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In 2001, the German Multiple Sclerosis Society, facing lack of data, founded the German MS Registry (GMSR) as a long-term data repository for MS healthcare research. By the establishment of a network of participating neurological centres of different healthcare sectors across Germany, GMSR provides observational real-world data on long-term disease progression, sociodemographic factors, treatment and the healthcare status of people with MS. This paper aims to illustrate the framework of the GMSR. Structure, design and data quality processes as well as collaborations of the GMSR are presented. The registry’s dataset, status and results are discussed. As of 08 January 2021, 187 centres from different healthcare sectors participate in the GMSR. Following its infrastructure and dataset specification upgrades in 2014, more than 196,000 visits have been recorded relating to more than 33,000 persons with MS (PwMS). The GMSR enables monitoring of PwMS in Germany, supports scientific research projects, and collaborates with national and international MS data repositories and initiatives. With its recent pharmacovigilance extension, it aligns with EMA recommendations and helps to ensure early detection of therapy-related safety signals.

Background: Epileptic seizures can occur throughout the course of multiple sclerosis (MS) and are associated with increasing disability progression over time. However, there are no data on whether epileptic seizures at the onset of MS also lead to increasing disability. Objective: To examine disease progression over time for MS patients with epileptic seizures at onset. Methods: We analyzed the data of 30,713 patients on the German Multiple Sclerosis Register in a case–control study for more than 15 years. MS patients with seizures at onset were further divided into subgroups with polysymptomatic and monosymptomatic onset to assess the impact of additional symptoms on disease progression. Results: A total of 46 patients had seizures as onset symptoms. Expanded Disability Status Scale (EDSS) within the first year was lower in the group with seizures at onset compared to controls (0.75 versus 1.6, p < 0.05), which changed until the last reported visit (3.11 versus 3.0). Both subgroups revealed increased EDSS progression over time compared to controls. Conclusion: Epileptic seizures at MS onset are associated with a higher amount of disability progression over time. Additional longitudinal data are needed to further clarify the impact of seizures on the pathophysiology of MS disease progression.

Background: Treatment guidelines recommend early disease-modifying therapy (DMT) initiation after diagnosis of multiple sclerosis (MS). Multinational comparative studies that assess time to DMT initiation in MS may allow detection of barriers inherent to healthcare systems to explain potential adverse systematic delays in commencing DMTs. Objectives: To investigate and compare the time to first DMT and its association with sociodemographic and clinical variables after MS diagnosis in three large MS registries. Design: This observational study was conducted using data from the German MS Registry (GMSR), the North American Research Committee on MS Registry (NARCOMS, US data only), and the United Kingdom MS Registry (UKMSR, both self- and clinician-reported). Methods: Data from relapsing people with MS (PwMS), with a diagnosis of MS between 2014 and 2019, and available DMT and disability status were pooled using a meta-analytic approach. Results: A total of 5395 PwMS were included in the analysis (GMSR: n = 2658; NARCOMS: n = 447; UKMSR: n = 2290). Kaplan–Meier estimates for the time to first DMT [median months (95% CI)] were 2.0 (1.9–2.0), 3.0 (2–4), and 9.0 (7.7–10.6) for GMSR, NARCOMS, and UKMSR, respectively. Pooled multivariable Cox regression demonstrated shorter time to first DMT for PwMS diagnosed after 2017 [1.65 (1.42–1.92), p < 0.01], and longer time to DMT when a higher-efficacy DMT was selected (0.69 (0.54–0.90), p < 0.0001]. Conclusion: Time to DMT initiation differs across the populations studied, indicating that barriers may exist in early access to DMT, particularly in the United Kingdom. However, a consistent decrease in time to DMT initiation was noted since 2017 across all registries. Further studies are warranted comparing the effects of time to DMT and time to higher-efficacy DMT on long-term outcome.

