Publications by authors named "Melinda Magyari"

91 Publications

Incidence of malignancy in multiple sclerosis: A cohort study in the Danish Multiple Sclerosis Registry.

Mult Scler J Exp Transl Clin 2021 Oct 23;7(4):20552173211053939. Epub 2021 Nov 23.

Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Denmark.

Background: The association between multiple sclerosis and malignancy is controversial and a current appraisal is needed.

Objective: To determine the incidence of malignancy in patients with multiple sclerosis compared with the general population and in relation to disease-modifying therapy.

Methods: Patients with multiple sclerosis (1995 - 2015) were matched by birth year and sex to individuals without multiple sclerosis in the general population. Patients with multiple sclerosis initiating disease-modifying therapy were evaluated using landmark period analysis. Malignancy risk was assessed by incidence rates, incidence rate ratios, and standardised incidence ratios.

Results: The standardised incidence ratio of any malignancy (excluding non-melanoma skin cancer) in patients with multiple sclerosis ( = 10,557) was 0.96 (95% CI 0.88 - 1.06), and there was no increased incidence of specific malignancy types compared with the general population cohort ( = 103,761). At the 48-month landmark period, the age-adjusted incidence per 100,000 person-years of any malignancy (excluding non-melanoma skin cancer) was 436.7 (95% CI 361.0 - 512.4) in patients newly treated with immunomodulator-only and 675.1 (95% CI 130.4 - 1219.9) in patients newly treated with immunosuppressant-only.

Conclusions: There was no increased incidence of malignancy overall or by type in patients with multiple sclerosis compared neither with the general population nor in relation to disease-modifying therapy.
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http://dx.doi.org/10.1177/20552173211053939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613897PMC
October 2021

Pregnancy in women with MS: Impact on long-term disability accrual in a nationwide Danish Cohort.

Mult Scler 2021 Nov 18:13524585211057767. Epub 2021 Nov 18.

The Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark/The Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark/Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Background: Pregnancy is considered to influence the disease course in women with multiple sclerosis (MS).

Objective: The aim of this study was to investigate the effect of pregnancy on long-term disability accrual in women with MS.

Methods: The Danish Multiple Sclerosis Registry (DMSR) was used to identify women diagnosed with clinically isolated syndrome or relapsing-remitting MS. Cox models with pregnancy as a time-dependent exposure and propensity score (PS) models were used to evaluate time to reach confirmed Expanded Disability Status Scale (EDSS) score of 4 and 6.

Results: A total of 425 women became parous and 840 remained nulliparous. When including pregnancy as a time-dependent exposure, a non-significant association with time to reach EDSS 4 (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.61-1.20) and EDSS 6 (HR 0.70, 95% CI 0.40-1.20) was found. Correspondingly, the PS model showed no association with pregnancy on time to reach EDSS 4 (HR 0.85, 95% CI 0.56-1.28).

Conclusion: This study concludes that pregnancy does not affect long-term disability accumulation.
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http://dx.doi.org/10.1177/13524585211057767DOI Listing
November 2021

Fitbeat: COVID-19 estimation based on wristband heart rate using a contrastive convolutional auto-encoder.

Pattern Recognit 2022 Mar 26;123:108403. Epub 2021 Oct 26.

The RADAR-CNS Consortium, London, United Kingdom.

This study proposes a contrastive convolutional auto-encoder (contrastive CAE), a combined architecture of an auto-encoder and contrastive loss, to identify individuals with suspected COVID-19 infection using heart-rate data from participants with multiple sclerosis (MS) in the ongoing RADAR-CNS mHealth research project. Heart-rate data was remotely collected using a Fitbit wristband. COVID-19 infection was either confirmed through a positive swab test, or inferred through a self-reported set of recognised symptoms of the virus. The contrastive CAE outperforms a conventional convolutional neural network (CNN), a long short-term memory (LSTM) model, and a convolutional auto-encoder without contrastive loss (CAE). On a test set of 19 participants with MS with reported symptoms of COVID-19, each one paired with a participant with MS with no COVID-19 symptoms, the contrastive CAE achieves an unweighted average recall of , a sensitivity of and a specificity of , an area under the receiver operating characteristic curve (AUC-ROC) of 0.944, indicating a maximum successful detection of symptoms in the given heart rate measurement period, whilst at the same time keeping a low false alarm rate.
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http://dx.doi.org/10.1016/j.patcog.2021.108403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547790PMC
March 2022

Application of definitions for conversion to secondary progressive MS in a Danish nationwide population.

Mult Scler Relat Disord 2021 Oct 10;56:103319. Epub 2021 Oct 10.

The Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark; Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: The number of patients with relapsing remitting multiple sclerosis (RRMS) who convert to secondary progressive (SP) MS is uncertain, and with emerging treatment options for SPMS, it is important to identify RRMS patients in transition to the SP phase. The objective of the present study was to characterize clinical parameters and use of disease modifying therapies in patients diagnosed with SPMS and RRMS patients already entered the SP phase by use of the Danish Multiple Sclerosis Registry (DMSR).

Methods: We used a cross-sectional design, including all living patients with MS as of June 30, 2020 from DMSR. First, we applied the MSBase definition of SPMS on all RRMS patients. Second, we applied the slightly modified inclusion criteria from the EXPAND clinical trial on patients with clinically confirmed SPMS and patients with RRMS fulfilling the MSBase definition of SPMS to identify SPMS patients recently progressed who may benefit from treatment with disease modifying therapy. We compared clinical characteristics and disease-modifying therapy use in the different patient groups.

Results: Among patients with clinically confirmed SPMS, application of a slightly modified EXPAND trial inclusion criteria for SPMS (m-EXPAND) captured patients who had converted to SPMS more recently and who had relapsed and initiated high-efficacy treatment more frequently. Moreover, our RRMS patients fulfilling the "SPMS"-criteria according to MSBase and recently progression according to m-EXPAND had similar characteristics and remarkably resembled the SPMS population in the EXPAND trial.

