Publications by authors named "Nils Koch-Henriksen"

86 Publications

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

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

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

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

It is safe to switch therapy from interferon beta or glatiramer acetate to oral therapy in patients with relapsing multiple sclerosis with stable disease.

J Neurol Neurosurg Psychiatry 2021 May 9;92(5):457. Epub 2021 Feb 9.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

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http://dx.doi.org/10.1136/jnnp-2020-325684DOI 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

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

Exposure to passive smoking during adolescence is associated with an increased risk of developing multiple sclerosis.

Mult Scler 2021 02 23;27(2):188-197. Epub 2020 Mar 23.

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

Background: Environmental factors are associated with acquiring multiple sclerosis (MS) particularly in adolescence.

Objective: To test for association between MS and exposure to passive smoking at the age of 10-19.

Methods: A total of 919 patients from the Danish MS Registry and Biobank and 3419 healthy blood donors who had not smoked before the age of 19 were targeted. We analyzed separately for each sex and for those never-smokers (cohort 1) and active smokers above the age of 19 (cohort 2). All participants completed standardized questionnaires about smoking and lifestyle. We matched cases and controls in the ratio of 1:2 by propensity scores discarding unmatchable individuals and used logistic regression adjusted for all covariates and interactions.

Results: After matching, we included 110/213 male cases/controls and 232/377 female case/controls in cohort 1. In cohort 2, the numbers were 160/320 and 417/760, respectively. Among women in cohort 1, the odds ratio (OR) for MS by passive smoking at the age of 10-19 was 1.432 ( = 0.037) but in men it was 1.232 ( = 0.39). Among men in cohort 2, OR was 1.593 ( = 0.022) but among women it was only 1.102 ( = 0.44).

Conclusion: Among never smokers, female MS cases were more often than female controls reported with passive smoking between the age of 10 and 19, and among smokers above the age of 19, male MS patients were more often than male controls reported with passive smoking.
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http://dx.doi.org/10.1177/1352458520912500DOI Listing
February 2021

Changes in the sex ratio are a good indicator of changes in MS incidence - No.

Mult Scler 2019 10 15;25(12):1568-1569. Epub 2019 May 15.

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

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http://dx.doi.org/10.1177/1352458519837926DOI Listing
October 2019

Multiple sclerosis among first- and second-generation immigrants in Denmark: a population-based cohort study.

Brain 2019 06;142(6):1587-1597

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

Multiple sclerosis is a disease with a highly variable incidence worldwide. While knowledge about multiple sclerosis risk factors has grown over the years, the aetiology of multiple sclerosis has still not been fully established. We examined multiple sclerosis incidence rates among first-generation immigrants in Denmark, a high-incidence country, and their Danish-born children (second-generation immigrants), to evaluate the importance and timing of exposure to environmental factors in the aetiology of multiple sclerosis. By means of the Danish Civil Registration System we identified 9 121 187 individuals living in Denmark between 1968 and 2015, including 1 176 419 first-generation and 184 282 second-generation immigrants. Study participants were followed for multiple sclerosis in the Danish Multiple Sclerosis Registry from 1968 to 2015. The relative risk (RR) of multiple sclerosis according to immigration status was estimated by means of multiple sclerosis incidence rate ratios obtained in log-linear Poisson regression analysis. Altogether, 16 905 cases of multiple sclerosis were identified in the study cohort, 578 among first-generation and 106 among second-generation immigrants. Multiple sclerosis risk among first-generation immigrants whose parents were born in low, intermediate and high multiple sclerosis risk areas were 21% (RR = 0.21; 95% CI: 0.16-0.28), 43% (RR = 0.43; 95% CI: 0.36-0.50) and 75% (RR = 0.75; 95% CI: 0.67-0.83), respectively, of that among ethnic Danes (test for trend P < 0.0001). First-generation immigrants arriving in Denmark before age 15 years had a multiple sclerosis risk higher than that in their country of birth but lower than that in Denmark, reaching on average 69% of the multiple sclerosis risk among ethnic Danes (RR = 0.69; 95% CI: 0.55-0.87). Multiple sclerosis risk among individuals who came to Denmark at a later age remained closer to that of their country of birth, corresponding to 45% of the multiple sclerosis risk among ethnic Danes (RR = 0.45; 95% CI: 0.41-0.49). Our study supports the idea that environmental factors exerting their role in childhood or adolescence may be of aetiological relevance in multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awz088DOI Listing
June 2019