Background: The spectrum of disease-modifying therapies (DMTs) for people with multiple sclerosis (PwMS) has expanded over years, but data on treatment strategies is largely lacking. DMT switches are common clinical practice. Objective: To compare switchers and non-switchers, characterize the first DMT switch and identify reasons and predictors for switching the first DMT. Methods: Data on 2722 PwMS from the German MS Registry were retrospectively analyzed regarding sociodemographic/clinical differences between 1361 switchers (PwMS discontinuing the first DMT) and non-switchers matched according to age, sex, and observation period. Frequencies of first and second DMTs were calculated and switch reasons identified. Predictors for DMT switches were revealed using univariable and multivariable regression models. Results: Switchers and non-switchers differed significantly regarding time to first DMT, education, calendar period of the first DMT start (2014–2017 versus 2018–2021), first DMT class used [mild-to-moderate efficacy (MME) versus high-efficacy (HE) DMT], time on first DMT, and disease activity at first DMT start or cessation/last follow-up. The majority of PwMS started with MME DMTs (77.1%), with the most common being glatiramer acetate, dimethyl/diroximel fumarate, and beta-interferon variants. Switchers changed treatment more often to HE DMTs (39.6%), most commonly sphingosine-1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, and natalizumab. Fewer PwMS switched to MME DMTs (35.9%), with the most common being dimethyl/diroximel fumarate, teriflunomide, or beta-interferon. Among 1045 PwMS with sufficient data (76.8% of 1361 switchers), the most frequent reasons for discontinuing the first DMT were disease activity despite DMT (63.1%), adverse events (17.1%), and patient request (8.3%). Predictors for the first DMT switch were MME DMT as initial treatment [odds ratio (OR) = 2.83 (1.76–4.61), p < 0.001; reference: HE DMT], first DMT initiation between 2014 and 2017 [OR = 11.55 (6.93–19.94), p < 0.001; reference: 2018–2021], and shorter time on first DMT [OR = 0.22 (0.18–0.27), p < 0.001]. Conclusion: The initial use of MME DMTs was among the strongest predictors of DMT discontinuation in a large German retrospective MS cohort, arguing for the need for prospective treatment strategy trials, not only but also on the initial broad use of HE DMTs in PwMS.

Objective Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state‐of‐the‐art clinical settings and trials applying combined outcome parameters. Methods Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed‐25‐foot walk test (T25FW), and nine‐hole‐peg‐test (9HPT)). Results 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7–61.2], 135 female, median follow‐up: 29.3 months [17.9–40.9]) were included. NfL (age‐) and GFAP (age‐ and sex‐) adjusted Z scores were higher in pwPMS compared to HC (p < 0.001 for both). 111 (32.8%) CDP events were diagnosed in participants with ≥3 visits (n = 169). GFAP Z score >3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12–5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21–6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53–12.13], p = 0.006). Interpretation Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non‐active pwPMS with particularly high progression risk.

Background: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease whose aetiology is not fully understood. The female sex is clearly predominant, with a sex ratio between 2 and 3. In primary progressive MS the sex ratio almost balances out. Since the age at onset is higher for patients with progressive onset (POMS) than for relapsing onset (ROMS), it can be hypothesized that the age at onset is a decisive factor for the sex ratio. Methods: To address this aspect, we compare clinical and demographic data between females and males for the different disease courses within the population of the German MS Register by the German MS Society. Only patients with complete details in mandatory data items and a follow-up visit since 01. Jan 2018 were included. Results: A total of 18,728 patients were included in our analyses, revealing a female-to-male ratio of 2.6 (2.7 for patients with ROMS and 1.3 for POMS). The age at diagnosis is higher in patients with POMS (43.3 and 42.3 years for females and males versus 32.1 and 33.2 years, respectively). Females irrespective of disease course are statistically significantly more often affected by cognitive impairment (POMS: p = 0.013, ROMS: p = 0.001) and depression (POMS: p = 0.002, ROMS: 0.001) and suffer more often from pain (POMS and ROMS: p < 0.001). Fatigue is significantly more often seen in females with ROMS (p < 0.001) but not in POMS. Females with ROMS retire significantly (p < 0.001) earlier (42.8 versus 44.2 years) and to a greater extent than males (28 versus 24%). Disease progression was similar for women and men. Conclusion: Our analysis shows that clinical and demographic data differ more between disease courses than between men and women. For pain, depression and cognitive impairment the female sex is the decisive factor. Whether these factors are responsible for the earlier retirement of females with ROMS is not clear. Appropriate measures for optimization of symptomatic treatment as well as to promote employment should be taken.

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing–remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender (p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score (p = 0.004), and the presence of monitoring (p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 – UK portal 0.311). Those with higher EDSS at index (p < 0.03) and female gender (p < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment. Discussion: This highlights the importance of a healthcare system’s approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment.