Conclusion: Our results indicate that data-driven diagnostic definitions might help identify RRMS patients at risk for SPMS and we highlight the challenges and reluctance in diagnosing SPMS in clinical practice.
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http://dx.doi.org/10.1016/j.msard.2021.103319DOI Listing
October 2021

Ocrelizumab treatment in multiple sclerosis: A Danish population-based cohort study.

Eur J Neurol 2021 Oct 13. Epub 2021 Oct 13.

The Danish Multiple Sclerosis Registry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

Background And Purpose: Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting.

Methods: A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed.

Results: A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections.

Conclusions: It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.
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http://dx.doi.org/10.1111/ene.15142DOI Listing
October 2021

Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis.

Neurology 2021 11 5;97(19):e1870-e1885. Epub 2021 Oct 5.

From the CORe (S.S.-Y., T.K.), Department of Medicine, and Neuroepidemiology Unit (S.S.-Y., N.N., A.F.), Melbourne School of Population & Global Health, University of Melbourne, Parkville, Australia; Menzies Institute for Medical Research (S.S.-Y.), University of Tasmania, Hobart, Australia; ESAT-STADIUS (E.D.B., Y.M., A.P.), KU Leuven, Belgium; Department of Neurology (T.K.), Melbourne MS Centre, Royal Melbourne Hospital, Parkville, Australia; MS International Federation (N.R., C.W.), London, UK; Department of Clinical Neuroscience (J.A.H., T.S., L.F., A.G.), Swedish MS Registry, Stockholm, Sweden; Department of Neurology (G.E.), CHU Pontchaillou, Rennes, France; Karolinska Institutet (T.S.), Solna, Sweden; Biomedical Research Institute-Data Science Institute (L.G., A.P., L.P.), Hasselt University, Belgium; Department of Medical Informatics (T.P.), University Medical Center Göttingen, Germany; Department of Computer Science and AI (C.G.), KU Leuven, Belgium; QMENTA (N.L.), Barcelona, Spain; Medpace Reference Laboratories (A.A.), Molecular Unit, Leuven, Belgium; iConquerMS People-Powered Research Network (R. McBurney, H.S.), Accelerated Cure Project for MS, Waltham, MA; NeuroTransData Study Group (A.B.B., S.B.), NeuroTransData, Neuburg, Germany; German MS-Register by the National MS Society (A. Stahmann), MS Forschungs- und Projektentwicklungs-gGmbH, Hannover, Germany; UK MS Register (R. Middleton, R.S.N.), Swansea University, UK; COViMS (A. Salter, R.J.F.), US; Division of Biostatistics (A. Salter), Washington University in St. Louis, St Louis, MO; Mellen Center for Multiple Sclerosis (R.J.F.), Cleveland Clinic, Cleveland, OH; Department of Neuroscience (A.v.d.W., H.B.), Central Clinical School, Monash University, Melbourne, Australia; Al-Amiri Hospital (R.A.), Kuwait City, Kuwait; Dokuz Eylul University (S.O.), Izmir, Turkey; Neurology Department (J.I.R.), Hospital Universitario de CEMIC; RELACOEM (J.I.R., R.N.A.), Buenos Aires, Argentina; Australian MS Longitudinal Study (I.v.d.M.), Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; Bulgarian SmartMS COVID-19 Dataset (R.I.), Sofia, Bulgaria; ABEM-Brazilian MS Patients Association (G.S.d.O., A.E.D.), São Paulo, Brazil; Danish Multiple Sclerosis Registry (M.M.), Department of Neurology, University Hospital Rigshospitalet, Glostrup, Denmark; Universidade Estadual Paulista (D.B.), Unesp, Faculdade de Medicina, Botucatu, Brazil; REDONE.br-Brazilian Registry of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders (D.B., M.F.M.); Irmandade da Santa Casa de Misericórdia de São Paulo (M.F.M.), Brazil; Multiple Sclerosis University Center (R.N.A.), Ramos Mejia Hospital-EMA, Buenos Aires, Argentina; Imperial College London (R.S.N.); Swansea University (R.S.N.), Swansea, UK; Mental Health Area (J.B.); MS and Demyelinating Diseases (A.S.C.)., Hospital Británico de Buenos Aires, EMA, Argentina; Servei de Neurologia-Neuroimmunologia (A.Z., G.A.), Centre d'Esclerosi Múltiple de Catalunya, (Cemcat); Vall d'Hebron Institut de Recerca (A.Z., G.A.), Vall d'Hebron Hospital Universitari; Universitat Autònoma de Barcelona (A.Z., G.A.), Spain; and Institute of Experimental Neurology (G.C.), Ospedale San Raffaele, Milan, Italy.

Background And Objectives: People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS.

Methods: Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score.

Results: Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02) and ICU admission (aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07) and ICU admission (aOR 2.55, 95% CI 1.49-4.36; aOR 4.32, 95% CI 2.27-8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13-3.07; aOR 2.88, 95% CI 1.68-4.92) and ICU admission (aOR 2.13, 95% CI 0.85-5.35; aOR 3.23, 95% CI 1.17-8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71-17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity.

Discussion: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.
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http://dx.doi.org/10.1212/WNL.0000000000012753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601210PMC
November 2021

Apparent changes in the epidemiology and severity of multiple sclerosis.

Nat Rev Neurol 2021 Nov 28;17(11):676-688. Epub 2021 Sep 28.

The Danish Multiple Sclerosis Registry, Copenhagen University Hospital, Copenhagen, Denmark.