Worsening of disability caused by relapses in multiple sclerosis: A different approach.

Mult Scler Relat Disord 2019 Jul 15;32:1-8. Epub 2019 Apr 15.

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

Background: In multiple sclerosis (MS) the quantitative role of relapses in Expanded Disability Status Scale (EDSS) worsening beyond the recovery phase is not well known. Most studies have examined the predictive role of early relapses in more distant endpoints. Relapses and worsening may be associated because they could be independent effects of the same underlying disease characteristics without causal relationship. With the design of the present study we aim to estimate the direct effect on disability of relapses.

Methods: We used data from the obligatory bi-annually registration in the Danish Multiple Sclerosis Registry of relapses and EDSS for all patients treated with disease modifying drugs for relapsing/remitting MS from 1996 to 2015 with exclusion of patients in whom no relapses had ever been recorded during treatment. We paired two consecutive control periods into study intervals which were the actual study units. Study intervals were qualified and included if they were at length 12-24 months, with EDSS ≤ 5.5 at start, and if a preceding relapse had been no closer than nine months to the EDSS assessment at the start or end of the study interval to eliminate relapse-related temporary EDSS worsening. We compared EDSS worsening in study intervals with and without relapses. The same patients could contribute with study intervals with and without relapses. For statistical analyses we used Generalized Estimating Equations to account for intra-patient correlations.

Results: We analysed 5187 study intervals from 2015 MS patients. The mean of EDSS increase was 0.205 units in qualifying study intervals with relapses and 0.065 without relapses when adjusted for length of study interval, sex, and EDSS at start of interval; p < 0.0001. However, the effect of relapses on EDSS was absent in male patients (p = 0.521), and when EDSS was ≥ 4.0 at start of the study interval (p = 0.726).

Conclusion: Relapses play an independent and significant role for worsening of MS in patients under disease-modifying therapy (DMT) and eliminating relapses would not only free the patients from the temporary perils of relapses but would also reduce the worsening of the disease.
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http://dx.doi.org/10.1016/j.msard.2019.04.017DOI Listing
July 2019

Nationwide prevalence and incidence study of neuromyelitis optica spectrum disorder in Denmark.

Neurology 2018 12 9;91(24):e2265-e2275. Epub 2018 Nov 9.

From the Department of Neurology (V.P., K.S., T.P.), Aarhus University Hospital; Department of Neurology (Z.I., H.H.N.), Odense University Hospital; Institute of Clinical Research (Z.I., H.H.N.), Institute of Molecular Biology (H.H.N.), and Department of Regional Health Research, Faculty of Health Sciences (E.S.), University of Southern Denmark, Odense; The Danish Multiple Sclerosis Center (M.M., P.E.H.J., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen; The Danish Multiple Sclerosis Registry (M.M., N.K.-H.), Department of Neurology, Rigshospitalet, Copenhagen University Hospital; Department of Clinical Epidemiology, Clinical Institute (N.K.-H.), and Department of Biomedicine (T.C.), Aarhus University; MS-Clinic of Southern Jutland (Sønderborg, Esbjerg, Kolding) (M.K., E.S.), Department of Neurology, Hospital of Southern Jutland, Sønderborg; Department of Neurology (C.C.P., Z.M.), Aalborg University Hospital; Multiple Sclerosis Unit (S.F.R.), Department of Neurology, Herlev Hospital, Copenhagen; Department of Neurology (M.B.J.), Nordsjællands Hospital, Hillerød; Department of Neurology (A.E.P.), Hospital of Southwest Jutland, Esbjerg; Department of Neurology (L.R.), Hospital of Central Denmark Region, Viborg; Department of Autoimmunology and Biomarkers (M.C.L., N.H.), Statens Serum Institut, Copenhagen; and Department of Neurology (J.L.F.), Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objectives: To estimate the nationwide population-based incidence, prevalence, and geographical distribution of neuromyelitis optica (NMO) spectrum disorder (NMOSD) in Denmark based on the 2015 International Panel for NMO Diagnosis (IPND) criteria.

