Multiple sclerosis in Denmark (1950-2023): mean age, sex distribution, incidence and prevalence.

With rising life expectancy and advancements in disease management, we expect the multiple sclerosis population is getting older. However, evidence supporting this hypothesis remains sparse. Our study aimed to determine whether the mean age of the Danish multiple sclerosis population has increased and to analyse the developments in sex distribution, incidence, and prevalence, all of which affect age composition. We conducted a cohort study by linking nationwide data from the Danish Multiple Sclerosis Registry to the Population Statistics Registry, the Danish Cause of Death Registry, and the Historical Migration Registry. We included all living patients with a confirmed multiple sclerosis diagnosis who lived in Denmark on the 1st of January each year from 1950 to 2023. We calculated the mean and median age, age distribution, sex distribution, incidence, and prevalence of the Danish MS population annually from 1950 to 2023. We included 28,145 individuals with multiple sclerosis. The mean age of the Danish multiple sclerosis population increased until the late 1970s to around 52.5 years, where it stabilised until 1990. The mean age experienced a slight decline to 51.2 years in 2005, followed by a subsequent rise to its peak of 54.2 years in 2023. In 1975, females comprised 58.7% of the multiple sclerosis population, increasing to 65.7% by 2000 and 68.5% in 2023. The incidence of multiple sclerosis remained stable at around 3.5 per 100,000 until 1975 and steadily increased by more than 2.5 times in 2000 to 11.4 per 100,000. Despite fluctuations, it remained relatively stable from 2000 until 2022, showing a slight decrease in 2022 compared to the previous two decades. Both overall and sex-specific prevalence exhibited an upward trend, particularly among females. Our study demonstrates that the mean age of the Danish multiple sclerosis population has increased, although not as decisively as expected. The female proportion has grown in tandem with prevalence, while incidence appears to have stabilised in recent decades after years of increase. Denmark's robust registry data and universal healthcare system offer a unique opportunity for reliable epidemiological analysis. Our results establish a benchmark for future demographic studies in the field of multiple sclerosis.

Socioeconomic burden of AQP4-antibody seropositive NMOSD: a nationwide registry-based study.

BACKGROUND: AQP4-antibody seropositive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) may cause reduced work capability due to disability. Here, we evaluated the socioeconomic status of patients with AQP4-Ab+NMOSD in off-label therapy era compared with the general population. METHODS: A longitudinal nationwide population-based study including all Danish patients with AQP4-Ab+NMOSD and matched controls from the general population. The cohort was linked to other Danish nationwide population-based databases. The study period was from 1992 to 2021. The main outcomes were loss of income from salary, limited work capability, disability pension and civil status. The longitudinal risks of outcomes were presented in cumulative incidence curves. Fisher's exact test, χ2 test or Wilcoxon test were applied for comparison. RESULTS: We included 65 patients with a median follow-up of 8.6 years. Annual income declined significantly after disease onset (index year) compared with the general population. One year after the index year, the median annual income in 2015-indexed Euro for patients averaged 13 285 (IQR: 139 to 36 336) versus controls 33 035 (IQR: 6870 to 45 978); p=0.04. Five years postindex year, the average income for patients further dropped to 276 (IQR: 0 to 23 691) versus controls 22 141 (IQR: 0 to 42 986); p=0.03. At the end of follow-up, significantly higher proportion of patients were either in 'flexjob' (36.9% patients vs 14% controls, p<0.00) or receiving disability pension (16.9% patients vs 4.3% controls, p<0.00). CONCLUSIONS: The socioeconomic status of patients with AQP4-Ab+NMOSD deteriorates rapidly following disease onset. A substantial proportion of these patients lose their work capacity leading to increased financial burden on both their families and society.

Prognostic factors for disease activity in newly diagnosed teriflunomide-treated patients with multiple sclerosis: a nationwide Danish study.