Multiple sclerosis (MS) is an immunological disease that causes acute inflammatory lesions and chronic inflammation in the CNS, leading to tissue damage and disability. As awareness of MS has increased and options for therapy have come into use, a large amount of epidemiological data have been collected, enabling studies of changes in incidence and disease course over time. Overall, these data seem to indicate that the incidence of MS has increased, but the course of the disease has become milder, particularly in the 25 years since the first disease-modifying therapies (DMTs) became available. A clear understanding of these trends and the reasons for them is important for understanding the factors that influence the development and progression of MS, and for clinical management with respect to prevention and treatment decisions. In this Review, we consider the evidence for changes in the epidemiology of MS, focusing on trends in the incidence of the disease over time and trends in the disease severity. In addition, we discuss the factors influencing these trends, including refinement of diagnostic criteria and improvements in health-care systems that have increased diagnosis in people with mild disease, and the introduction and improvement of DMT.
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http://dx.doi.org/10.1038/s41582-021-00556-yDOI Listing
November 2021

Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts.

CNS Drugs 2021 11 18;35(11):1217-1232. Epub 2021 Sep 18.

Neurology Unit, Garibaldi Hospital, Catania, Italy.

Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined.

Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest.

Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients' sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed with weighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score.

Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15-41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65-0.88); in those aged ≤ 38 years (0.64; 0.54-0.76); in those with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51).

Conclusions: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity.
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http://dx.doi.org/10.1007/s40263-021-00860-7DOI Listing
November 2021

Pregnancy-Related and Perinatal Outcomes in Women With Multiple Sclerosis: A Nationwide Danish Cross-sectional Study.

Neurol Clin Pract 2021 Aug 3;11(4):280-290. Epub 2021 Feb 3.

Department of Neurology (JBA, TIK), The Danish Multiple Sclerosis Registry, University of Copenhagen; and Department of Neurology (FS, MM), The Danish Multiple Sclerosis Center, University of Copenhagen, Denmark.

Objective: To investigate differences in pregnancy-related and perinatal outcomes in women with multiple sclerosis (MS) compared with the general population.

Methods: We conducted a cross-sectional study including pregnancies from January 1, 1997, to December 31, 2016, to women registered in the Danish Multiple Sclerosis Registry (the study cohort). Pregnancy-related and perinatal outcomes were compared with a randomly selected subcohort of pregnancies from the general population (the comparison cohort) using logistic regression adjusted for possible confounders.

Results: In total, 2,930 pregnancies were included in the study cohort and 56,958 pregnancies in the comparison cohort. No differences were found in pregnancy-related complications (preeclampsia/gestational diabetes or placenta complications), emergency caesarean section (c-section), instrumental delivery, low Apgar score, stillbirth, preterm birth, or congenital malformations. Elective c-section (odds ratio [OR] 1.89 [95% confidence interval (CI) 1.65-2.16]), induced delivery (OR 1.15 [95% CI 1.01-1.31]), and being born small for gestational age (SGA) (OR 1.29 [95 %CI 1.04-1.60]) had a higher prevalence in the study cohort, whereas the prevalence of signs indicating asphyxia was lower in the study cohort (OR 0.87 [95% CI 0.78-0.97]) relative to the comparison cohort.

Conclusion: We found a higher prevalence of elective c-sections, induced delivery, and infants being SGA among newborns to women with MS, whereas the prevalence of asphyxia was lower in the study cohort. There were no significant differences in severe adverse perinatal outcomes when comparing women with MS and their newborns with those of the general population.
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http://dx.doi.org/10.1212/CPJ.0000000000001035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382416PMC
August 2021

Treatment Escalation vs Immediate Initiation of Highly Effective Treatment for Patients With Relapsing-Remitting Multiple Sclerosis: Data From 2 Different National Strategies.

JAMA Neurol 2021 Oct;78(10):1197-1204

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.

Importance: Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The difference in the association of these national strategies with clinical outcomes is unknown.

Objective: To investigate the association of national differences in disease-modifying treatment (DMT) strategies for RRMS with disability outcomes.

Design, Setting, And Participants: This cohort study used data on 4861 patients from the Danish and Swedish national multiple sclerosis (MS) registries from the date of index DMT initiation (between January 1, 2013, and December 31, 2016) until the last recorded visit at time of data extraction (October 2, 2019).

Exposures: All MS-specific DMTs initiated during the observation period were included in the analysis.

Main Outcomes And Measures: The primary study outcome was time to 24-week confirmed disability worsening. Secondary outcomes were 24-week confirmed disability improvement, milestone Expanded Disability Status Scale scores of 3 and 4, annualized relapse rate, time to first relapse, and treatment switching. Data were analyzed using inverse probability of treatment weighting-based models using a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the 2 countries.

Results: A total of 2700 patients from the Swedish MS registry (1867 women [69.2%]; mean [SD] age, 36.1 [9.5] years) and 2161 patients from the Danish MS registry (1472 women [68.1%]; mean [SD] age, 37.3 [9.4 years]) started a first DMT between 2013 and 2016, were included in the analysis, and were observed for a mean (SD) of 4.1 (1.5) years. A total of 1994 Danish patients (92.3%) initiated a low to moderately effective DMT (teriflunomide, 907 [42.0%]) and 165 (7.6%) initiated a highly effective DMT, whereas a total of 1769 Swedish patients (65.5%) initiated a low to moderately effective DMT (teriflunomide, 64 [2.4%]) and 931 (34.5%) initiated a highly effective DMT. The Swedish treatment strategy was associated with a 29% reduction in the rate of postbaseline 24-week confirmed disability worsening relative to the Danish treatment strategy (hazard ratio, 0.71; 95% CI, 0.57-0.90; P = .004). The Swedish treatment strategy was also associated with a 24% reduction in the rate of reaching an expanded disability status scale score of 3 (hazard ratio, 0.76; 95% CI, 0.60-0.97; P = .03) and a 25% reduction in the rate of reaching an expanded disability status scale score of 4 (hazard ratio, 0.75; 95% CI, 0.61-0.96; P = .01) relative to Danish patients.

