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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.
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Esclerosis Múltiple , Humanos , Caminata , Prueba de Paso , FatigaRESUMEN
Objective: The aim of this study was to evaluate the association between changes in the autonomic control of cardiorespiratory system induced by walk tests and outcome measures in people with Multiple Sclerosis (pwMS). Methods: Electrocardiogram (ECG) recordings of 148 people with Relapsing-Remitting MS (RRMS) and 58 with Secondary Progressive MS (SPMS) were acquired using a wearable device before, during, and after walk test performance from a total of 386 periodical clinical visits. A subset of 90 participants repeated a walk test at home. Various MS-related symptoms, including fatigue, disability, and walking capacity were evaluated at each clinical visit, while heart rate variability (HRV) and ECG-derived respiration (EDR) were analyzed to assess autonomic nervous system (ANS) function. Statistical tests were conducted to assess differences in ANS control between pwMS grouped based on the phenotype or the severity of MS-related symptoms. Furthermore, correlation coefficients (r) were calculated to assess the association between the most significant ANS parameters and MS-outcome measures. Results: People with SPMS, compared to RRMS, reached higher mean heart rate (HRM) values during walk test, and larger sympathovagal balance after test performance. Furthermore, pwMS who were able to adjust their HRM and ventilatory values, such as respiratory rate and standard deviation of the ECG-derived respiration, were associated with better clinical outcomes. Correlation analyses showed weak associations between ANS parameters and clinical outcomes when the Multiple Sclerosis phenotype is not taken into account. Blunted autonomic response, in particular HRM reactivity, was related with worse walking capacity, yielding r = 0.36 r = 0.29 (RRMS) and r > 0.5 (SPMS). A positive strong correlation r > 0.7 r > 0.65 between cardiorespiratory parameters derived at hospital and at home was also found. Conclusion: Autonomic function, as measured by HRV, differs according to MS phenotype. Autonomic response to walk tests may be useful for assessing clinical outcomes, mainly in the progressive stage of MS. Participants with larger changes in HRM are able to walk longer distance, while reduced ventilatory function during and after walk test performance is associated with higher fatigue and disability severity scores. Monitoring of disorder severity could also be feasible using ECG-derived cardiac and respiratory parameters recorded with a wearable device at home.
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BACKGROUND: Natalizumab is a widely used high-efficacy treatment in multiple sclerosis (MS). Real-world evidence regarding long-term effectiveness and safety is warranted. We performed a nationwide study evaluating prescription patterns, effectiveness, and adverse events. METHODS: A nationwide cohort study using the Danish MS Registry. Patients initiating natalizumab between June 2006 and April 2020 were included. Patient characteristics, annualized relapse rates (ARRs), confirmed Expanded Disability Status Scale (EDSS) score worsening, MRI activity (new/enlarging T2- or gadolinium-enhancing lesions), and reported adverse events were evaluated. Further, prescription patterns and outcomes across different time periods ("epochs") were analysed. RESULTS: In total, 2424 patients were enrolled, with a median follow-up time of 2.7 years (interquartile range (IQR) 1.2-5.1). In recent epochs, patients were younger, had lower EDSS scores, had fewer pre-treatment relapses and were more often treatment naïve. At 13 years of follow-up, 36% had a confirmed EDSS worsening. On-treatment ARR was 0.30, corresponding to a 72% reduction from pre-initiation. MRI activity was rare, 6.8% had activity within 2-14 months from treatment start, 3.4% within 14-26 months, and 2.7% within 26-38 months. Approximately 14% of patients reported adverse events, with cephalalgia constituting the majority. During the study, 62.3% discontinued treatment. Of these, the main cause (41%) was due to JCV antibodies, while discontinuations due to disease activity (9%) or adverse events (9%) were less frequent. CONCLUSION: Natalizumab is increasingly used earlier in the disease course. Most patients treated with natalizumab are clinically stable with few adverse events. JCV antibodies constitute the main cause for discontinuation.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Natalizumab/efectos adversos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inducido químicamente , Estudios de Cohortes , Estudios de Seguimiento , Resultado del Tratamiento , Anticuerpos , Dinamarca/epidemiología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inducido químicamente , Factores Inmunológicos/efectos adversosRESUMEN
BACKGROUND: Changes in lifestyle, finances and work status during COVID-19 lockdowns may have led to biopsychosocial changes in people with pre-existing vulnerabilities such as Major Depressive Disorders (MDDs) and Multiple Sclerosis (MS). METHODS: Data were collected as a part of the RADAR-CNS (Remote Assessment of Disease and Relapse-Central Nervous System) program. We analyzed the following data from long-term participants in a decentralized multinational study: symptoms of depression, heart rate (HR) during the day and night; social activity; sedentary state, steps and physical activity of varying intensity. Linear mixed-effects regression analyses with repeated measures were fitted to assess the changes among three time periods (pre, during and post-lockdown) across the groups, adjusting for depression severity before the pandemic and gender. RESULTS: Participants with MDDs (N = 255) and MS (N = 214) were included in the analyses. Overall, depressive symptoms remained stable across the three periods in both groups. A lower mean HR and HR variation were observed between pre and during lockdown during the day for MDDs and during the night for MS. HR variation during rest periods also decreased between pre- and post-lockdown in both clinical conditions. We observed a reduction in physical activity for MDDs and MS upon the introduction of lockdowns. The group with MDDs exhibited a net increase in social interaction via social network apps over the three periods. CONCLUSIONS: Behavioral responses to the lockdown measured by social activity, physical activity and HR may reflect changes in stress in people with MDDs and MS. Remote technology monitoring might promptly activate an early warning of physical and social alterations in these stressful situations. Future studies must explore how stress does or does not impact depression severity.