BACKGROUND: Clinicians frequently rely on relapse counts, T2 MRI lesion load (T2L) and Expanded Disability Status Scale (EDSS) scores to guide treatment decisions for individuals diagnosed with multiple sclerosis (MS). This study evaluates how these factors, along with age and sex, influence prognosis during treatment with teriflunomide (TFL). METHODS: We conducted a nationwide cohort study using data from the Danish Multiple Sclerosis Registry.Eligible participants had relapsing-remitting MS or clinically isolated syndrome and initiated TFL as their first treatment between 2013 and 2019. The effect of age, pretreatment relapses, T2L and EDSS scores on the risk of disease activity on TFL were stratified by sex. RESULTS: In total, 784 individuals were included (57.4% females). A high number of pretreatment relapses (≥2) was associated with an increased risk of disease activity in females only (OR and (95% CI): 1.76 (1.11 to 2.81)). Age group 50+ was associated with a lower risk of disease activity in both sexes (OR females=0.28 (0.14 to 0.56); OR males=0.22 (0.09 to 0.55)), while age 35-49 showed a different impact in males and females (OR females=0.79 (0.50 to 1.23); OR males=0.42 (0.24 to 0.72)). EDSS scores and T2L did not show any consistent associations. CONCLUSION: A high number of pretreatment relapses was only associated with an increased risk of disease activity in females, while age had a differential impact on the risk of disease activity according to sex. Clinicians may consider age, sex and relapses when deciding on TFL treatment.

Stress and Multiple Sclerosis - Systematic review and meta-analysis of the association with disease onset, relapse risk and disability progression.

OBJECTIVE: This systematic review and meta-analysis address the evidence on the association of psychological stressors with onset of multiple sclerosis, inflammatory disease activity (relapses or new disease activity on magnetic resonance imaging, MRI) and disability progression. METHODS: PubMed was searched from 1946 to 15 July 2022. Studies and certain stressors were selected when they assessed stressors independent from stress elicited by the disease process itself. Risk of bias was assessed by the CASP Case Control Study Checklist and the CASP Cohort Study Checklist. Normal-Normal Hierarchical Model (NNHM) for random-effects meta-analysis was used in the Bayesian framework. RESULTS: 30 studies reporting data from 26 cohorts reporting on 24.781 cases could be identified. Ten studies addressed stressors and MS disease onset showing a weak to modest effect of psychological stressors. A meta-analysis of three studies investigating diagnosed stress disorders and MS risk showed a 1.87-fold (CI 1.061 to 3.429) increased MS risk. Stress and MS relapse risk were addressed in 19 heterogeneous studies. Meta-analyses from two independent cohorts investigating the same military threat of a population showed a threefold increased risk for relapses in association with war (relapse rate: 3.0, CI 1.56 to 5.81). In addition, two studies confirmed an association of stressful life events and MRI activity. Three studies of stressors and disease progression were included indicating some effect on disease progression. CONCLUSIONS: Taken together studies indicate a minor to modest impact of psychological stressors on disease onset, inflammatory activity and progression of MS. Possible case-selection bias and lack of confounder analysis were present in many studies.

Using instrumental variables to correct for bias in real-world cohort studies of the effects of disease-modifying treatment in MS.

BACKGROUND: Estimating the effect of disease-modifying treatment of MS in observational studies is impaired by bias from unmeasured confounders, in particular indication bias. OBJECTIVE: To show how instrumental variables (IVs) reduce bias. METHODS: All patients with relapsing onset of MS 1996-2010, identified by the nationwide Danish Multiple Sclerosis Registry, were followed from onset. Exposure was treatment index throughout the first 12 years from onset, defined as a cumulative function of months without and with medium- or high-efficacy treatment, and outcomes were hazard ratios (HRs) per unit treatment index for sustained Expanded Disability Scale Score (EDSS) 4 and 6 adjusted for age at onset and sex, without and with an IV. We used the onset cohort (1996-2000; 2001-2005; 2006-2010) as an IV because treatment index increased across the cohorts. RESULTS: We included 6014 patients. With conventional Cox regression, HRs for EDSS 4 and 6 were 1.15 [95% CI: 1.13-1.18] and 1.17 [1.13-1.20] per unit treatment index. Only with IVs, we confirmed a beneficial effect of treatment with HRs of 0.86 [0.81-0.91] and 0.82 [0.74-0.90]. CONCLUSION: The use of IVs eliminates indication bias and confirms that treatment is effective in delaying disability. IVs could, under some circumstances, be an alternative to marginal structural models.