Background: The manifestation of multiple sclerosis (MS) in childhood and adolescence occurs in 3%−5% of all MS cases. However, the immunomodulatory and symptomatic treatment options in this population group are still limited. Objective: We aimed to elucidate the prescription frequency of medications used in pediatric patients with multiple sclerosis (PwMS) compared with the general population, considering the entire spectrum of medications prescribed. Methods: Based on nationwide outpatient drug prescription data and statutory health insurance (SHI) physicians’ claims data from 2018, we conducted a population-based cross-sectional study in Germany. Children and adolescents aged ⩽17 years (n = 11,381,939) diagnosed with MS (n = 613), and a matched (age, sex, and health insurance sector) control group (n = 6130) were included. The prescription prevalence was measured as the proportion of MS patients with ⩾1 prescription. Results: Of the 613 pediatric PwMS with a median age of 16 years, 403 (65.7%) were female. For 15 out of the 18 different active agents analyzed, PwMS had a significantly higher prescription prevalence than the control group (Fisher’s exact test: p ⩽ 0.037). The most frequently prescribed drugs in PwMS were ibuprofen (28.4%; anti-inflammatory drug), cholecalciferol (23.0%; vitamin D3), and interferon beta-1a (21.5%; disease-modifying drug, DMD). The proportions of DMD prescriptions and antibiotic prescriptions were higher among PwMS aged 15–17 years than among those ⩽14 years (DMD: 43.4% vs 34.2%, p = 0.05; antibiotic: 34.1% vs 24.8%, p = 0.031). In contrast, younger PwMS were more likely to receive a prescription for anti-inflammatory/anti-rheumatic drugs (36.6% vs 26.5%, p = 0.02). Conclusion: Our study analyzing real-world medication data showed that interferon beta, anti-inflammatory drugs, and vitamins play an essential role in the treatment of pediatric PwMS. Future research should evaluate longitudinal treatment patterns of pediatric PwMS, paying particular attention to the time of diagnosis, time of first DMD initiation, and therapy switches.

Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the central nervous system in Europe, often causing severe physical, cognitive and emotional impairments. Currently, it is unclear whether the healthcare provisions of people with MS (PwMS) are in line with the recommendations for treatment based on guidelines or patients' needs. The main objectives of the study are as follows: (a) to investigate how well PwMS are treated; and (b) to develop a needs-oriented, patient-centred care model. This mixed-methods study focuses on adult PwMS living in Lower Saxony, a federal state in Germany. The qualitative study comprises focus groups with PwMS, physicians and people involved in the healthcare process as well as a future workshop. The quantitative study comprises a cross-sectional online survey and addresses the patient-relevant outcomes and needs, as previously determined by literature searches and focus groups. It will be administered to all PwMS who are insured by the statutory health insurance company involved in the project (n~7,000). The survey data will be linked to the longitudinal secondary data from the statutory health insurance company and data from the German MS registry where available. The linked and single data sources will be statistically analysed. By comprehensively comparing the current healthcare provisions with the needs and requirements of PwMS, the strengths and weaknesses of the overall healthcare process and provision of assistive devices can be identified. The barriers and facilitators of the health service providers and their impact on daily life will be explored (qualitative analyses). Reliable recommendations for improvements will be given based on a study population drawn from the largest statutory health insurance company in Lower Saxony (quantitative analyses). However, the inherent advantages and limitations of the qualitative and quantitative research approaches need to be considered. The study is registered at German Clinical Trials Register DRKS00021741.

Introduction Multiple sclerosis is a chronic inflammatory, degenerative disease of the central nervous system manifesting at first with relapses in about 85% of cases. In Germany, intravenous therapy with high-dose corticosteroids is the treatment standard of acute relapses. The treatment leads to a faster reduction of symptoms in about 25 of 100 treated patients but has no proven long-term benefits over placebo treatment. Intravenous treatment is not superior to oral treatment. Therefore, informed decisions on relapse management are required. An earlier randomised controlled trial showed that evidence-based patient information and education on relapse management leads to more informed decisions and more relapses not treated or treated with oral corticosteroids. This study aims to evaluate whether a web-based relapse management programme will positively change relapse management and strengthen autonomy in people with multiple sclerosis. Methods The pragmatic double-blind randomised controlled trial is accompanied by a mixed-methods process evaluation and a health economic evaluation and follows the UK Medical Research Council guidance on developing and evaluating complex interventions. A total of 188 people with possible or relapsing-remitting multiple sclerosis with ≥ 1 relapse within the last year and/or ≥ 2 relapses within the last 2 years will be recruited and randomised using blocks. The intervention group receives a web- and dialogue-based decision aid on relapse management, a nurse-led webinar and access to a monitored chat forum. The control group receives standard information, which will be made available via the same online platform as the intervention. The primary endpoint is the proportion of relapses not treated or treated with oral corticosteroids. Key secondary endpoints are the annualised relapse rate, decision-making, empowerment, quality of life and cost-effectiveness. Facilitators and barriers will be assessed by mixed-methods process evaluation measures. The study ends when 81 relapses have been documented or after 24 months of observation per individual patient. Analyses will follow the intention-to-treat principle. Discussion We hypothesise that the intervention will enhance patient empowerment and have a positive impact on patients’ relapse management. Trial registration ClinicalTrials.gov NCT04233970 . Registered on 18 January 2020