal (Other academic)
    Abstract [en]

    Background: Teriflunomid (TFM) is an oral therapy for relaps-ing-remitting multiple sclerosis (RRMS), which has been included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

    Objectives: To assess the long-term safety and effectiveness of TFM for patients treated in a real-world setting over time.

    Methods: A large majority of MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). The IMSE 4 study obtains descriptive data of adverse events (AEs), Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - Five Dimensions Test (EQ-5D) and Visual Analog Scale (VAS) from NeuroReg. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

    Results: 609 TFM-treated patients had been included in the IMSE 4 study from March 2014 to June 2020, 70% were female and mean age at treatment start was 46 years. Mean treatment duration was 27 months and 89% of the patients had RRMS. The most common prior treatment was interferon beta or glatiramer acetate (39%) and 17% of the patients were treatment naïve. The overall one- two- and three- year drug survival rates were 73%, 59% and 48% respectively. 307 (50%) patients had discontinued treatment at some point, of which 34% started rituximab treatment (36% had no new treatment registered). The most common rea-sons for discontinuation were AEs (42%) and lack of effect (40%). 204 patients had been continuously treated with TFM for ⩾36 months and significant changes in mean baseline values compared to values at 36 months were noted only for EDSS (2.0 ± 1.6 to 2.3 ± 1.8, n=49). All other clinical measures were stable. A total of 68 AEs were reported of which 20 events were classified as serious (S). The most common AE category was skin and subcutaneous tissue disorders for both serious and non-serious (NS) AEs (S: 25%, NS: 21%).

    Conclusions: NeuroReg proves to function well as a post-market-ing drug surveillance platform, providing data regarding drug effectiveness and AEs. Patients starting TMF are older at treat-ment start than patients initiating most other DMTs, which may explain the lack of significant improvement in most clinical meas-ures and the negative outcome of the EDSS scores. A longer fol-low-up period is needed to assess the real-world effectiveness and safety of TMF.

  • 29.
    Forsberg, L.
    et al.
    Karolinska Institutet, Solna, Sweden.
    Kågström, S.
    Karolinska Institutet, Solna, Sweden.
    Leandersson, Å.
    Karolinska Institutet, Solna, Sweden.
    Hillert, J.
    Karolinska Institutet, Solna, Sweden.
    Nilsson, P.
    Lund Univiversity, Lund, Sweden.
    Dahle, C.
    Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Danderyd, Sweden.
    Lycke, J.
    Institute of Neuroscience and Physiology, Gothenburg, Sweden.
    Landtblom, A. -M
    Uppsala University, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Danderyd, Sweden.
    Sundström, P.
    Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Piehl, F.
    Karolinska Institutet, Solna, Sweden.
    Olsson, T.
    Karolinska Institutet, Stockholm, Sweden.
    A swedish post-market surveillance study: long-term effectiveness and safety of cladribine tablets (IMSE 10) for patients treated at least 12 months2020In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 26, no 3 Suppl., p. 254-254Article in journal (Other academic)
    Abstract [en]

    Background: Cladribine is a deoxyadenosine analogue prodrug. Cladribine tablets (CT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). CT are included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE).

    Objectives: To assess the safety and effectiveness of CT in a real-world setting with focus on patients treated at least 12 months.

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

    Results: 85 patients were included in the IMSE 10 study since CT were introduced on the Swedish market in April 2018. 42 patients were treated for at least 12 months. Five AEs were reported since the study start, four were classified as infections and infestations. 25 % of the entire cohort was treated with CT as their first MS drug. 13 % were treated with natalizumab and 12 % with dimethyl fumarate prior to CT. Five AEs were reported since the study start, four were classified as infections and infestations. Relapse data was available for 27/42 patients in the 12-month cohort. The number of reported relapses decreased significantly from 208.6 per 1,000 patient years before treatment start to 83.6 during treatment. Only three patients in this cohort experienced a relapse during treatment of which two were during the first treatment year. Significant improvements in mean values at 12 months of treatment compared to baseline were noted for MSSS for the 12-month cohort (n=17). All other tests remained stable but significantly unchanged after one year of treat-ment. Lymphocyte levels decreased from a mean of 2.4 x 109/L at treatment start (n=8) to 1.2 x 109/L after 12 months of treatment (n=6) in the 12-month cohort. No patients were below the 0.8 x 109/L limit at 12 months.

    Conclusions: CT treatment demonstrates clinical stability in patients treated 12 months. However, continued follow-up is needed to assess the effectiveness and safety of CT over a longer time to assess if these results sustain after the final treatment course has been administered.

  • 30.
    Forsberg, Linda
    et al.
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Larsson, Veronica
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Hillert, Jan
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Nilsson, Petra
    Lund University, Department of Neurology, Lund, Sweden.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Svenningsson, Anders
    Danderyd Hospital, Department of Clinical Science, Stockholm, Sweden.
    Lycke, Jan
    University of Gothenburg, Department of Clinical Neuroscience, Gothenburg, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Department of Medical Sciences, Uppsala, Sweden.
    Burman, Joachim
    Uppsala University, Department of Medical Sciences, Uppsala, Sweden.
    Martin, Claes
    Danderyd Hospital, Department of Clinical Science, Stockholm, Sweden.
    Sundström, Peter
    Umeå University, Department of Science, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Piehl, Fredrik
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Olsson, Tomas
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    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 20212023In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 617-617, article id P716/2335Article in journal (Other academic)
    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.