Risk of cardiovascular disease in patients with multiple sclerosis treated with fingolimod compared to natalizumab: A nationwide cohort study of 2095 patients in Denmark.

BACKGROUND: Fingolimod may be associated with risk of developing cardiovascular disease (CVD). Studies including reference groups and long follow-up are scarce. OBJECTIVES: We hypothesized that patients treated with fingolimod would be at higher risk of developing CVD compared to patients treated with natalizumab. METHODS: A nationwide 12-year cohort study linking individual-level data from the Danish Multiple Sclerosis Registry with health registries on 2095 adult patients with multiple sclerosis (MS) without any health records of CVD at follow-up start. Exposure to fingolimod and natalizumab was defined by the first treatment of at least 3 months. Cohort entry was from 2011 to 2018. We defined CVD as a composite measure, including hypertension, ischemic heart disease, atrial fibrillation, heart failure, and stroke. We used multivariable adjusted Cox regression. RESULTS: There were 28.8 and 17.4 CVD events per 1000 person-years in fingolimod and natalizumab groups, respectively. Compared to natalizumab-treated patients, fingolimod-treated patients had a higher risk of CVD (hazard ratio (HR) = 1.57; 95% confidence interval (CI) = 1.18-2.08). Hypertension comprised 200 of 244 CVD events. CONCLUSION: We found an increased risk of CVD in patients with MS treated with fingolimod. This increased risk was mainly due to hypertension.

Torben Fog - A Danish pioneer in a multi-faceted spectrum of multiple sclerosis research.

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon.

Expert opinion on the use of contraception in people with multiple sclerosis.

BACKGROUND: Current guidance on the selection of appropriate contraception for people with multiple sclerosis (PwMS) is lacking. OBJECTIVE: To address this gap, an expert-led consensus program developed recommendations to support clinicians in discussing family planning and contraception with women and men with multiple sclerosis (MS). METHODS: A multidisciplinary steering committee (SC) of 13 international clinical experts led the program, supported by an extended faculty of 32 experts representing 18 countries. A modified Delphi methodology was used for decision-making and consensus-building. The SC drafted 15 clinical questions focused on patient-centered care, selection of contraception, and timing of stopping/starting contraception and disease-modifying therapies (DMTs). Statements addressing each question were drafted based on evaluation of published evidence and the experts' clinical experience. Consensus was reached if ⩾75% of respondents agreed (scoring 7-9 on a 9-point scale) with each recommendation. RESULTS: Consensus was reached on 24 of 25 proposed recommendations, including how and when to discuss contraception, types and safety of contraceptives, and how to evaluate the most appropriate contraceptive options for specific patient groups, including those with significant disability or being treated with DMTs. CONCLUSION: These expert recommendations provide the first practical, relevant, and comprehensive guidance for clinicians on the selection of contraception in PwMS.

Introducing a core dataset for real-world data in multiple sclerosis registries and cohorts: Recommendations from a global task force.

BACKGROUND: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited. OBJECTIVES: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts. METHODS: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset. RESULTS: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data). CONCLUSION: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.

A wearable device perspective on the standard definitions of disability progression in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a leading cause of disability among young adults, but standard clinical scales may not accurately detect subtle changes in disability occurring between visits. This study aims to explore whether wearable device data provides more granular and objective measures of disability progression in MS. METHODS: Remote Assessment of Disease and Relapse in Central Nervous System Disorders (RADAR-CNS) is a longitudinal multicenter observational study in which 400 MS patients have been recruited since June 2018 and prospectively followed up for 24 months. Monitoring of patients included standard clinical visits with assessment of disability through use of the Expanded Disability Status Scale (EDSS), 6-minute walking test (6MWT) and timed 25-foot walk (T25FW), as well as remote monitoring through the use of a Fitbit. RESULTS: Among the 306 patients who completed the study (mean age, 45.6 years; females 67%), confirmed disability progression defined by the EDSS was observed in 74 patients, who had approximately 1392 fewer daily steps than patients without disability progression. However, the decrease in the number of steps experienced over time by patients with EDSS progression and stable patients was not significantly different. Similar results were obtained with disability progression defined by the 6MWT and the T25FW. CONCLUSION: The use of continuous activity monitoring holds great promise as a sensitive and ecologically valid measure of disability progression in MS.