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Background Initiation of disease-modifying therapy early in the disease course of relapsing-remitting multiple sclerosis (RRMS) has demonstrated beneficial effects on clinical outcomes, but socioeconomic outcomes remain largely unexplored. Objective To investigate the association between the delay from disease onset to first treatment and the hazard of disability pension. Methods We performed a population-based cohort study with data from the nationwide Danish Multiple Sclerosis Registry and Danish nationwide registries. Patients with a disease onset between 1 January 1996 to 5 April 2016 were followed until disability pension or a competing risk/censoring event. 7859 patients were assessed for eligibility of which 5208 were included in the final cohort. Key inclusion criteria were: a diagnosis of multiple sclerosis, relapsing-remitting phenotype, treatment in history, age 18-65 years and an Expanded Disability Status Scale≤4. Patients were categorised according to time from onset to first treatment: within 1 year (early), between 1 and 4 years (intermediate) and from 4 to 8 years (late). Results Of the 5208 patients, 1922 were early, 2126 were intermediate and 1160 were late. Baseline clinical and socioeconomic variables were well balanced. The hazard of receiving disability pension increased with increasing delay of treatment initiation compared with the early group. Cox regression estimates adjusted for clinical and socioeconomic confounders: intermediate (HR, 1.37; 95% CI, 1.12 to 1.68) and late (HR, 1.97; 95% CI, 1.55 to 2.51). Conclusion Early treatment initiation is associated with a reduced risk of disability pension in patients with RRMS. This finding underlines the importance of early diagnosis and treatment on a patient-centred, socioeconomic disability milestone.
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Personas con Discapacidad , Esclerosis Múltiple Recurrente-Remitente , Pensiones , Tiempo de Tratamiento , Adolescente , Adulto , Anciano , Estudios de Cohortes , Dinamarca , Personas con Discapacidad/estadística & datos numéricos , Humanos , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/terapia , Pensiones/estadística & datos numéricos , Sistema de Registros , Medición de Riesgo , Tiempo de Tratamiento/estadística & datos numéricos , Adulto JovenRESUMEN
Background: Studies have demonstrated an increasing mean age of the population with multiple sclerosis (MS). The association between increased age and socioeconomic outcomes has been investigated sparsely. Objective: The purpose of this study is to describe the demographic and socioeconomic status of the current Danish population of patients with MS according to age and to assess the age-related risks of no income or losing all income from earnings or receiving disability pension. Methods: The nationwide population-based Danish Multiple Sclerosis Registry provided data linked with the Danish Income Statistics Register and the Danish Rational Economic Agents Model (DREAM) database. The prevalence of socioeconomic milestones of the current MS population was compared with healthy controls and the risks of reaching socioeconomic milestones were assessed using cause-specific Cox models and cumulative incidence functions compared to healthy controls. Results: The current Danish population of patients with MS of working age (18-65 years of age) consists of 11,287 patients, of which 29.3% was older than 55 years. In 2018, 38.0% of all patients and 18.9% of controls had no income from earnings, whereas 30.5% of all patients and 7.7% of controls received disability pension. The risk of losing all income from earnings was higher for patients with MS with a hazard ratio (HR) peaking at of 4.0 (95% CI, 3.8-4.2) for the ages of 45-54 years. The risk of receiving disability pension was much higher for patients with MS peaking at a HR of 22.6 (95% CI, 20.9-24.4) for the ages of 25-34 years. Likewise, the absolute risks of both outcomes were higher for the patients with MS at all ages. Conclusion: Danish patients with MS are at a higher risk of losing all income from earnings and at a much higher risk of receiving disability pension compared with healthy controls.