  • 31.
    Forsberg, Linda
    et al.
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Larsson, Veronica
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Hillert, Jan
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Nilsson, Petra
    Lund University, Department of Neurology, Lund, Sweden.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden.
    Svenningsson, Anders
    Danderyd Hospital, Department of Clinical Science, Stockholm, Sweden.
    Lycke, Jan
    University of Gothenburg, Department of Clinical Neuroscience, Gothenburg, Sweden.
    Landtblom, Anne-Marie
    Uppsala University, Department of Neuroscience, Uppsala, Sweden.
    Burman, Joachim
    Uppsala University, Department of Medical Science, Uppsala, Sweden.
    Martin, Claes
    Danderyd Hospital, Department of Clinical Science, Stockholm, Sweden.
    Sundström, Peter
    Umeå University, Department of Science, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Piehl, Fredrik
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    Olsson, Tomas
    Karolinska Institutet, Department of Neuroscience, Solna, Sweden.
    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)2023In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 965-966, article id P1512/2294Article in journal (Other academic)
    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.

  • 32.
    Fält, A.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Demirbuker, S. Safer
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological study of the long-term safety and effectiveness of alemtuzumab (IMSE 3)2018In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, no Suppl. 2, p. 706-707Article in journal (Other academic)
    Abstract [en]

    Background: Alemtuzumab (ALZ) is a modulatory drug for patients with relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important to assess the long term safety and effectiveness in a real-world setting. ALZ has therefore been included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology Study 3” (IMSE 3) upon launch in Sweden (March 2014).

    Objective: To follow up the effectiveness and long-term safety of ALZ in a real-world setting.

    Methods: Swedish MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). IMSE 3 includes patients starting ALZ treatment. Adverse events (AEs) and clinical meas-ures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS) are obtained from NeuroReg. The Wilcoxon signed-rank test was used to assess changes in effectiveness.

    Results: 110 patients (60% female; 95% RRMS) have been included in IMSE 3 between March 2014 and April 2018. Mean age at treatment start was 34 years and mean treatment duration was 28 months. Most patients (40%) switched from natalizumab and 14% were treatment naïve. 103 patients were currently treated with ALZ at cut-off date and 97 patients had been treated for at least 12 months. Seven patients had discontinued ALZ treatment, of which five patients switched to another disease modifying therapy, one patient died in association with the first ALZ treatment cycle due to fulminant viral hepatitis and one patient had no treatment registered after ALZ discontinuation. In total, 20 AEs were reported to the Swedish Medical Products Agency; 13 events were classified as non-serious. In patients treated at least 12 months significant improvements were seen for EDSS (2.0±1.4 to 1.6±1.3, n=67), MSSS (3.4±2.6 to 2.6±2.3, n=58), MSIS-29 Physical (22.9±21.0 to 17.5±18.0, n=83), VAS (66.9±22.0 to 73.7±18.5, n=68) and EQ-5D (0.7±0.3 to 0.8±0.3, n=74). MSIS-29 Psychological and SDMT did not improve significantly.

    Conclusions: NeuroReg functions well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. A longer follow-up period is needed to evaluate the real-world effectiveness and safety of ALZ.

  • 33.
    Fält, A.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Demirbüker, S. Safer
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological study of the long-term safety and effectiveness of fingolimod (IMSE 2)2018In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, no Suppl. 2, p. 696-697Article in journal (Other academic)
    Abstract [en]

    Background: Fingolimod (FGL) is an oral therapy for patients with relapsing-remitting multiple sclerosis (RRMS) and the efficacy has been shown in phase II and III studies. However; long-term surveillance and safety is important, therefore FGL is included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study 2” (IMSE 2).

    Objective: To follow up the effectiveness and long-term safety of FGL in a real-world setting.

    Methods: Swedish MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). IMSE 2 includes data of adverse events (AEs) and clinical measures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS), obtained from NeuroReg.

    Results: From September 2011 until April 2018, 1617 patients (67% female; 91% RRMS) were included in IMSE 2. At treatment start 38 patients were ≤20 years (yr), 308 aged 21-30 yr and 1271 aged >30 yr. Mean treatment duration was 34 months. 852 patients were currently treated with FGL at cut-off date and 1230 patients had been treated for at least 12 months. In total, 39% switched treatment from interferons or glatiramer acetate, 26% from natalizumab and 5% from dimethyl fumarate or teriflunomide. 803 patients have discontinued FGL at some point, mainly due to lack of effect (43%) or AEs (34%), most patients switched to rituximab after FGL discontinuation. Relapses were reduced from 281 to 87/1000 patient years (PY) when comparing before and during FGL treatment. In patients aged ≤20 yr, 21-30 yr and >30 yr relapses were reduced from 694 to 144/1000 PY, 455 to 129/1000 PY and 258 to 77/1000 PY, respectively. After 12 months significant improvements were seen in EQ-5D (0.7 to 0.8, n=752), MSSS (3.1 to 2.9, n=410), MSIS-29 Physical (21.1 to 20.0 n=812), MSIS-29 Psychological (29.2 to 24.9, n=812), SDMT (54.3 to 57.0, n=751) and VAS (70.9 to 72.8, n=692). When analysing age groups separately significant improvements were seen in MSSS, SDMT, and MSIS-29 Psychological in patients aged 21-30 yr and >30 yr. EQ-5D, VAS and MSIS-29 Physical significantly improved in patients aged >30 yr.