Methods: We conducted a multicentre, historically prospective study. Data were sourced from the Danish National Patient Registry, the Danish Multiple Sclerosis Registry, departments of neurology, and laboratories providing aquaporin-4 antibody test. Cases were selected based on the 2006 Wingerchuk and the 2015 IPND criteria and were individually validated by an expert panel.

Results: We confirmed NMO in 30 cases (2006 criteria) and NMOSD in 56 cases (2015 IPND criteria) between 2007 and 2014. Defined by the 2006 criteria, the incidence of NMO was 0.029 per 100,000 person-years (95% confidence interval [CI] 0.014-0.051), and the prevalence (aged 16 years and older) was 0.566 per 100,000 (95% CI 0.370-0.830). Based on the 2015 IPND criteria, the incidence of NMOSD was 0.070 per 100,000 person-years (95% CI 0.046-0.102), and the prevalence (aged 16 years and older) was 1.09 per 100,000 (95% CI 0.808-1.440), without regional differences.

Conclusions: Our estimates of incidence and prevalence are similar to other Caucasian population-based studies using the 2015 IPND criteria. We found no geographical clustering in Denmark.
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http://dx.doi.org/10.1212/WNL.0000000000006645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329324PMC
December 2018

Infections seem to be more frequent before onset of pediatric multiple sclerosis: A Danish nationwide nested case-control study.

Mult Scler 2019 05 17;25(6):783-791. Epub 2018 May 17.

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

Background: Infections are suspected environmental triggers for multiple sclerosis (MS). The relationship between the timing and cumulative number of childhood infections regarding pediatric MS risk is uninvestigated.

Objectives: To investigate whether childhood infections contribute to pediatric MS.

Methods: A nationwide nested case-control study with detailed MS case ascertainment including chart review was undertaken. For each MS case, we selected five control children using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data with the cumulative number of childhood infections as exposure and MS as outcome. Hazard ratios (HRs) including 95% confidence intervals (CIs) were estimated using Cox regression.

Results: We identified 212 children with MS and 1,060 controls. Median age at MS onset was 15.3 years (range: 7.6-17.8 years); 72% were girls. Each infection during the preceding 3 years increased the hazard for MS by 11% (95% CI = 1.01-1.22, p = 0.04); having 5+ infections compared with 0-4 infections in the preceding 3 years doubled the hazard for MS (HR: 2.18; 95% CI = 1.12-4.30, p = 0.02).

Conclusion: Children with MS appeared to have more infections in the 3 years preceding MS clinical onset; accordingly, immune response to infections may influence MS pathogenesis.
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http://dx.doi.org/10.1177/1352458518771871DOI Listing
May 2019

Small-scale geographical variation in multiple sclerosis: A case-control study using Danish register data 1971-2013.

Mult Scler Relat Disord 2018 Jul 4;23:40-45. Epub 2018 May 4.

National Institute of Public Health, University of Southern Denmark, Øster Farimagsgade 5A, 2, DK-1353, Copenhagen, Denmark.

Background: The aetiology of multiple sclerosis (MS) is largely unknown, but commonly assumed to be a complex interaction between genes and environmental exposures, presumably during early life. To evaluate the possible importance and timing of environmental exposures we investigated the spatial variation in the risk of MS in Denmark according to residence at birth, age 15, and clinical onset of disease.