Conclusions And Relevance: The findings of this study suggest that there is an association between differences in treatment strategies for RRMS and disability outcomes at a national level. Escalation of treatment efficacy was inferior to using more efficacious DMT as initial treatment.
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http://dx.doi.org/10.1001/jamaneurol.2021.2738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369379PMC
October 2021

Relapses add to permanent disability in relapsing multiple sclerosis patients.

Mult Scler Relat Disord 2021 Aug 17;53:103029. Epub 2021 May 17.

The Danish Multiple Sclerosis Registry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; The Danish Multiple Sclerosis Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Electronic address:

Objective: Whether relapses have direct effects on permanent disability in multiple sclerosis is still an unsettled issue. We aimed at investigating the cumulative effect of breakthrough relapses on the Expanded Disability Status Scale (EDSS) in relapsing-onset MS patients under disease modifying therapy (DMT).

Methods: From the Danish Multiple Sclerosis Registry we identified all patients in Denmark with relapsing-onset MS who had started DMT and followed them from the first day of treatment. We included patients aged 18-59 with Kurtzke's EDSS score < 6.0 at entry, and we compared patients with and without relapses during follow-up. Endpoints were 1) annualized increase in EDSS; 2) time to 6-month sustained EDSS-worsening; 3) time to EDSS 6.0; and 4) time to increase in pyramidal- and cerebellar functional systems. Patients with and without relapses after entry were 1:1 matched by sex, EDSS, and age at entry. We analysed EDSS-worsening with adjusted Generalized Linear Models and time to the endpoints with adjusted Cox regression.

Results: We included 1,428 patients with breakthrough relapses and 1,428 without. The adjusted annualized increase in EDSS was 0.179 in patients with relapses (95% CI 0.164 - 9.194) and 0.086 in patients without relapses (95% CI 0.074 - 0.097), but in patients with EDSS ≥ 4.0 at entry there was no difference. The hazard ratio for irreversible worsening of EDSS was 1.83 (95% CI 1.58 - 2.12) and for irreversible increase to EDSS 6.0 or more 1.62 (95% CI 1.25 - 2.10). Irreversible increase in pyramidal and cerebellar functional system scores also happened significantly earlier in patients with breakthrough relapses.

Conclusions: Our results indicate that breakthrough relapses under DMT is associated with increasing permanent disability in patients with EDSS < 4.0 at treatment start which calls for effective prevention of relapses.
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http://dx.doi.org/10.1016/j.msard.2021.103029DOI Listing
August 2021

The effectiveness of natalizumab vs fingolimod-A comparison of international registry studies.

Mult Scler Relat Disord 2021 Aug 8;53:103012. Epub 2021 May 8.

KTU Medical Faculty Farabi Hospital, Trabzon, Turkey.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening.

Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting.

Results: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod.

Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.
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http://dx.doi.org/10.1016/j.msard.2021.103012DOI Listing
August 2021

Real-world outcomes for a complete nationwide cohort of more than 3200 teriflunomide-treated multiple sclerosis patients in The Danish Multiple Sclerosis Registry.

PLoS One 2021 18;16(5):e0250820. Epub 2021 May 18.

The Danish Multiple Sclerosis Registry, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.

Objective: Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013-2019.

Methods: This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits.

Results: A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p<0.0001). Furthermore, 85% of the patients with available data were free of disability worsening at the end of follow-up.

Conclusions: Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130956PMC
November 2021

Early treatment delays long-term disability accrual in RRMS: Results from the BMSD network.

Mult Scler 2021 09 26;27(10):1543-1555. Epub 2021 Apr 26.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Background: The optimal timing of treatment starts for achieving the best control on the long-term disability accumulation in multiple sclerosis (MS) is still to be defined.

Objective: The aim of this study was to estimate the optimal time to start disease-modifying therapies (DMTs) to prevent the long-term disability accumulation in MS, using a pooled dataset from the Big Multiple Sclerosis Data (BMSD) network.

Methods: Multivariable Cox regression models adjusted for the time to first treatment start from disease onset (in quintiles) were used. To mitigate the impact of potential biases, a set of pairwise propensity score (PS)-matched analyses were performed. The first quintile, including patients treated within 1.2 years from onset, was used as reference.

Results: A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively. The risk of reaching all the disability outcomes was significantly lower ( < 0.0004) for the first quintile patients' group.

Conclusion: Real-world data from the BMSD demonstrate that DMTs should be commenced within 1.2 years from the disease onset to reduce the risk of disability accumulation over the long term.
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http://dx.doi.org/10.1177/13524585211010128DOI Listing
September 2021

Disease-modifying therapies and SARS-CoV-2 vaccination in multiple sclerosis: an expert consensus.

J Neurol 2021 Nov 12;268(11):3961-3968. Epub 2021 Apr 12.

MS Center and Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.

Coronavirus disease (COVID-19) appeared in December 2019 in the Chinese city of Wuhan and has quickly become a global pandemic. The disease is caused by the severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2), an RNA beta coronavirus phylogenetically similar to SARS coronavirus. To date, more than 132 million cases of COVID19 have been recorded in the world, of which over 2.8 million were fatal ( https://coronavirus.jhu.edu/map.html ). A huge vaccination campaign has started around the world since the end of 2020. The availability of vaccines has raised some concerns among neurologists regarding the safety and efficacy of vaccination in patients with multiple sclerosis (MS) taking immunomodulatory or immunosuppressive therapies.
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http://dx.doi.org/10.1007/s00415-021-10545-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038920PMC
November 2021

Treatment Switching and Discontinuation Over 20 Years in the Big Multiple Sclerosis Data Network.