    Conclusions: FGL is a generally well-tolerated drug that reduces the clinical activity in MS patients. NeuroReg functions well as a drug surveillance platform, enabling monitoring of long-term effectiveness and AEs.

  • 34.
    Fält, A.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Forsberg, L.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A swedish post-market surveillance study of the long-term effectiveness and safety of alemtuzumab (IMSE 3) for patients treated at least 24 months2019In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, no Suppl. 2, p. 327-328Article in journal (Other academic)
    Abstract [en]

    Background: Alemtuzumab (ALZ) is an approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important to assess the long term safety and effectiveness in a real-world setting. ALZ has therefore been included into the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE) upon launch in Sweden (March 2014).

    Objective: To track effectiveness and long-term safety of ALZ in a real-world setting.

    Methods: Swedish MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). IMSE 3 includes all patients starting ALZ treatment with annual clinical measures obtained from NeuroReg; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimension Test (EQ-5D) and Visual Analogue Scale (VAS).

    Results: A total of 118 MS patients (59% female; 95% RRMS) were included in IMSE 3 between March 2014 and April 2019. 95 patients had started ALZ >24 months ago (63% female; 98% RRMS) at cut-off date (31st of Mars 2019), where only 3 patients had switched to another DMT. Mean age at treatment start for patients treated at least 24 months was 34 years and mean treatment duration was 42 months. Mean number of drugs prior ALZ initiation was 2.3. Most patients (41/95) switched to ALZ from natalizumab, while 14/95 patients were treatment naïve with ALZ. The number of relapses per 1,000 patient years decreased from 471 before ALZ initiation to 65 during ALZ treatment (n=83, missing data; n=12). In patients treated ⩾ 24 months significant improvements in mean were seen for EDSS (1.9 ± 1.4 to 1.6 ± 1.3, n=57), MSSS (3.3 ± 2.6 to 2.4 ± 2.1, n=48) and EQ-5D (0.7 ± 0.3 to 0.8 ± 0.3, n=53), while MSIS-29, SDMT and VAS scores remained stable. A total of 28 adverse events were reported to the Swedish Medical Products Agency, 12 events were classified as serious and 16 events as non-serious. Two patients died during ALZ treatment, of which one patient died in association with the first ALZ treatment cycle due to fulminant viral hepatitis.

    Conclusions: Patients treated with ALZ for at least 24 months improved or remained stable across all effectiveness measures. Only a very small percentage of patients switched to other DMTs. Continued follow-up is needed to address long term effectiveness and safety of ALZ.

  • 35.
    Fält, A.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Kågström, S.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Forsberg, L.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Science, Danderyd, Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Science, Danderyd, Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A Swedish real word study of the long-term effectiveness and safety of fingolimod (IMSE 2) with focus on patients treated at least 48 months2019In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, no Suppl. 2, p. 536-537Article in journal (Other academic)
    Abstract [en]

    Background: Fingolimod (FGL) is an oral disease-modifying therapy (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS) introduced in Sweden 2011. Already from launch FGL was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE) in order to enable long-term surveillance of effectiveness and safety aspects in a large population-based cohort.

    Objective: To track the effectiveness and long-term safety of FGL in a real-world setting.

    Methods: Swedish MS patients are registered into the nationwide Swedish Neuro Registry (NeuroReg). IMSE 2 includes patients starting FGL treatment and clinical and demographic data are collected from the NeuroReg. The Wilcoxon signed-rank test was used to assess changes in effectiveness measures.

    Results: From September 2011 until April 2019, 1652 MS patients (67% female; 90% RRMS) were included in IMSE 2. Mean age at treatment start was 39 years and mean treatment duration in the entire cohort was 39 months. 608 patients (64% female; 91% RRMS) had been treated with FGL for at least 48 months with a mean age at treatment start of 40 years and a mean treatment duration of 70 months. A majority (330/608) switched to FGL from interferons/glatiramer acetate, while 194/608 switched from natalizumab. 105/608 patients had discontinued FGL at some point, mainly due to lack of effect (31%) and adverse events (31%). Most patients (57/105) switched to rituximab after FGL discontinuation. The number of relapses per 1,000 patient years were reduced from 275 before FGL initiation to 40 during FGL treatment (27% missing data). In patients treated with FGL at least 48 months significant changes (mean) were seen in Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT) and Visual Analogue Scale (VAS). 80/184 patients had a 4-point or 10% increase in SDMT score between baseline and 48 months. In total 167 adverse events were reported to the Swedish Medical Products Agency of which 77 events were classified as serious.

    Conclusions: FGL displays a relatively high degree of drug persistence and clinical effectiveness is retained over time with significant improvements in MSSS, SDMT and VAS in patients treated at least 48 months. Furthermore, NeuroReg functions well as a drug surveillance platform, enabling monitoring of long-term effectiveness and safety.