Methods: We carried out a nationwide, register-based case-control study including 12 993 Danish MS cases with onset of disease 1971-2013. Information on exact residential addresses was available for all study subjects in the Danish Civil Registration System. The spatial variation in risk of MS was estimated by kernel regression.

Results: We identified spatial variation in the risk of MS according to residence at birth, age 15, and onset of disease. Several high- and low-risk areas were identified across the country with some variation between birth, age 15, and onset.

Conclusions: Small-scale geographical variation in the risk of MS suggests that local environmental risk factors could be at play and may be related to life style factors.
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http://dx.doi.org/10.1016/j.msard.2018.04.021DOI Listing
July 2018

Implications of the International Paediatric Multiple Sclerosis Study Group consensus criteria for paediatric acute disseminated encephalomyelitis: a nationwide validation study.

Dev Med Child Neurol 2018 11 10;60(11):1123-1131. Epub 2018 May 10.

Department of Paediatrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Aim: The International Paediatric Multiple Sclerosis Study Group (IPMSSG) has proposed criteria for acute disseminated encephalomyelitis (ADEM) not evaluated in clinical practice. Our objective was to assess epidemiological implications of the IPMSSG criteria for ADEM in a cohort study using prospectively collected data.

Method: We identified all diagnosed cases of ADEM in Denmark between 2008 and 2015 from the Danish National Patient Register by International Classification of Diseases 10 codes assigned to acute demyelinating episodes, and we reviewed all medical records to validate ADEM.

Results: We found 52 children up to the age of 18 years with a verified clinical diagnosis of ADEM (incidence rate 0.54/100 000 person-years; all had abnormal brain magnetic resonance imaging). Only 18 (35%) fulfilled the IPMSSG criteria regarding encephalopathy and polyfocal neurological deficits. Among all 52 children with ADEM, 33 per cent had clinical sequelae after a median follow-up of 4 years 6 months (range: 10mo-8y 3mo). Surprisingly, none progressed to multiphasic ADEM or multiple sclerosis, but median age at end of follow-up was only 10 years 9 months (range: 2y-24y 3mo).

Interpretation: Among 52 children with ADEM, none converted to multiphasic ADEM or multiple sclerosis (median follow-up: 4y 6mo; range: 10mo-8y 3mo). Applying the IPMSSG criteria to all children with a diagnosis of ADEM leaves 65 per cent of the cases without a diagnosis and lowers the incidence rate of paediatric ADEM.

What This Paper Adds: The incidence of paediatric acute disseminated encephalomyelitis (ADEM) was 0.54 per 100 000 person-years in children younger than 18 years. Only 35 per cent of children with ADEM fulfilled the International Paediatric Study Group consensus criteria. ADEM in clinical practice was primarily based on magnetic resonance imaging findings. Paediatric neurologists diagnosed ADEM in the absence of encephalopathy. None of the children with ADEM progressed to multiple sclerosis/multiphasic ADEM during follow-up.
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http://dx.doi.org/10.1111/dmcn.13798DOI Listing
November 2018

Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women.

Neurology 2018 05 2;90(22):e1954-e1963. Epub 2018 May 2.

From the Clinical Institute (N.K.-H.), Department of Clinical Epidemiology, University of Aarhus; Danish Multiple Sclerosis Registry (N.K.-H., E.S., M.M.) and Department of Neurology (M.M.), Rigshospitalet, University of Copenhagen; National Institute of Public Health (L.C.T., B.L.), University of Southern Denmark in Copenhagen; Institute of Regional Health Research (E.S.), University of Southern Denmark, Odense.

Objective: To describe the pattern of development of incidence of multiple sclerosis (MS) over 60 years in Denmark with age-period-cohort analyses and seasonality of birth.