Sleep disorders and sleep disturbances in persons with multiple sclerosis: A population-based matched case-control study in Denmark.

Introduction Adverse sleep is common in multiple sclerosis (MS). Population-based studies including adequate control groups are lacking. We hypothesized that the prevalence of sleep disorders and other sleep disturbances would be higher in persons with MS than in controls. Methods We conducted a population-based study linking individual-level data from the Danish MS Registry (n=21,943 persons with MS) and the Danish Population Registry (n=109,715 matched controls) with information on sleep disorders from the Danish National Patient Registry and other sleep disturbances assessed by dispensed prescription drugs from the Danish National Prescription Registry. Results Prevalence of diagnosed sleep disorders in terms of central hypersomnia (0.15% vs. 0.06%), sleep disturbances (1.05% vs. 0.70%), and sleep movements (0.22% vs. 0.13%) and other sleep disturbances identified by dispensed central acting (10.73% vs. 1.10%) and hypnotic use (30.65% vs. 20.13%) medication was statistically significantly higher among persons with MS when compared to controls. We found no statistically significant difference in the prevalence of sleep apnea and parasomnia between groups. Stratified by sex and age at MS diagnosis, results for differences between persons with MS and controls were similar. Conclusion In this registry-based study, we found that the prevalence of several diagnosed sleep disorders was higher persons with MS than in controls, that is those reflecting insomnia and daytime symptoms including hypersomnia. Other sleep disturbances identified by dispensed prescription medication was markedly higher in persons with MS than controls.

COVID-19 vaccination and relapse activity: A nationwide cohort study of patients with multiple sclerosis in Denmark.

BACKGROUND AND PURPOSE: We evaluated whether there was a difference in the occurrence of relapses pre- and post-COVID-19 vaccination in a nationwide cohort of Danish patients with relapsing multiple sclerosis. METHODS: We conducted a population-based, nationwide cohort study with a cutoff date of 1 October 2022. We used McNemar tests to assess changes in the proportion of patients with recorded relapses within 90 days and 180 days before and after first vaccine dose, and a negative binomial regression model to compare the 90 and 180 days postvaccination annualized relapse rate (ARR) to the 360 days prevaccination ARR. Multivariate Cox regression was used to estimate relapse risk factors. RESULTS: We identified 8169 vaccinated (87.3% Comirnaty) patients without a recorded history of a positive COVID-19 test. We did not find statistically significant changes in the proportion of patients with relapses in the 90 days (1.3% vs. 1.4% of patients, p = 0.627) and 180 days (2.7% vs. 2.6% of patients, p = 0.918) pre- and postvaccination. Also, a comparison of the ARR 360 days before (0.064, 95% confidence interval [CI] = 0.058-0.070) with the ARR 90 (0.057, 95% CI = 0.047-0.069, p = 0.285) and 180 (0.055, 95% CI = 0.048-0.063, p = 0.060) days after vaccination did not show statistically significant differences. Lower age, higher Expanded Disability Status Scale score, and relapse within 360 days before vaccination were associated with a higher risk of relapse. CONCLUSIONS: We did not find evidence of increased relapse activity following the administration of the first dose of the COVID-19 vaccine.

Long-Term Safety of Teriflunomide in Multiple Sclerosis Patients: Results of Prospective Comparative Studies in Three European Countries.