  • 36.
    Granqvist, Mathias
    et al.
    Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.
    Burman, Joachim
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Lycke, Jan
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Nilsson, Petra
    Neurology Clinic, Skåne University Hospital, Lund, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.
    Sundström, Peter
    Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Svenningsson, Anders
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Vrethem, Magnus
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Frisell, Thomas
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.
    Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS2020In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 26, no 12, p. 1532-1539Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited.

    OBJECTIVE: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden.

    METHODS:  We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF (n = 641) or interferons/glatiramer acetate (IFN/GA; n = 555) as the initial therapy, or DMF (n = 703) or fingolimod (FGL; n = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016.

    RESULTS: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58, p < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09, p < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13; p < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04; p = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy (p < 0.05 and p = 0.20, respectively).

    CONCLUSION: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.

  • 37.
    Grut, Viktor
    et al.
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Biström, Martin
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Salzer, Jonatan
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Stridh, Pernilla
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Jons, Daniel
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Gustafsson, Rasmus
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Fogdell-Hahn, Anna
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Huang, Jesse
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Brenner, Nicole
    Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Butt, Julia
    Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Bender, Noemi
    Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Lindam, Anna
    Department of Public Health and Clinical Medicine, Unit of Research, Education and Development Östersund Hospital, Umeå University, Umeå, Sweden.
    Alonso-Magdalena, Lucia
    Department of Neurology, Skåne University Hospital in Malmö/Lund and Institution of Clinical Sciences, Neurology, Lund University, Lund, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Vrethem, Magnus
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Bergström, Tomas
    Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Kockum, Ingrid
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Waterboer, Tim
    Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Sundström, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis: a presymptomatic case-control study2021In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 28, no 9, p. 3072-3079Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: 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, we sought to increase the understanding of CMV in MS aetiology.

    METHODS: We performed a nested case-control study with presymptomatically collected blood samples identified through cross-linkage 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 intervals (CI) for CMV seropositivity as 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 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: CMV 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.

  • 38.
    Grut, Viktor
    et al.
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Biström, Martin
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Salzer, Jonatan
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Stridh, Pernilla
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Lindam, Anna
    Department of Public Health and Clinical Medicine, Unit of Research, Education and Development Östersund Hospital, Umeå University, Umeå, Sweden.
    Alonso-Magdalena, Lucia
    Department of Neurology, Skåne University Hospital in Malmö/Lund and Department of Clinical Sciences, Neurology, Lund University, Lund, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Jons, Daniel
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Vrethem, Magnus
    Department of Neurology and Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden.
    Hultdin, Johan
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Sweden.
    Sundström, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Free Vitamin D3 Index and Vitamin D-binding protein in multiple sclerosis: a presymptomatic case-control study2022In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 29, no 8, p. 2335-2342Article in journal (Refereed)
    Abstract [en]

    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.

  • 39.
    Grut, Viktor
    et al.
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Biström, Martin
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Salzer, Jonatan
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Stridh, Pernilla
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Lindam, Anna
    Department of Public Health and Clinical Medicine, Unit of Research, Education and Development Östersund Hospital, Umeå University, Umeå, Sweden.
    Alonso-Magdalena, Lucia
    Department of Neurology, Skåne University Hospital and Department of Clinical Sciences, Neurology, Lund University, Lund, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Jons, Daniel
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Vrethem, Magnus
    Department of Neurology and Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden.
    Hultdin, Johan
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    Sundström, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Systemic inflammation and risk of multiple sclerosis: A presymptomatic case-control study2022In: Multiple Sclerosis Journal, Experimental, Translational and Clinical, E-ISSN 2055-2173, Vol. 8, no 4, article id 20552173221139768Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: C-reactive protein (CRP) is a marker of systemic inflammation. Increased levels of CRP in young persons have been suggested to decrease the risk of multiple sclerosis (MS). OBJECTIVES: To assess CRP as a risk factor for MS. METHODS: Levels of CRP were measured with a high-sensitive immunoassay in biobank samples from 837 individuals who later developed MS and 984 matched controls. The risk of developing MS was analysed by conditional logistic regression on z-scored CRP values. RESULTS: Levels of CRP were not associated with MS risk. CONCLUSIONS: We found no association between CRP levels and risk of MS development.

  • 40.
    Gunnarsson, Martin
    et al.
    Örebro University, School of Medicine, Örebro University, Sweden.
    Udumyan, Ruzan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bahmanyar, S.
    Clinical Epidemiology Unit and Centre for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden; Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran .
    Nilsagård, Ylva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Research Department of Epidemiology and Public Health, University College London, London, United Kingdom .
    Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men: cohort study2015In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 22, no 7, p. 1131-1137Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Associations with multiple sclerosis (MS) of living conditions in childhood and characteristics in adolescence including physical fitness, cognitive function and psychological stress resilience were investigated.

    Methods: A cohort of male Swedish residents born 1952-1956 who were included in the Swedish Military Conscription Register was used to create a nested case-control study comprising 628 MS cases and 6187 controls matched on birth year, county of residence and vital status at time of diagnosis. Conscription examination records were linked with other national register data. Conditional logistic regression was used to evaluate associations with MS subsequent to the conscription examination.