Front Neurol 2021 17;12:647811. Epub 2021 Mar 17.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Although over a dozen disease modifying treatments (DMTs) are available for relapsing forms of multiple sclerosis (MS), treatment interruption, switching and discontinuation are common challenges. The objective of this study was to describe treatment interruption and discontinuation in the Big MS data network. We merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2016 from five clinical registries in this cohort study. Treatment stop was defined as a clinician recorded DMT end for any reason and included treatment interruptions, switching to alternate DMTs and long-term or permanent discontinuations. The incidence of DMT stopping cross the full observation period was lowest in FTY (19.7 per 100 person-years (PY) of treatment; 95% CI 19.2-20.1), followed by NAT (22.6/100 PY; 95% CI 22.2-23.0), IFNβ (23.3/100 PY; 95% CI 23.2-23.5). Of the 184,013 observed DMT stops, 159,309 (86.6%) switched to an alternate DMT within 6 months. Reasons for stopping a drug were stable during the observation period with lack of efficacy being the most common reason followed by lack of tolerance and side effects. The proportion of patients continuing on most DMTs were similarly stable until 2014 and 2015 when drop from 83 to 75% was noted. DMT stopping reasons and rates were mostly stable over time with a slight increase in recent years, with the availability of more DMTs. The overall results suggest that discontinuation of MS DMTs is mostly due to DMT properties and to a lesser extent to risk management and a competitive market.
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http://dx.doi.org/10.3389/fneur.2021.647811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010264PMC
March 2021

Alemtuzumab treatment in Denmark: A national study based on the Danish Multiple Sclerosis Registry.

Mult Scler 2021 Dec 29;27(14):2254-2266. Epub 2021 Mar 29.

Department of Neurology, Odense University Hospital, Odense, Denmark/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

Objective: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark.

Methods: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits.

Results: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab ( < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88,  < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95,  = 0.001).

Conclusion: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.
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http://dx.doi.org/10.1177/13524585211003291DOI Listing
December 2021

Population-based head-to-head comparison of the clinical characteristics and epidemiology of AQP4 antibody-positive NMOSD between two European countries.

Mult Scler Relat Disord 2021 Jun 3;51:102879. Epub 2021 Mar 3.

Department of Neurology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

Background: Population-based clinical studies in neuromyelitis optica spectrum disorder (NMOSD) and epidemiological and clinical comparisons of White ethnicities are missing. In a large population-based international cohort, we extensively characterized aquaporin-4 antibody seropositive (AQP4-Ab+) NMOSD, and also compared the clinical, radiological and epidemiological features between two European populations residing in different areas.

Methods: Between self-reported Danish and Hungarian ethnicities, we compared the population-based clinical features, disability outcomes, and death of 134 AQP4-Ab+ NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis (IPND) criteria. For precise comparison of epidemiology, we conducted a population-based head-to-head comparative study of the age-standardized prevalence (January 1, 2014) and incidence (2007-2013) of AQP4-Ab+ NMO/NMOSD among adults (≥16 years) in Denmark (4.6 million) and Hungary (6.4 million) by applying 2015 IPND (NMOSD) criteria and 2006 Wingerchuk (NMO).

Results: Danes were more likely to present with transverse myelitis and were more affected by spinal cord damage on long-term disability. Hungarians presented most often with optic neuritis, although visual outcome was similar in the groups. No differences were observed in sex, disease course, relapse rate, autoimmune comorbidity, mortality, brain MRI, and treatment strategies. The age-standardized prevalence estimates of AQP4-Ab+ NMOSD (2015 IPND criteria) in Denmark vs. Hungary were 0.66 vs. 1.43 (/100,000) while incidence rates were 0.04 vs. 0.11 (/100,000 person-years); similar differences were found based on the 2006 NMO criteria.

Conclusions: This head-to-head comparative study indicates different disease characteristics and epidemiology among White populations in Europe, and substantiates the need for population-based genetic and environmental studies in NMOSD.
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http://dx.doi.org/10.1016/j.msard.2021.102879DOI Listing
June 2021

Late-onset MS is associated with an increased rate of reaching disability milestones.

J Neurol 2021 Sep 7;268(9):3352-3360. Epub 2021 Mar 7.

Department of Neurology, Danish Multiple Sclerosis Center, Rigshospitalet Glostrup, Valdemar Hansens Vej 2, indgang 8, 2. sal, 2600, Glostrup, Denmark.

Objective: To describe patient characteristics and assess the risk of disability worsening in patients of different age groups with focus on late-onset multiple sclerosis (LOMS) defined as disease onset after the age of 50 years.

Methods: The nationwide population-based Danish Multiple Sclerosis Registry served as data source. We described baseline characteristics and analyzed rates of reaching Expanded Disability Status Scale (EDSS) milestones.

Results: We identified 28,232 patients with MS with a known year of clinical onset, of which 2661 had LOMS. The LOMS group had a higher proportion of males and patients with primary progressive disease course, and they were less likely to receive disease-modifying therapy. The initial rate of reaching EDSS milestone 6 after diagnosis was higher in LOMS [hazard ratio (HR) 1.53; 95% confidence interval (CI) 1.14-2.06]; however, when assessing the risk of reaching EDSS 6 according to age, the HR was significantly lower for the LOMS group (HR 0.307; 95% CI 0.221-0.426).

Conclusion: The clinical characteristics and treatment approaches for patients with LOMS differ from their younger counterparts. Following diagnosis, patients with LOMS initially have an increased rate of reaching EDSS score 6; however, the risk of reaching EDSS score 6 at any given age is higher in patients with non-LOMS.
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http://dx.doi.org/10.1007/s00415-021-10490-0DOI Listing
September 2021

Age and sex as determinants of treatment decisions in patients with relapsing-remitting MS.

Mult Scler Relat Disord 2021 May 5;50:102813. Epub 2021 Feb 5.

Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Denmark.

Background: . Most patients with relapsing-remitting multiple sclerosis (RRMS) are initially treated with moderate efficacy disease-modifying therapies (meDMTs), and only a smaller group of highly active patients are initiated on a high efficacy disease-modifying therapy (heDMT). Real-world data have shown that choosing a heDMT as the initial therapy in highly active RRMS patients is more effective than using a meDMT, and that in patients with breakthrough disease on a meDMT escalation of treatment to a heDMT is more effective than staying on the same or switching to another meDMT. The role of age and sex as determinants for selection of the initial treatment intensity, and for using escalation of treatment intensity in patients with relapse activity on treatment with meDMTs, is only partially known.