Methods: Data on virtually all patients with onset of MS have since 1950 been prospectively recorded and kept in the Danish Multiple Sclerosis Registry with multiple sources of notification. Annualized incidence rates per 100,000 were directly standardized to the European Standard Population.

Results: We have registered 19,536 cases with clinical onset of confirmed MS in Denmark from 1950 to 2009. From the 1950-1959 to the 2000-2009 onset period, incidence more than doubled in women, with an increase from 5.91 (95% confidence interval [CI]: 5.60-6.24) to 12.33 (95% CI: 11.91-12.75) per 100,000 per year compared with a modest 24% increase in men from 4.52 (95% CI: 4.24-4.81) to 6.08 (95% CI: 5.79-6.38). With age at onset of 50 years and older, incidence increased with a factor 4.30 in women and 2.72 in men. The female/male sex ratio increased over time and with year of birth. Age-period-cohort analysis revealed a significant birth cohort effect in addition to the age and period effect. We found no statistically significant seasonality of births.

Conclusion: The incidence of MS has doubled in women, most pronounced with late onset, and has only modestly increased in men. Lifestyle changes in the female population that could include fewer childbirths, increased occurrence of obesity, and increased cigarette consumption may have a role.
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http://dx.doi.org/10.1212/WNL.0000000000005612DOI Listing
May 2018

Smoking affects the interferon beta treatment response in multiple sclerosis.

Neurology 2018 02 17;90(7):e593-e600. Epub 2018 Jan 17.

From the Danish Multiple Sclerosis Center (E.R.P., A.B.O., M.M., P.S.S., F.S., H.B.S.), Department of Neurology, and Danish Multiple Sclerosis Treatment Register (N.K.-H., M.M.), Rigshospitalet, University of Copenhagen; and Department of Clinical Epidemiology (N.K.-H), Clinical Institute, University of Aarhus, Denmark.

Objective: To investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)-DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 () variant rs7388368A.

Methods: DNA from 834 IFN-β-treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.

Results: We found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021-1.416, = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056-1.537, = 0.012). We found no association or interaction with HLA and the NAT1 variant.

Conclusion: In this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.
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http://dx.doi.org/10.1212/WNL.0000000000004949DOI Listing
February 2018

Psychiatric morbidity develops after onset of pediatric multiple sclerosis: A Danish nationwide population-based study.

Mult Scler Relat Disord 2018 Jan 31;19:30-34. Epub 2017 Oct 31.

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

Background: Pediatric-onset multiple sclerosis (MS) affects life at a stage vital for social and educational achievements and psychiatric co-morbidity is common after MS onset. Few studies have examined psychiatric morbidity before MS onset.

Methods: In this nationwide study, detailed case ascertainment was performed in all children with pediatric MS, including chart review. For each MS patient, we selected five controls using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data as a nested case-control study with psychiatric morbidity as exposure and MS as outcome, and a matched cohort study with MS as exposure and psychiatric co-morbidity as outcome. Hazard ratios (HR) including 95% confidence intervals (CI) were estimated using Cox regression.

Results: We identified 212 children with MS and 1060 controls. No association between psychiatric morbidity and the rate of MS was found before MS onset. After MS onset, children with MS had two times higher hazard for psychiatric co-morbidity compared with children without MS (HR=2.0; 95% CI=1.3-3.1; p<0.001).

Conclusion: Psychiatric morbidity seems to commence after MS onset, making screening for neuropsychiatric conditions pertinent in newly-diagnosed children with MS.
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http://dx.doi.org/10.1016/j.msard.2017.10.018DOI Listing
January 2018

Comorbidity in multiple sclerosis is associated with diagnostic delays and increased mortality.

Neurology 2017 Oct 20;89(16):1668-1675. Epub 2017 Sep 20.