    Results and conclusions: Men with MS were less likely to be from more crowded households in childhood (>two persons per room) with an adjusted odds ratio of 0.67 (95% confidence interval 0.51-0.86, P=0.023). They had lower physical working capacity in adolescence with adjusted odds ratio of 0.94 (95% confidence interval 0.89-0.99, P=0.026). Cognitive function and stress resilience scores displayed no significant differences between cases and controls. Parental occupation in childhood and body mass index in adolescence were not associated with future MS risk. The inverse association of MS risk with higher levels of household crowding may reflect environmental factors such as the pattern of exposure to microorganisms. Lower physical fitness in men at MS risk may indicate a protective effect of exercise or could be due to prodromal disease activity, although there was no association with cognitive function. Poor psychological stress resilience (and thus risk of chronic stress arousal) was not associated with MS.

  • 41.
    Jons, D.
    et al.
    University of Gothenburg, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Göteborg, Sweden.
    Bergström, T.
    University of Gothenburg, Clinical Microbiology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Zetterberg, H.
    University of Gothenburg, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Dahlgren’s Academy, Göteborg, Sweden.
    Biström, M.
    Umeå University, Department of Clinical Science, Neurosciences, Umeå, Sweden.
    Alonso-Magdalena, L.
    Skåne University Hospital, Department of Neurology, Lund, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Vrethem, M.
    Linköping University, Department of Neurology and Department of Clinical and Experimental Medicine, Linköping, Sweden.
    Blennow, K.
    University of Gothenburg, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Dahlgren’s Academy, Göteborg, Sweden.
    Nilsson, S.
    University of Gothenburg, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, Göteborg, Sweden.
    Huang, J.
    Karolinska Institute, Neuroimmunology Unit, The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience, Stockholm, Sweden.
    Kockum, I.
    Karolinska Institute, Neuroimmunology Unit, The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience, Stockholm, Sweden.
    Olsson, T.
    Karolinska Institute, Neuroimmunology Unit, The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience, Stockholm, Sweden.
    Waterboer, T.
    German Cancer Research Center (DKFZ), Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, Heidelberg, Germany.
    Sundström, P.
    Umeå University, Department of Clinical Science, Neurosciences, Umeå, Sweden.
    Andersen, O.
    University of Gothenburg, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Göteborg, Sweden.
    Increase in Epstein Barr virus serologies precedes neuroaxonal damage in pre-symptomatic multiple sclerosis2022In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 28, no Suppl. 3, p. 86-87, article id O111Article in journal (Other academic)
    Abstract [en]

    Introduction: Epstein-Barr virus (EBV) infection may be a pre-condition  for  the development  of  multiple  sclerosis  (MS).  EBV  antibodies, predominantly anti-EBNA1, develop in the presymp-tomatic phase of virtually all MS patients. Using material from a serum repository, studies in advance of MS onset indicated that EBV  seropositivity  preceded  the  first  expression  of  incipient  axonal lesions, serum Neurofilament Light (sNFL) .

    Objectives: To  determine  the  onset  and  individual  order  of  appearance  of EBV  seroreactivity  and  the  serum  neuroaxonal  injury marker neurofilament light (sNfL) in a wide age spectrum of presymptomatic MS patients.

    Aims: To  characterize  the  presymptomatic  appearance  of  anti-bodies against an intranuclear (EBNA1) and a surface EBV anti-gen (gp350) and sNfL.Methods:  A nested  case-control  study  in  669  pre-symptomati-cally acquired blood samples from persons who later received an MS diagnosis, and from 1:1 matched control persons. Serum lev-els of EBNA1, VCA and gp350 IgG antibodies and sNFL (n=519) were   measured   in   individual   presymptomatic   samples   and   expressed  as delta  scores  with  matched  controls  in  relation  to  time until MS onset.

    Results: Serum levels expressed as delta scores for anti EBV and NfL IgG showed an incipient increase for anti EBNA1 and gp350 from  15-20  years  before  MS debut.  Significant  (p=0.001  and  p=0.002) from 10-15 years, with consistent delta-scores succes-sively closer to MS onset. These findings contrasted to the level of sNfL which increasingly diverged from matched controls from 5-10 years before the onset of MS. None of the individual sam-ples  negative  for  both EBNA1 and  VCA  IgG  antibodies  in  the  pre-MS group (n = 36) showed any elevation of the sNfL level.

    Conclusions: In  a  pre-MS  material,  the  seroreactivity  against  EBNA1  was followed  by  VCA  and  gp350,  before  increased  sNFL appeared, indicating incipient axonal injury. Together with its biological characteristics this temporal order confirms the role of EBV as a trigger of MS.

  • 42.
    Jons, Daniel
    et al.
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Department of Clinical Neuroscience, Göteborg, Sweden.
    Grut, Viktor
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Bergström, Tomas
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, the Sahlgrenska Academy, Gothenburg, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bistrom, Martin
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Vrethem, Magnus
    Department of Neurology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Brenner, Nicole
    Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Staffan
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Kockum, Ingrid
    The Karolinska Neuroimmunology & Multiple Sclerosis Center, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Waterboer, Tim
    Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Olsson, Tomas
    The Karolinska Neuroimmunology & Multiple Sclerosis Center, Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Sundstrom, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Andersen, Oluf Andersen
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Department of Clinical Neuroscience, Göteborg, Sweden.
    Epstein-Barr virus seroreactivity, putative autoimmunity and axonal injury in pre-symptomatic multiple sclerosis2023In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 29, no Suppl. 3, p. 39-40Article in journal (Other academic)
    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.