Methods: . We included all Danish patients with RRMS registered in The Danish Multiple Sclerosis Registry who began a DMT since 2014 and stratified the cohort according to sex and age < 40 and ≥ 40 years at first DMT treatment. We studied determinants, with emphasis on age and sex, for the primary choice of therapy, for adherence to the initial therapy and for treatment escalation. Based on existing literature and clinical relevance, we included the following potential confounders in the analyses: DMT efficacy, pre-treatment relapse activity, disease duration, Expanded Disability Status Scale (EDSS) score, and, in a subgroup, MRI activity.

Results: . With all covariates mutually adjusted, patient age was a strong decisive factor for choosing a heDMT with odds ratio 1.69 for starting a heDMT in patients < 40 years compared with patients ≥ 40 years. Men had odds ratio 1.53 for starting with a heDMT compared with women. The odds ratio of heDMT in patients with EDSS > 3 vs ≤ 3 was 3.49, and every additional relapse was associated with increased odds ratio 2.33 for heDMT. Patients were more adherent to the initial heDMTs than to the initial meDMTs. Patients above 40 years were more prone to stay on the initial treatment compared to patients below 40, regardless of whether the initial treatment was meDMT (p<0.001) or heDMT (p=0.008) (covariates mutually adjusted). Relapse activity resulted in escalation of therapy to a heDMT in 67% of patients aged < 40 years (N=273) and in 56% patients aged 40 years or above (N=159) (p=0.008), and younger patients had odds ratio 1.46 of escalating therapy compared to older patients. Male patients were more likely to have treatment escalation to heDMTs than female patients (odds ratio 2.03).

Conclusion: . Age and sex appear to be independent determinants for the choice of the initial DMT and for the decision of treatment escalation in patients with breakthrough disease on a meDMT. It is unfortunate, if older age is a factor that make choice of a heDMT more unlikely, as many DMTs seems to be less efficacious in older patients.
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http://dx.doi.org/10.1016/j.msard.2021.102813DOI Listing
May 2021

Seasonal patterns of relapse and disability in Danish MS patients: A population-based cohort study.

Mult Scler Relat Disord 2021 Apr 7;49:102739. Epub 2021 Jan 7.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, Denmark.

Background: The importance of environmental risk factors in the onset of multiple sclerosis (MS) has been studied extensively. Similarly, a growing number of studies address the importance of environmental factors, including seasonality, for ongoing activity of established disease. Specifically, past research demonstrates higher rates of relapse activity in summer months among individuals with MS. Our study adds to the existing literature on seasonality of disease relapse by analysing a large population-based and virtually complete cohort of patient with relapsing and remitting MS (RRMS) in an area of temperate climate.

Methods: The Danish Multiple Sclerosis Registry includes follow-up for all patients receiving disease modifying treatment from 1996-2020, with near-complete registration of all relapses and their dates. We compared the observed and expected numbers of relapses for each calendar month and calculated month-specific annualized relapse rates (ARR) using Poisson regression. In addition, we analysed seasonal variation in disability as measured by the Expanded Disability Status Scale (EDSS).

Results: From 1996 to 2020 we followed 13,575 MS patients treated with disease modifying therapy (4165 men and 9410 women) for a total of 82,187 person years and 134,593 control visits. The mean age at entry was 41.1 years with standard deviation 10.9 years. We recorded 16,083 relapses throughout the observation period, and for 15,728 of the relapses the date of onset was known. Relapses were unevenly distributed by calendar month (p < 0.00001). The most prominent deviation was a paucity of relapses in July in which the ARR was 0.166 compared with mean of 0.191 for the whole year. Otherwise, the ARR formed a plateau slightly above mean during the spring months. Mean EDSS was slightly higher in autumn (2.78) than in spring (2.74), but there was no difference between winter and summer; p < 0.0001.

Conclusion: In contrast with previous studies, we observed a nadir of relapses in July among Danish patients with RRMS. This finding may be related to increased exposure to sunlight in the summer, particularly during vacation when outdoor recreational activities are more frequent and potential exposure to infections is decreased. Confirmation of this in future studies is warranted.
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http://dx.doi.org/10.1016/j.msard.2021.102739DOI Listing
April 2021

Effect of lateral therapy switches to oral moderate-efficacy drugs in multiple sclerosis: a nationwide cohort study.

J Neurol Neurosurg Psychiatry 2021 May 12;92(5):556-562. Epub 2021 Jan 12.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Switching between first-line disease-modifying therapies in patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) due to reasons other than disease activity is frequent, but evidence on the effect of this practice is limited. We investigated the effect of switching patients with stable RRMS on occurrences of disability accumulation, relapses and future treatment discontinuation.

Methods: Using the Danish Multiple Sclerosis Registry, we identified patients with RRMS without disease activity who either (1) stayed on injectable platform therapy (interferon-β or glatiramer acetate) or (2) switched to dimethyl fumarate (DMF) or teriflunomide (TFL) and compared treatment outcomes using propensity-score-based methods and marginal structural models (MSM).

Results: We included 3206 patients in the study. We found no change in risk of 6-month confirmed Expanded Disability Status Scale score worsening in patients switching to DMF (HR: 1.15, 95% CI 0.88 to 1.50) or TFL (HR: 1.16, 95% CI 0.92 to 1.46). The risk of suffering any relapse tended to decrease when switching to DMF (HR: 0.73, 95% CI 0.51 to 1.04) and tended to increase when switching to TFL (HR: 1.25, 95% CI 0.96 to 1.63). Absolute risk differences were small. MSM analyses showed similar results but did not find an increased relapse risk in TFL switchers.