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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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Crotonatos/uso terapéutico , Hidroxibutiratos/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/epidemiología , Nitrilos/uso terapéutico , Toluidinas/uso terapéutico , Adulto , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Sistema de Registros , Resultado del TratamientoRESUMEN
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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Personas con Discapacidad , Esclerosis Múltiple , Edad de Inicio , Evaluación de la Discapacidad , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/terapia , Modelos de Riesgos ProporcionalesRESUMEN
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-ß 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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Acetato de Glatiramer/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Estudios de Cohortes , Sustitución de Medicamentos , Femenino , Acetato de Glatiramer/administración & dosificación , Humanos , Inmunosupresores/administración & dosificación , Interferón beta/administración & dosificación , Masculino , Sistema de Registros , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine the effectiveness of high-efficacy disease-modifying therapies (heDMTs) vs medium-efficacy disease-modifying therapies (meDMT) as the first treatment choice in treatment-naive patients with multiple sclerosis (MS) on disability worsening and relapses. We assessed this using a nationwide population-based MS registry. METHODS: We identified all patients starting a heDMT as first-time treatment from the Danish Multiple Sclerosis Registry and compared treatment outcomes with a propensity score matched sample of patients starting meDMT. RESULTS: We included 388 patients in the study: 194 starting initial therapy with heDMT matched to 194 patients starting meDMT. At 4 years of follow-up, the probabilities of a 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening were 16.7% (95% confidence interval [CI] 10.4%-23.0%) and 30.1% (95% CI 23.1%-37.1%) for heDMT and meDMT initiators, respectively (hazard ratio [HR] 0.53, 95% CI 0.33-0.83, p = 0.006). Patients initiating heDMT also had a lower probability of a first relapse (HR 0.50, 95% CI 0.37-0.67). Results were similar after pairwise censoring and in subgroups with high baseline activity, diagnosis after 2006, or information on baseline T2 lesion load. CONCLUSION: We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.
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Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Some patients with multiple sclerosis who are treated with interferon-ß(IFNß) develop neutralizing antibodies (NAbs), which reduce or abolish the therapeutic effects of the treatment. These patients are usually switched to a non-IFNß treatment, such as glatiramer acetate (GA). It is unknown whether a patient's previous disease activity in combination with their NAb-status can provide further insights on their risk of future disease activity. Consequently, we investigated treatment outcomes in patients switching from IFNß to GA according to NAb-status and clinical disease activity, while on IFNß. METHODS: We identified all patients switching from IFNß to GA and having information on NAb-status from the Danish Multiple Sclerosis Registry and compared treatment outcomes while on GA according to previous disease activity and the presence of NAbs. RESULTS: We included 568 patients in the study: 107 NAb-negative patients switched due to adverse events (group 1), 24 NAb-negative patients switched with disease activity (group 2), 397 NAb-positive patients switched without disease activity (group 3) and 40 NAb-positive patients switched with disease activity (group 4). Compared to the reference (group 1), group 2 had an increased risk of future relapses (HR 1.79 95% Confidence interval (CI): 1.00-3.19). Group 3 showed a trend of a lower risk of future relapses (HR 0.74, 95%CI: 0.53-1.04). Group 4 had, on average, a similar risk of future relapses (HR 1.15 95% CI: 0.69-1.92). Similarly, group 2 had a higher probability of treatment discontinuation due to disease activity compared to the other groups. CONCLUSION: While on GA, patients switched from IFNß in the context of disease activity and no NAbs had the highest risk of future disease activity, while NAb positive patients without previous activity had the lowest. We did not find any average difference between NAb-positive patients switching in a context of disease activity and NAb-negative patients switched due to adverse events, although carefulness in the interpretation of this result is advised.
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OBJECTIVE: To compare on-treatment efficacy and discontinuation outcomes in teriflunomide (TFL) and dimethyl fumarate (DMF) in the treatment of relapsing-remitting multiple sclerosis (RRMS) in a real-world setting. METHODS: We identified all patients starting TFL or DMF from the Danish Multiple Sclerosis Registry and compared on-treatment efficacy outcomes between DMF using TFL, adjusted for clinical baseline variables and propensity score-based methods. RESULTS: We included 2,236 patients in the study: 1,469 patients on TFL and 767 on DMF. Annualized relapse rates (ARRs) in TFL and DMF were 0.16 (95% confidence interval [CI] 0.13-0.20) and 0.09 (95% CI 0.07-0.12), respectively. Relapse rate ratio for DMF/TFL was 0.58 (95% CI 0.46-0.73, p < 0.001). DMF had a higher relapse-free survival proportion at 48 months of follow-up (p < 0.05). We observed no difference in Expanded Disability Status Scale score worsening. Discontinuations due to disease breakthrough were 10.2% (95% CI 7.6%-12.8%) and 22.1% (95% CI 19.2%-25.0%) for DMF and TFL, respectively. A subgroup analysis of ARRs in 708 patients with available baseline MRI T2 lesion amount reported similar results after adjustment. CONCLUSION: We found lower ARR, higher relapse-free survival, and lower incidence of discontinuation due to disease breakthrough on treatment with DMF compared with TFL. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, DMF is more effective in preventing relapses and has lower discontinuation due to disease breakthrough compared with TFL.