From the Danish Multiple Sclerosis Center (A.T., P.S.S., M.M.), Department of Neurology, University of Copenhagen, Rigshospitalet; The Danish Multiple Sclerosis Registry (A.T., N.K.-H., M.M.), Department of Neurology, Rigshospitalet, Copenhagen; Department of Clinical Epidemiology (N.K.-H.), Clinical Institute, University of Aarhus; and The Danish National Institute of Public Health (B.L.), University of Southern Denmark, Copenhagen.

Objective: To investigate the effect of chronic comorbidity on the time of diagnosis of multiple sclerosis (MS) and on mortality in MS.

Methods: We conducted a population-based, nationwide cohort study including all incident MS cases in Denmark with first MS symptom between 1980 and 2005. To investigate the time of diagnosis, we compared individuals with and without chronic comorbidity using multinomial logistic regression. To investigate mortality, we used Cox regression with time-dependent covariates, following study participants from clinical MS onset until endpoint (death) or to the end of the study, censuring at emigration.

Results: We identified 8,947 individuals with clinical onset of MS between 1980 and 2005. In the study of time of diagnosis, we found statistically significant odds ratios for longer diagnostic delays with cerebrovascular comorbidity (2.01 [1.44-2.80]; <0.0005), cardiovascular comorbidity (4.04 [2.78-5.87]; <0.0005), lung comorbidity (1.93 [1.42-2.62]; <0.0005), diabetes comorbidity (1.78 [1.04-3.06]; 0.035), and cancer comorbidity (2.10 [1.20-3.67]; 0.009). In the mortality study, we found higher hazard ratios with psychiatric comorbidity (2.42 [1.67-3.01]; <0.0005), cerebrovascular comorbidity (2.47 [2.05-2.79]; <0.0005), cardiovascular comorbidity (1.68 [1.39-2.03]; <0.0005), lung comorbidity (1.23 [1.01-1.50]; 0.036), diabetes comorbidity (1.39 [1.05-1.85]; 0.021), cancer comorbidity (3.51 [2.94-4.19]; <0.0005), and Parkinson disease comorbidity (2.85 [1.34-6.06]; 0.007).

Conclusions: An increased awareness of both the necessity of neurologic evaluation of new neurologic symptoms in persons with preexisting chronic disease and of optimum treatment of comorbidity in MS is critical.
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http://dx.doi.org/10.1212/WNL.0000000000004508DOI Listing
October 2017

Dietary sodium intake: An etiologic dead end in multiple sclerosis.

Neurology 2017 09 25;89(13):1314-1315. Epub 2017 Aug 25.

From The Danish Multiple Sclerosis Registry (N.K.-H.), Copenhagen University Hospital, Rigshospitalet; Department of Clinical Epidemiology (N.K.-H.), University of Aarhus, Denmark; and private practice (neuroepidemiologist, K.L.), Griesheim, Germany.

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http://dx.doi.org/10.1212/WNL.0000000000004426DOI Listing
September 2017

Excess mortality among patients with multiple sclerosis in Denmark has dropped significantly over the past six decades: a population based study.

J Neurol Neurosurg Psychiatry 2017 08;88(8):626-631

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

Background: Lifetime expectancy in multiple sclerosis (MS) is reduced. Few studies have had sufficient follow-up or sufficient number of patients to assess if survival has improved with time. However, a recent meta-analysis found no time-dependent change in MS excess mortality across studies over recent decades.

Objective: To investigate whether short-term all-cause excess mortality in patients with MS in the total Danish population has changed over the last six decades.

Patients And Methods: We included all patients with MS recorded in the nationwide Danish MS Registry with definite or probable MS and onset from 1950 through 1999. The Danish Civil Registration System provided date of death for all deceased patients with follow-up in 2015, and Statistics Denmark supplied specific population mortality. We calculated excess number of death per 1000 person-years (EDR) and standardised mortality ratio (SMR).