Conclusion: Switching from injectable platform therapies to oral first-line therapies in patients with clinically stable RRMS does not increase the risk of disability accumulation. While the postswitch risk of relapses trended towards marginally higher on TFL, this trend was eliminated by adjustment for time-variant confounders.
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http://dx.doi.org/10.1136/jnnp-2020-324869DOI Listing
May 2021

Maternal diabetes and risk of multiple sclerosis in the offspring: A Danish nationwide register-based cohort study.

Mult Scler 2021 10 17;27(11):1686-1694. Epub 2020 Dec 17.

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Background: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM).

Objectives: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers.

Methods: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring.

Results: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35-3.75,  = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49-2.16),  = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78-2.54),  = 11).

Conclusion: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.
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http://dx.doi.org/10.1177/1352458520977120DOI Listing
October 2021

Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.

Neurology 2021 01 11;96(2):59-77. Epub 2020 Dec 11.

From the Department of Neurology (V.P., Z.I.), Odense University Hospital; Danish Multiple Sclerosis Center (M.M.), Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Neurology (O.A.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology (T.B.), Medical University of Vienna, Austria; Menzies Health Institute Queensland (S.A.B.), Griffith University, Gold Coast; Department of Neurology (S.A.B.), Gold Coast University Hospital, Australia; Department of Neurology (P.C.), Fort-de-France University Hospital Center, Pierre Zobda Quitman Hospital, Fort-de-France, Martinique, France; Department of Neurology (A.J.), The Walton Centre, Liverpool, UK; Cleveland Clinic (A.J.), Abu Dhabi, United Arab Emirates; Departments of Neurology (J.K., J.P.), Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Nuffield Department of Clinical Neurosciences (M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK; Service de Neurologie (R.M.), Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, et Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France; Department of Neurology (K.M.), Kindai University Graduate School of Medicine, Osaka, Japan; Center of Neuroimmunology (A.S., M.S.), Service of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Department of Neurology (O.S.), Karolinska University Hospital and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Clinical Research (Z.I.), University of Southern Denmark, Odense, Denmark; and Institute of Molecular Medicine (Z.I.), University of Southern Denmark, Odense.

Objective: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies.

Methods: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence.

Results: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time.

Conclusion: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.
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http://dx.doi.org/10.1212/WNL.0000000000011153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905781PMC
January 2021

Magnetic resonance imaging at baseline and follow-up to differentiate between pediatric monophasic acquired CNS demyelination and MS.

Mult Scler Relat Disord 2020 Nov 21;46:102590. Epub 2020 Oct 21.

Department of Radiology, Diagnostic Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: It is essential to distinguish acute disseminated encephalomyelitis (ADEM) from MS early. Our aim was to determine MRI features at baseline and follow-up to distinguish pediatric ADEM from MS stratified according to age at onset.

Methods: Using hospital ICD-10 codes for acquired demyelinating syndromes from a nationwide register and subsequent chart review, we identified 52 children (<18 years) with ADEM and 66 children with MS. We undertook a retrospective analysis of MRI scans at onset and at follow-up. The MRI rater was a senior neuroradiologist blinded to clinical characteristics.

Results: At baseline, children with ADEM had more diffuse poorly demarcated lesions, particularly in the basal ganglia/thalamus (p = 0.001) and cerebellar peduncles (p < 0.0001). Further, longitudinal extensive transverse myelitis was strongly associated with ADEM (p<0.0001). Children with ADEM had fewer contrast-enhancing lesions (p = 0.0004), occipital lesions (p = 0.01), optic nerve lesions (p = 0.01), periventricular lesions, well-defined lesions only (p<0.0001), and fewer fulfilled dissemination in time according to the McDonald 2017 criteria (p = 0.005). On baseline MRI, dissemination in space and time was fulfilled in 17% of children with ADEM and in 34% of children with MS (p = 0.06), and 60% of children with ADEM fulfilled the criterion for dissemination in space. The mean time from baseline MRI to follow-up MRI was 1.0 year for children with ADEM and 2.1 years for children with MS. On follow-up MRI, 85% of children with ADEM had partial or complete T2 lesion resolution, but in the 58% without complete resolution lesions were predominantly frontal. Only 47% of children with MS had partial or complete T2 lesion resolution, and therefore more MRI features differed between children with ADEM and MS on follow-up. MRI had the greatest distinguishing value after age 11 years because MS is exceptional in the first decade of life.

Conclusion: Age at onset and the timing of MRI in relation to disease onset are critical in the interpretation of MRI to distinguish between ADEM and MS.
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http://dx.doi.org/10.1016/j.msard.2020.102590DOI Listing
November 2020

The Danish Multiple Sclerosis Registry.

Brain Behav 2021 01 30;11(1):e01921. Epub 2020 Oct 30.

Department of Neurology, The Danish Multiple Sclerosis Registry, Rigshospitalet, Glostrup, Denmark.

Objectives: The Danish Multiple Sclerosis Registry is the oldest operative and nationwide MS registry. We present The Danish Multiple Sclerosis Registry with its history, data collection, scientific contribution, and national and international research collaboration.

Materials And Methods: Detailed description of data collection, completeness, quality optimizing procedures, funding, and legal, ethical and data protection issues are provided.

Results: The total number of registered cases with clinical isolated syndrome and multiple sclerosis since 1956 was by start of May 2020 30,023 of whom 16,515 cases were alive and residing in Denmark, giving a prevalence rate of about 284 per 100,000 population. The mean annual number of new cases receiving an MS diagnosis was 649 per year in the period 2010 to 2019. In total, 7,945 patients (48.1%) are receiving disease modifying therapy at the start of May 2020.