  • 43.
    Jons, Daniel
    et al.
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
    Grut, Viktor
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Bergström, Tomas
    Department of Infectious Diseases, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Department of Clinical Microbiology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Biström, Martin
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Vrethem, Magnus
    Department of Neurology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Brenner, Nicole
    Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center, Heidelberg, Germany.
    Butt, Julia
    Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center, Heidelberg, Germany.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Nilsson, Staffan
    Mathematical Sciences, Chalmers University of Technology, Göteborg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Goteborg, Sweden.
    Kockum, Ingrid
    Department of Clinical Neuroscience, The Karolinska Neuroimmunology & Multiple Sclerosis Center, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, The Karolinska Neuroimmunology & Multiple Sclerosis Center, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Waterboer, Tim
    Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center, Heidelberg, Germany.
    Sundström, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden .
    Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage2023In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, article id jnnp-2023-331868Article in journal (Refereed)
    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.

  • 44.
    Jons, Daniel
    et al.
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Dahlgren's Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Centre for Neurodegenerative Diseases, Hong Kong, China.
    Biström, Martin
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Alonso-Magdalena, Lucia
    Department of Neurology, Skåne University Hospital, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Neurology.
    Vrethem, Magnus
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Dahlgren's Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Nilsson, Staffan
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Sundström, Peter
    Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.
    Andersen, Oluf
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis2022In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 9, no 6, p. 882-887Article in journal (Refereed)
    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.

  • 45.
    Krauss, Wolfgang
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medicine, Örebro University, Sweden.
    Andersson, Torbjorn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Thunberg, Per
    Department of Medical Physics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Accuracy and reproducibility of a quantitative magnetic resonance imaging method for concurrent measurements of tissue relaxation times and proton density2015In: Magnetic Resonance Imaging, ISSN 0730-725X, E-ISSN 1873-5894, Vol. 33, no 5, p. 584-591Article in journal (Refereed)
    Abstract [en]

    Purpose: To evaluate the accuracy and reproducibility of a quantitative magnetic resonance (qMR) imaging method (QRAPMASTER) for simultaneous measurements of T1 and T2 relaxation times, and proton density (PD).

    Materials and Methods: Measurements of T1, T2, and PD with qMR were performed using phantoms with different relaxation times and concentrations of heavy water. Healthy volunteers were examined with different head coils. Regional measurements were performed in normal-appearing white and gray matter from the healthy control subjects, and in multiple sclerosis (MS) patients.

    Results: In phantom measurements, QRAPMASTER slightly underestimated T1, and T2 variations between repeated measurements were modest. PD was generally overestimated. The overall relative difference was 1.2 5.3% (T1), 6.6 1.9% (12), and 0.7 5.1% (PD). In healthy volunteers, there were no statistically significant differences of T1, T2 or PD using different head coils. Values of T1, T2, and PD obtained in healthy controls and MS patients were within reference ranges. However, significant differences were found in normal-appearing gray and white matter.

    Conclusion: QRAPMASTER can be considered a sufficiently accurate and reproducible method for use in clinical practice. Neuropathology in normal-appearing brain tissue may be revealed using this MR method, with putative implications for quantification of tissue damage in neurological diseases. (C) 2015 Elsevier Inc. All rights reserved.

  • 46.
    Krauss, Wolfgang
    et al.
    Örebro University, School of Medical Sciences. Department of Radiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology and Neurophysiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nilsson, Margareta
    Centre for Medical Imaging and Physiology, Skåne University Hospital, Lund, Sweden.
    Thunberg, Per
    Örebro University, School of Medical Sciences. Department of Medical Physics, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Conventional and synthetic MRI in multiple sclerosis: a comparative study2018In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 28, no 4, p. 1692-1700Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To compare the assessment of patients with multiple sclerosis (MS) using synthetic and conventional MRI.

    MATERIALS AND METHODS: Synthetic and conventional axial images were prospectively acquired for 52 patients with diagnosed MS. Quantitative MRI (qMRI) was used for measuring proton density and relaxation times (T1, T2) and then, based on these parameters, synthetic T1W, T2W and FLAIR images were calculated. Image stacks were reviewed blindly, independently and in random order by two radiologists. The number and location for all lesions were documented and categorised. A combined report of lesion load and presence of contrast-enhancing lesions was compiled for each patient. Agreement was evaluated using kappa statistic.

    RESULTS: There was no significant difference in lesion detection using synthetic and conventional MRI in any anatomical region or for any of the three image types. Inter- and intra-observer agreements were mainly higher (p < 0.05) using conventional images but there was no significant difference in any specific region or for any image type. There was no significant difference in the outcome of the combined reports.

    CONCLUSION: Synthetic MR images show potential to be used in the assessment of MS dissemination in space (DIS) despite a slightly lower inter- and intra-observer agreement compared to conventional MRI.

    KEY POINTS:

    • Synthetic MR images may potentially be useful in the assessment of MS.

    • Examination times may be shortened.