Results: We included 18 847 patients among whom 6102 had died as opposed to 2492 expected deaths. EDR was 10.63 (95% CI 10.19 to 11.09) and a SMR was 2.45 (95% CI 2.39 to 2.51). The 15-year EDR dropped gradually from 11.29 (95% CI 9.95 to 12.73) in the 1950-1959 onset cohort to 2.56 (95% CI 1.98 to 3.18) in the 1990-1999 onset cohort, and SMR dropped from 4.48 (95% CI 4.06 to 4.92) to 1.80 (95% CI 1.62 to 1.99).

Conclusion: The decline in short-term excess mortality in MS started decades before disease-modifying treatment of MS became available, before use of MRI became widespread, and before the McDonald diagnostic criteria were introduced. A change in the MS cohorts with fewer malignant cases may be a significant contributor.
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http://dx.doi.org/10.1136/jnnp-2017-315907DOI Listing
August 2017

Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: A nationwide population-based incidence study.

Mult Scler 2018 07 13;24(8):1077-1086. Epub 2017 Jun 13.

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

Background: The incidence of acquired demyelinating syndromes (ADS) including multiple sclerosis (MS) has never been investigated in a Danish pediatric population.

Objectives: We estimated the nationwide age- and sex-specific incidence of pediatric ADS including MS.

Methods: Data were sourced from the Danish Multiple Sclerosis Registry, providing cases of pediatric MS for 1977-2015, and the National Patient Register, providing cases of ADS during 2008-2015. All medical records were reviewed to validate the register-based diagnoses.

Results: We identified 364 cases of pediatric MS occurring during 1977-2015 (incidence rate = 0.79 per 100,000 person-years). MS was exceptionally rare before puberty, but the incidence rose considerably from 9 years in girls and 11 years in boys. The female-to-male ratio was 2.5; the median age at onset was 16 years (range = 7-17 years). The MS incidence rate was relatively stable through the study period. During 2008-2015, we identified 219 ADS cases. The incidence was 2.29 per 100,000 person-years with considerable differences in the age peaks for the separate ADS.

Conclusion: The incidence rates of MS and other ADS in Denmark were higher than those reported for some other European countries. Referral bias and classification differences may account for this disparity, in particular the age-intervals and the definition of onset.
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http://dx.doi.org/10.1177/1352458517713669DOI Listing
July 2018

Age at Menarche and Risk of Multiple Sclerosis: A Prospective Cohort Study Based on the Danish National Birth Cohort.

Am J Epidemiol 2017 04;185(8):712-719

Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark.

Few studies have addressed the possible association between age at menarche and multiple sclerosis (MS), and results are conflicting. We studied this issue in a large prospective cohort study. The study cohort comprised 77,330 women included in the Danish National Birth Cohort (1996-2002). Information on menarcheal age was ascertained at the first interview, which took place in the 16th week of pregnancy. Women were followed for MS from the first interview to December 31, 2011. Associations between age at menarche and risk of MS were evaluated with hazard ratios and 95% confidence intervals using Cox proportional hazards regression models. Overall, 226 women developed MS during an average follow-up period of 11.7 years. Age at menarche among women with MS was generally lower than that among women without MS (Wilcoxon rank-sum test; P = 0.002). We observed an inverse association between age at menarche and MS risk. For each 1-year increase in age at menarche, risk of MS was reduced by 13% (hazard ratio = 0.87, 95% confidence interval: 0.79, 0.96). Early age at menarche appears to be associated with an increased risk of MS. The mechanisms behind this association remain to be established.
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http://dx.doi.org/10.1093/aje/kww160DOI Listing
April 2017

Inverse comorbidity in multiple sclerosis: Findings in a complete nationwide cohort.

Mult Scler Relat Disord 2016 Nov 29;10:181-186. Epub 2016 Oct 29.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.

Background: Inverse comorbidity is disease occurring at lower rates than expected among persons with a given index disease. The objective was to identify inverse comorbidity in MS.