Conclusions: Multiple Sclerosis registers are becoming increasingly important, not only for epidemiological research but also by quantifying the burden of the disease for the patients and society and helping health care providers and regulators in their decisions. The Danish Multiple Sclerosis Registry has served as data source for a number of scientific publications including epidemiological studies on changes in incidence and mortality, cohort studies investigating risk factors for developing MS, comorbidities and socioeconomic outcomes in the MS population, and observational studies on effectiveness of disease modifying treatments outside the narrow realms of randomized clinical trials.
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http://dx.doi.org/10.1002/brb3.1921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821574PMC
January 2021

Intake of dietary fibre, red and processed meat and risk of late-onset Chronic Inflammatory Diseases: A prospective Danish study on the "diet, cancer and health" cohort.

Int J Med Sci 2020 9;17(16):2487-2495. Epub 2020 Sep 9.

Focused Research Unit for Molecular Diagnostic and Clinical Research, IRS-Center Sonderjylland, Hospital of Southern Jutland, Aabenraa, Denmark.

Human and animal studies support the involvement of diet in the development of CID -chronic inflammatory diseases such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, psoriatic arthritis, and multiple sclerosis. This cohort study aimed to investigate the association between intake of fibre, red and processed meat, and occurrence of late-onset CID (50+ years of age) in the DCH: Danish Diet, Cancer and Health cohort. We hypothesised that risk of late-onset CID would be lower among those with high intake of fibre and/or low intake of meat compared to individuals with low fibre and/or high meat intake. The DCH recruited 56,468 individuals, aged 50-64 years, between 1993 and 1997. At recruitment, diet intake was registered using food frequency questionnaires as well as lifestyle factors in 56,075 persons. Exposure variables were generated as sex-adjusted tertiles of fibre and meat (g/day). Development of CIDs was identified in national registries. Hazard ratios (HR) of late-onset CIDs (adjusted for age, sex, energy intake, alcohol, smoking, education, comorbidity, and civil status) were estimated for all three exposure variables. During follow-up of 1,123,754 years (median (Interquartile range) = 22.2 (20.1-23.1)), 1,758 (3.1%) participants developed at least one CID. The adjusted HRs for developing CID ( 1.04 [0.89-1.22] and 1.04 [0.91-1.18] (high fibre as reference), and 0.96 [0.86-1.09] and 0.94 [0.82-1.07] (low meat as reference)) or the individual diseases were not statistically significant. This large study did not support that a high intake of fibre and/or a low intake of meat had a high impact on the risk of late-onset CID.
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http://dx.doi.org/10.7150/ijms.49314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532485PMC
July 2021

School performance, psychiatric comorbidity, and healthcare utilization in pediatric multiple sclerosis: A nationwide population-based observational study.

Mult Scler 2021 02 25;27(2):259-267. Epub 2020 Sep 25.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark/Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: Pediatric multiple sclerosis (MS) may hamper educational achievements due to psychiatric comorbidity and cognitive impairment. Our aims were to investigate school performance, psychiatric comorbidity, and healthcare utilization following pediatric MS and to differentiate between disability in MS and that arising from a non-brain-related chronic disease.

Methods: We included all children (<18 years) with MS onset during 2008-2015 in Denmark with a medical record-validated MS diagnosis. The control groups were children from the general population or children with non-brain-related chronic diseases. Outcomes were register-based on 9-12 grade point average, psychiatric comorbidity, and healthcare visits.

Results: Cohorts were children with MS ( = 92), control children matched to children with MS ( = 920), children with non-brain-related chronic diseases ( = 9108), and "healthy" children with neither MS nor brain-related chronic disease ( = 811,464). School performance in grades 9-12 was similar, but children with MS compared to those with non-brain-related chronic disease had an almost doubled hazard for psychiatric comorbidity (hazard ratio = 1.87; 95% confidence interval = 1.38-2.53;  < 0.0001) and a higher rate of all hospital visits ( < 0.0001) but a lower rate of hospital admissions ( = 0.001).

Conclusion: Children with MS have a seemingly standard school performance but increased psychiatric comorbidity and a high rate of healthcare utilization.
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http://dx.doi.org/10.1177/1352458520959673DOI Listing
February 2021

Comorbidity in Multiple Sclerosis.

Front Neurol 2020 21;11:851. Epub 2020 Aug 21.

Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Rigshospitalet, Denmark.

Comorbidities in patients with multiple sclerosis (MS) has become an area of increasing interest in the recent years. A comorbidity is defined as any additional disease that coexists in an individual with a given index disease and that is not an obvious complication of the index disease. The aim of this review is to describe the current evidence regarding the range of comorbidities in the population with MS reported in different countries and the current knowledge about the influence of comorbidities on the clinical features and therapeutic challenges in MS. Certain comorbidities are more prevalent in people with MS such as depression, anxiety, cerebro- and cardiovascular diseases, and certain autoimmune disorders such as diabetes, thyroid disease, and inflammatory bowel disease. A previous perception of a trend toward a lower overall risk of cancer in patients with MS appears to be challenged, but there is no evidence on any higher occurrence of malignancies in the population with MS. Comorbidities may modify the clinical presentation of MS, and have implications for treatment choice, adherence, and outcome. Several comorbid conditions are associated with increased disability progression, including diabetes, hypertension, and chronic obstructive pulmonary disease. Comorbidities are common in MS from the time of diagnosis and may account for some of the heterogeneity observed in MS, including diagnostic delay, clinical presentation, degree of disability progression, rate of health care utilization, working ability, employment status, and quality of life. Coexisting diseases and polypharmacy increase the complexity of patient management and poses major challenges, particularly with the increasing number of immunosuppressive disease-modifying therapies.
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http://dx.doi.org/10.3389/fneur.2020.00851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473304PMC
August 2020

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

Mult Scler 2020 09 14;26(10):1157-1162. Epub 2020 Jul 14.

MSBase Registry, Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.

Background: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale.

Objectives: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible.

Methods: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale.

Results: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process.

Conclusions: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.
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http://dx.doi.org/10.1177/1352458520941485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361123PMC
September 2020
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