BACKGROUND AND OBJECTIVES: Teriflunomide is a disease-modifying therapy (DMT) for multiple sclerosis (MS). This post authorisation safety study assessed risks of adverse events of special interest (AESI) associated with teriflunomide use. METHODS: Secondary use of individual data from the Danish MS Registry (DMSR), the French National Health Data System (SNDS), the Belgian national database of health care claims (AIM-IMA) and the Belgian Treatments in MS Registry (Beltrims). We included patients treated with a DMT at the date of teriflunomide reimbursement or initiating another DMT. Adjusted hazard rates (aHR) and 95% confidence intervals were derived from Cox models with time-dependent exposure comparing teriflunomide treatment with another DMT. RESULTS: Of 81 620 patients (72% women) included in the cohort, 22 324 (27%) were treated with teriflunomide. After a median follow-up of 4 years, teriflunomide use compared to other DMT was not associated with a risk of all-cause mortality, severe infection, pneumoniae, herpes zoster reactivation, pancreatitis, cardiovascular condition and cancers. For opportunistic infections, aHR for teriflunomide versus other DMT was 2.4 (1.2-4.8) in SNDS, which was not bound to a particular opportunistic agent. The aHR was 2.0 (1.1-3.7) for renal failures in the SNDS, but no association was found in other data sources. A total of 187 SNDS patients had a history of renal failure prior to cohort entry. None of these patients (0%) had a renal failure recurrence when treated with teriflunomide for 19 (13%) recurrences reported for patients on another DMT. DISCUSSION: We found no evidence that teriflunomide use would be associated with an increased risk of AESI. Trial Registration EUPAS register: EU PAS 19610.

Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network.

BACKGROUND: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time. METHODS: All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4. RESULTS: A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria. CONCLUSIONS: Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.

ECTRIMS/EAN consensus on vaccination in people with multiple sclerosis: Improving immunization strategies in the era of highly active immunotherapeutic drugs.

BACKGROUND: With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. OBJECTIVE: To develop a European evidence-based consensus for the vaccination strategy of pwMS who are candidates for disease-modifying therapies (DMTs). METHODS: This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions, and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk-benefit balance. RESULTS: Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in sub-populations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines, and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus. CONCLUSION: This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.

Pregnancy outcomes after early fetal exposure to injectable first-line treatments, dimethyl fumarate, or natalizumab in Danish women with multiple sclerosis.

BACKGROUND AND PURPOSE: Data on pregnancy outcomes following fetal exposure to disease-modifying drugs (DMDs) in women with multiple sclerosis (MS) are sparse although growing. METHODS: Data from the Danish Multiple Sclerosis Registry were linked with nationwide registries enabling an investigation of adverse pregnancy outcomes in newborns of women with MS following fetal exposure to injectable first-line treatments, dimethyl fumarate, glatiramer acetate, or natalizumab. Logistic regression models accounting for clustered data were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for individual and composite adverse outcomes after adjusting for relevant covariates. RESULTS: A total of 1009 DMD-exposed pregnancies were compared with 1073 DMD-unexposed pregnancies as well as 91,112 pregnancies from the general population. No association of an increased risk of any perinatal outcome was found when comparing newborns with fetal exposure with the general population, including preterm birth (OR = 1.19, 95% CI = 0.86-1.64), small for gestational age (OR = 1.38, 95% CI = 0.92-2.07), spontaneous abortion (OR = 1.04, 95% CI = 0.84-1.27), congenital malformation (OR = 0.99, 95% CI = 0.68-1.45), low Apgar score (OR = 0.62, 95% CI = 0.23-1.65), stillbirth (OR = 1.05, 95% CI = 0.33-3.31), placenta complication (OR = 0.53, 95% CI = 0.22-1.27), and any adverse event (OR = 1.10, 95% CI = 0.93-1.30). Similar results were found when comparing DMD-exposed pregnancies with DMD-unexposed pregnancies. CONCLUSIONS: We found no increased association of adverse pregnancy outcomes in newborns with fetal exposure to DMDs when compared with either DMD-unexposed pregnancies or the general population.

European Committee for Treatment and Research in Multiple Sclerosis and European Academy of Neurology consensus on vaccination in people with multiple sclerosis: Improving immunization strategies in the era of highly active immunotherapeutic drugs.

BACKGROUND AND PURPOSE: With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. We aimed to develop a European evidence-based consensus for the vaccination strategy of pwMS who are candidates for disease-modifying therapies (DMTs). METHODS: This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk-benefit balance. RESULTS: Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in subpopulations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus. CONCLUSION: This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.

Automatic Assessment of the 2-Minute Walk Distance for Remote Monitoring of People with Multiple Sclerosis.