    • Inter- and intra-observer agreement is generally higher using conventional MRI.

  • 47.
    Kågström, S.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fält, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Demirbuker, S. Safer
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Berglund, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Göteborg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Real-world longitudinal data of peginterferon beta-1a from a Swedish national post-marketing surveillance study (IMSE 6) - efficacy and safety profile2018In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, no Suppl. 2, p. 927-928Article in journal (Other academic)
    Abstract [en]

    Background: Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. Phase II and III studies have shown that PegIFN reduces relapse rate and reduces the tendency to deteriorate disabilities. However, the long-term safety is important, therefore PegINF is included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study 6” (IMSE 6). Which characterizes the real-world profile of PegIFN, including efficacy, safety, tolerability and patient outcome parameters.

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

    Methods: Approximately 60 collaborating neurology clinics continuously recruited PegIFN patients and documented clinical and demographic data in the nationwide Swedish Neuro Registry (NeuroReg). Data were obtained from NeuroReg between June 2015 and April 2018 for the IMSE 6 study.

    Results: A total of 324 patients (78% female; 88% RRMS; mean age at treatments start 43 years) were followed up to 34 months (mean 15 months) with 26% treatment naïve and 49% switched from other injectables. Mean duration from initial symptom(s) to treatment start was 114 months, and 69 months from MS diagnosis to treatment start. In total, 169 patients discontinued for vari-ous reasons (60% adverse events, 24% lack of effect) and switched mainly to rituximab (63 patients, 37%). The discontinuation rate at 12 months was 42.6%. Relapses before treatment were reduced from 207 to 130/1000 patient years during treatment. With 55% having no relapse and 9% having 1 relapse during treatment period (35% missing data). After 12 months, all clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5-Dimension test (EQ-5D), Visual Analogue Score (VAS), and the mean Symbol Digit Modalities Test (SDMT)) remained stable. A total number of 9 adverse events (6 serious: 1 gastrointestinal disorder, 2 general disorder and administrations site, 2 skin, 1 reproductive) were reported to Swedish Medical Product Agency (MPA).

    Conclusions: NeuroReg proves to function well as a post-marketing drug surveillance platform, providing data regarding drug effectiveness and AEs. This real-world study presentation from IMSE 6 shows a stable efficacy and safety profile in long-term clinical use.

  • 48.
    Kågström, S.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fält, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Demirbüker, S. Safer
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Berglund, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Göteborg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Martin, C.
    Department of Clinical Sciences, Danderyd Hospital, Stockholm, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A Swedish nationwide pharmaco-epidemiological and genetic study of the long-term safety and effectiveness of natalizumab (IMSE 1)2018In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, no Suppl. 2, p. 699-700Article in journal (Other academic)
    Abstract [en]

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

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

    Methods: In Sweden MS patients are registered in the nationwide Swedish Neuro Registry (NeuroReg). IMSE 1 includes patients starting NTZ treatment and data is collected from NeuroReg. Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures are registered prospectively.

    Results: 3052 patients (72% female; 82% RRMS; mean age at treatment start 36 years; mean treatment duration 45.9 months) have been included in IMSE 1 from August 2006 until April 2018. A total of 1234 RRMS patients where included year ≥2011 (JCV test introduction) and had information on JCV (482 anti-JCV anti-bodies (JCV+), 752 JCV negative (JCV-)). 691 of these patients were currently treated with NZT at cutoff date, 88 (13%) of which were JCV+ with a mean JCV index at 1.1±1.1. A total of 612/1234 (49%) discontinued NTZ treatment at some time point of which 266/403 (66%) JCV+ discontinued due to JCV+. JCV- patients mainly discontinued due to pregnancy/planning pregnancy (78/209, 37%) and other reasons (57/209, 27%). The one and two-year drug survival rate was 79% and 45% for JCV+ and 90% and 82% for JCV-. The overall drug survival rate was 16% for JCV+ and 72% for JCV-. In patients with continuous NTZ treatment for ≥2 years (n=738), long lasting stabilization of disease activity was observed. From year 2006 until cutoff, 96 Serious AEs had been reported to the Swedish MPA and included 8 cases (1 fatal) of progressive multifocal leukoencephalopathy (PML), reported between 2008 and 2012. A total of 14 patients have died during or within 6 months after NTZ discontinuation, as reported in NeuroReg. None were reported to be associated to NTZ.

    Conclusions: NeuroReg functions well as a post-marketing drug surveillance platform, providing long-term data on drug effects and AEs. NTZ is generally well tolerated with sustained effective-ness. The introduction of JCV testing has led to fewer treated JCV+ patients, which likely explains a reduced incidence of PML.

  • 49.
    Kågström, S.
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fält, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Forsberg, L.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Berglund, A.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Hillert, J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, P.
    Department of Neurology, Lund University, Lund, Sweden.
    Dahle, C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Lycke, J.
    Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, Göteborg, Sweden.
    Landtblom, A. -M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Burman, J.
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Sundström, P.
    Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
    Martin, C.
    Department of Clinical Science, Danderyd Hospital, Stockholm, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences. Department of Neurology.
    Piehl, F.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Olsson, T.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Improved clinical outcomes in patients treated with natalizumab for at least 8 years - real-world data from a Swedish national post-marketing surveillance study (IMSE 1)2019In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, no Suppl. 2, p. 763-764Article in journal (Other academic)
    Abstract [en]

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

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

    Methods: In Sweden MS patients are registered in the nationwide Swedish Neuro Registry (NeuroReg). IMSE 1 includes patients starting NTZ treatment and data is collected from NeuroReg. Adverse events (AEs), JC-virus status (JCV) and clinical effec-tiveness measures are registered prospectively.