Methods: We performed a combined case-control and cohort study in a total nationwide cohort of cases with clinical onset of MS 1980-2005. We randomly matched each MS-case with five population controls. Comorbidity data were obtained from multiple, independent nationwide registries. Cases and controls were followed from January 1977 to the index date, and from the index date through December 2012. We controlled for false discovery rate and investigated each of eight pre-specified comorbidity categories: psychiatric, cerebrovascular, cardiovascular, lung, and autoimmune comorbidities, diabetes, cancer, and Parkinson's disease.

Results: A total of 8947 MS-cases and 44,735 controls were eligible for inclusion. We found no inverse associations with MS before the index date. After the index date, we found a decreased occurrence of chronic lung disease (asthma and chronic obstructive pulmonary disease) (HR 0.80 (95% CI 0.75-0.86, p<0.00025)) and overall cancer (HR 0.88 (95% CI 0.81-0.95, p=0.0005)) among MS-cases.

Conclusion: This study showed a decreased risk of cancers and pulmonary diseases after onset of MS. Identification of inverse comorbidity and of its underlying mechanisms may provide important new entry points into the understanding of MS.
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http://dx.doi.org/10.1016/j.msard.2016.10.008DOI Listing
November 2016

Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study.

Neurology 2017 Jan 30;88(1):44-51. Epub 2016 Nov 30.

From the Department of Epidemiology Research (N.M.N., K.T.J., J.S., T.J.) and the Danish Centre for Neonatal Screening, Department for Congenital Disorders (D.M.H., M.L., A.C.), Statens Serum Institut, Copenhagen, Denmark; Departments of Nutrition (K.L.M., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; The Danish Multiple Sclerosis Registry (N.K.-H., M.M., E.S.), Danish Multiple Sclerosis Centre, Department of Neurology, University of Copenhagen (M.M.), and Danish Multiple Sclerosis Research Centre, Department of Neurology, Neuroscience Centre (M.M.), Rigshospitalet, Copenhagen, Denmark; Institute of Regional Health Research (E.S.), University of Southern Denmark, Odense, Denmark, and National Institute of Public Health (E.S.), University of Southern Denmark, Copenhagen; Department of Neurology (E.S.), Multiple Sclerosis Clinic of Southern Jutland (Sønderborg, Vejle, Esbjerg), Sønderborg, Denmark; Department of Clinical Epidemiology, Clinical Institute (N.K.-H.), University of Aarhus, Aarhus, Denmark; and Channing Division of Network Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Objective: As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS.

Methods: We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1-2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models.

Results: We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36-0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57-0.84).

Conclusion: Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.
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http://dx.doi.org/10.1212/WNL.0000000000003454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200855PMC
January 2017

The Danish Multiple Sclerosis Treatment Register.

Clin Epidemiol 2016 25;8:549-552. Epub 2016 Oct 25.

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

Aim Of The Database: The Danish Multiple Sclerosis Treatment Register (DMSTR) serves as a clinical quality register, enabling the health authorities to monitor the quality of the disease-modifying treatment, and it is an important data source for epidemiological research.

Study Population: The DMSTR includes all patients with multiple sclerosis who had been treated with disease-modifying drugs since 1996. At present, more than 8,400 patients have been registered in this database. Data are continuously entered online into a central database from all sites in Denmark at start and at regular visits.

Main Variables: Include age, sex, onset year and year of the diagnosis, basic clinical information, and information about treatment, side effects, and relapses.

Descriptive Data: Notification is done at treatment start, and thereafter at every scheduled clinical visit 3 months after treatment start, and thereafter every 6 months. The longitudinally collected information about the disease activity and side effects made it possible to investigate the clinical efficacy and adverse events of different disease-modifying therapies.

Conclusion: The database contributed to a certain harmonization of treatment procedures in Denmark and will continue to be a major factor in terms of quality in clinical praxis, research and monitoring of adverse events, and plays an important role in research.
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http://dx.doi.org/10.2147/CLEP.S99500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094645PMC
October 2016
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