The aim of this study was to investigate the feasibility of automatically assessing the 2-Minute Walk Distance (2MWD) for monitoring people with multiple sclerosis (pwMS). For 154 pwMS, MS-related clinical outcomes as well as the 2MWDs as evaluated by clinicians and derived from accelerometer data were collected from a total of 323 periodic clinical visits. Accelerometer data from a wearable device during 100 home-based 2MWD assessments were also acquired. The error in estimating the 2MWD was validated for walk tests performed at hospital, and then the correlation (r) between clinical outcomes and home-based 2MWD assessments was evaluated. Robust performance in estimating the 2MWD from the wearable device was obtained, yielding an error of less than 10% in about two-thirds of clinical visits. Correlation analysis showed that there is a strong association between the actual and the estimated 2MWD obtained either at hospital (r = 0.71) or at home (r = 0.58). Furthermore, the estimated 2MWD exhibits moderate-to-strong correlation with various MS-related clinical outcomes, including disability and fatigue severity scores. Automatic assessment of the 2MWD in pwMS is feasible with the usage of a consumer-friendly wearable device in clinical and non-clinical settings. Wearable devices can also enhance the assessment of MS-related clinical outcomes.

Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis.

OBJECTIVE: To quantify sex differences in activity and severity of multiple sclerosis (MS) and how it depends on disease duration and time since clinical onset. METHODS: All Danish citizens with onset of relapsing MS since 1996 who have received disease-modifying therapy have been followed with annual or biannual control visits with mandatory notification of the Danish Multiple Sclerosis Registry. Men and women were compared by the inverse probability of being female. Relapse rates and changes in the Expanded Disability Status Scale (EDSS) scores were analysed with weighted general linear models, and we used weighted Cox regression for HRs between men and women for different EDSS endpoints. RESULTS: We included 3028 men and 6619 women. The weighted female:male relapse rate ratio was 1.16 (95% CI: 1.10 to 1.22) but after age 50 years, the difference disappeared. The annualised increase in EDSS was 0.07 in men (95% CI: 0.05 to 0.08) and 0.05 in women (95% CI: 0.04 to 0.06); p=0.017. With women as reference, the HR for reaching EDSS 4 was 1.34 (95% CI: 1.23 to 1.45; p<0.001), and for reaching EDSS 6 it was 1.43 (95% CI: 1.28 to 1.61; p<0.001). The diagnostic delay did not differ significantly between the sexes. CONCLUSION: Women have more inflammatory disease activity in terms of relapses than men up to the age of menopause indicating that sex hormones may play a role. Men are more subject to the neurodegenerative component of MS than women, particularly after the age of 45 years.

Rebound of clinical disease activity after fingolimod discontinuation? A nationwide cohort study of patients in Denmark.

OBJECTIVE: We investigated whether clinical rebound occurred after fingolimod discontinuation in a complete population of patients with relapsing-remitting multiple sclerosis (RRMS) in Denmark. We further identified clinical and demographical factors associated with disease reactivation after fingolimod discontinuation. METHODS: The population comprised 992 RRMS patients treated with fingolimod for 6 months or more. We estimated annualised relapse rates (ARR) before, during and after treatment. We estimated overall ARRs and ARRs stratified by disease activity before discontinuation. We calculated the proportion of patients with a higher clinical disease activity after discontinuation than before treatment start. Finally, we analysed the association between variables at discontinuation and time to first relapse after discontinuation. RESULTS: The ARR 3 months after discontinuation (ARR=0.56; 95% CI=0.47 to 0.66) was statistically significantly lower (p<0.01) than the ARR 1 year before treatment (ARR=0.74; 95% CI=0.69 to 0.80). Results were similar when repeating analyses in patients with and without disease activity before discontinuation. In total, 124 patients (12.5%) had clinical rebound. Of those, 36 had no disease breakthrough before discontinuation (3.6% of total population). On treatment disease activity (HR=1.98, p<0.01), lower age (HR=0.98, p=0.01) and female sex (HR=1.68, p=0.02) were associated with a higher relapse risk after discontinuation. CONCLUSIONS: Based on average ARR levels, there was no evidence of clinical rebound after fingolimod discontinuation. In total, 12.5% of patients had clinical rebound. Only 3.6%, however, had clinical rebound without disease activity before discontinuation. Disease activity before discontinuation, female sex and younger age were statistically significantly associated with a higher relapse risk after discontinuation.