    Results: A total of 3141 patients were included in the IMSE 1 study from August 2006 until April 2019 (72% female; men age 35 years; 79% RRMS; mean treatment duration 50 months) and 288 had been treated for at least 96 months. 71% of these 288 patients (71% female; men age 37 years; 82% RRMS; mean treatment duration 118 months) were treated with interferons and glatiramer acetate prior NTZ. At some point of time, 31% (90/288) discontin-ued NTZ treatment of which 41% discontinued due to JCV posi-tive (JCV+). In total, 30% (86/288) of these patients were JCV+with a mean JCV index of 1.2±1.0 (6% missing data). Relapses before treatment were reduced from 388/1000 patient years to 54 during treatment, 62% were relapse-free and 17% had 1 relapse during the entire treatment period (12% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT)) showed statistically significant improvement between baseline and 96 months. Over the entire observation time, 104 Serious AEs had been reported to the Swedish MPA and included 9 cases (2 fatal) of progressive multifocal leukoencephalopathy (PML) of which 8 between 2008 and 2012, and 1in 2018. 16 patients died during or within 6 months of last NTZ infusion. None were judged to be directly associated with NTZ.

    Conclusions: NTZ is generally well tolerated with sustained effectiveness regarding cognitive, physical and psychological measures, as well as relapse-control. Introduction of JCV testing has led to fewer treated JCV+ patients, which likely explains a drastic drop in the incidence of PML.

  • 50.
    Kågström, S.
    et al.
    Karolinska Institutet, Solna, Sweden.
    Leandersson, Å.
    Karolinska Institutet, Solna, Sweden.
    Forsberg, L.
    Karolinska Institutet, Solna, Sweden.
    Berglund, A.
    Karolinska Institutet, Solna, Sweden.
    Hillert, J.
    Karolinska Institutet, Solna, Sweden.
    Nilsson, P.
    Lund University, Lund, Sweden.
    Dahle, C.
    Linköping University, Linköping, Sweden.
    Svenningsson, A.
    Danderyd Hospital, Danderyd, Sweden.
    Lycke, J.
    Institute of Neuroscience and Physiology, Gothenburg, Sweden.
    Landtblom, A. -M
    Uppsala University, Uppsala, Sweden.
    Burman, J.
    Uppsala University, Uppsala, Sweden.
    Martin, C.
    Danderyd Hospital, Danderyd, Sweden.
    Sundström, P.
    Umeå University, Umeå, Sweden.
    Gunnarsson, Martin
    Örebro University, School of Medical Sciences.
    Piehl, F.
    Karolinska Institutet, Solna, Sweden.
    Olsson, T.
    Karolinska Institutet, Solna, Sweden.
    Real-world data of peginterferon beta-1a from a swedish national post-marketing surveillance study (IMSE 6) - effectiveness and safety profile2020In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 26, no 3 Suppl., p. 302-302Article in journal (Other academic)
    Abstract [en]

    Background: Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. The clinical trial program showed that PegIFN reduced the relapse rate and proportion with disability progression compared to placebo. At its launch in Sweden, PegIFN was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 6), providing possibilities to track long-term effectiveness and safety in a population-based setting.

    Objectives: To follow-up the long-term effectiveness and safety of PegIFN treatment in Swedish patients in a real-world context.

    Methods: Data was obtained from the nationwide Swedish Neuro Registry (NeuroReg) between June 2015 and May 2020. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

    Results: A total of 364 patients (78% female; 87% RRMS; mean age at treatments start 43 years) were followed up to 57 months (mean 20 months), of which 200 (55%) patients had been treated for at least 12 months. The majority of the patients had switched from other injectables (164 patients, 45%) or were treatment naïve (90 patients, 25%) prior to treatment with PegIFN. Over the dura-tion of the follow-up, 68% (247/364) patients discontinued their PegIFN treatment for various reasons (60% adverse events, 24% lack of effect) and switched mainly to rituximab (105 patients, 43%). The overall drug survival was 32%, 40% for men and 30% for women. The one- and two-year drug survival rate was 57% and 40%, respectively. The mean number of relapses were reduced from 0.35 one year before treatment start to 0.11 one year after (35% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5-Dimension test (EQ-5D), Visual Analogue Score (VAS) and Symbol Digit Modalities Test (SDMT)) remained stable. Statistically significant changes were observed in SDMT (p=0.027). A total number of 18 adverse events (6 serious) were reported to Swedish Medical Product Agency.

    Conclusions: These findings are consistent with PegIFN being a safe disease modifying treatment, however, a relatively high pro-portion of patients switched due to adverse events. All clinical effectiveness measures remained stable in patients treated with PegIFN for at least 12 months in this nationwide population-based real-world study. Longer follow up is needed to address the long-term effectiveness.

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