Introduction Advances in ultrasensitive assay techniques have enabled precise quantification of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP), highlighting their potential as dynamic biomarkers for detecting neuroaxonal injury, disease activity and progression in multiple sclerosis (MS). In the NeuroFilMS study, sNfL is being investigated prospectively as a prognostic biomarker for clinical and radiological disease activity in relapsing MS, while sGFAP is retrospectively explored as a marker of disease progression. The aim is to assess whether longitudinal monitoring of sNfL can inform diagnostic and therapeutic decisions in the treatment of people with MS (pwMS) and whether retrospective sGFAP measurements provide additional insights into disease progression. The study additionally aims to evaluate the comparability of different assay methods.Methods and analysis NeuroFilMS is a prospective, multicentre study that will be conducted across multiple MS study centres throughout Germany, in collaboration with the German Multiple Sclerosis Registry set up by the German National Multiple Sclerosis Society (Deutsche Multiple Sklerose Gesellschaft). The study aims to enrol 1500 pwMS diagnosed with relapsing MS. Participants will be randomised in a 2:1 ratio (n=1000 vs n=500) to either immediate sNfL reporting or delayed sNfL reporting to treating physicians, in order to evaluate how sNfL availability influences therapeutic decision-making in routine healthcare regarding diagnostics and therapy decisions. Over a 2-year follow-up period, pwMS will attend three study visits integrated into routine care, including blood sampling for sNfL, clinical evaluations and routine MRI assessments; sGFAP will be measured retrospectively in batches, as it is not currently available for routine diagnostic use. The study follows the standardised protocols for biosample collection, performed both within clinical routine laboratory procedures and through research collaboration. Statistical analyses will involve both descriptive and inferential methods to evaluate biomarker performance and clinical associations.Ethics and dissemination The study has received ethical approval from the Clinical Ethics Committee of Charité–Universitätsmedizin Berlin (EA4/136/24) and will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Findings will be disseminated through peer-reviewed publications, conference presentations and engagement with patient organisations and clinical networks.Trial registration number DRKS00034337.

BACKGROUND:Multiple sclerosis (MS) is the most common neuroimmunological disease in young adults. Data on its clinical onset before the age of 18 (paediatric-onset MS (POMS)) are limited. METHODS:This observational study present data on >1000 POMS compared with adult-onset MS (AOMS) and analysed patients regarding diagnostic delay, initial symptoms and long-term outcome using generalised additive models and adjustment for relevant confounders. RESULTS:The results showed a diagnostic delay and a higher proportion of women with POMS vs AOMS. Sensory (57%) and visual (48%) disturbances were the most common initial symptoms of POMS. Relapse rates were higher in POMS than in AOMS within the first 15 years after the clinical onset. The proportion of patients reaching an Expanded Disability Status Scale (EDSS) score of 3.0 by 15 years was lower in POMS (41%) than in AOMS (age-dependent, 48%-71%). A plateau phase in EDSS was observed in patients with POMS after age 40, which was not seen in those with AOMS. This plateau phase was responsible for the equalisation of the EDSS score with advanced age between POMS and AOMS. Cerebellar and polysymptomatic symptoms at clinical onset and male sex were predictors of higher EDSS scores in POMS, whereas in AOMS, pyramidal dysfunction was a predictor of worse outcomes. CONCLUSIONS:This largest and longest follow-up study of POMS to date revealed that women are more likely to develop MS at younger ages and experience different symptoms than men. Patients with POMS tend to have higher relapse rates but may recover more quickly from relapses and experience a more stable disease course later in life.

IntroductionMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Immunotherapies such as natalizumab are associated with rare, serious adverse events that were identified by the spontaneous reporting system.ObjectiveTo replicate safety signals from the spontaneous reporting system for natalizumab treatment in MS patients using two data sources (ds) of German statutory health insurance (SHI) data.MethodsWe analyzed administrative SHI claims data from 44 company medical funds (ds1, 2010-2018) and 12 German physicians' associations (ds2, 2013-2018). Patients with a validated MS diagnosis (ICD-10-GM G35) treated with natalizumab until either subsequent other immunotherapies (natalizumab-switcher) or no other following immunotherapy (natalizumab-non-switcher) were included. We searched for safety signals, based on a list of signals derived from the EMA spontaneous reporting system, and calculated odds ratios (ORs) for incident diseases using interferon therapy as a comparison.ResultsOverall, 36,798 MS patients were included. Although case numbers were low for most investigated diseases, a safety signal of progressive multifocal leukoencephalopathy (PML) could be replicated for natalizumab-switcher (ds1: OR = 28.88 [6.02, 138.50]; ds2: OR = 59.94 [28.43, 147.32]) and natalizumab-non-switcher (ds1: OR = 28.74 [5.82, 141.88]; ds2: OR = 34.33 [15.43, 87.43]). For natalizumab-switcher, furthermore, a safety signal for herpes simplex was reproduced (ds1: OR = 1.84 [1.27, 2.68]; ds2: OR = 1.48 [1.24, 1.77]). In ds2, increased risks were observed also for herpes zoster (natalizumab-switcher: OR = 1.74 [1.49, 2.03]; natalizumab-non-switcher: OR = 1.36 [1.17, 1.58]) and "other polyneuropathies" (natalizumab-switcher: OR = 1.42 [1.17, 1.70]).ConclusionsReplication of safety signals for specific medications using German administrative SHI data is possible but requires very large datasets to obtain a sufficiently large study sample that allows the identification of rare adverse events such as PML.

Background: Bladder dysfunctions (BL-D) are common in people with multiple sclerosis (pwMS), significantly affecting daily life, infection risk, and survival. Nonetheless, BL-D are frequently stigmatized and inadequately addressed in clinical practice. To date, no comprehensive analysis of BL-D has been conducted in Germany. Objective: To assess the prevalence of BL-D and its subtypes in a German cohort and identify associated factors and treatment patterns. Methods: Data were analyzed from individuals enrolled in the German MS Register, aged ⩾18 with definite MS. Inclusion required ⩾3 visits and complete data on MS onset, diagnosis date, and BL-D status. BL-D were subclassified into urinary urgency, voiding dysfunction, bladder incontinence, and other BL-D. PwMS with different subtypes were compared regarding clinical, sociodemographic, and therapeutic characteristics and associated factors were identified using logistic regression. Results: The study cohort included 10,572 pwMS (71.7% female) with a mean age of 48.2 years, disease duration of 16.0 years, and median Expanded Disability Status Scale score of 2.0. BL-D was present in 38.0% of pwMS, with urinary urgency being the leading subtype (41.0%). Associations included older age, longer disease duration, progressive disease course, polysymptomatic onset, and receiving disease-modifying therapy. Interestingly, 37.1% of pwMS with BL-D received no bladder treatment, while 36.9% received pharmaceutical and 36.4% non-pharmaceutical bladder treatment. Conclusion: The results highlight the clinical relevance and burden of BL-D in MS and provide first insights into subtype-specific differences in the German MS population. Providing appropriate BL-D care requires investigation into causal factors and a deeper understanding of the underlying reasons of the treatment gap. Design: Retrospective, cross-sectional study.

BACKGROUND:The number of patients with late-onset multiple sclerosis (pwLOMS: initial MS symptoms after 50 years of age) is increasing. Therefore, we investigated pwLOMS compared with patients with adult-onset MS (pwAOMS) using epidemiologic, clinical and diagnostic comparative parameters. METHODS:Using data from the German MS Register, pwLOMS (onset: ≥50 years) were compared with pwAOMS (onset: 18-34 years, 35-49 years). Following outcome measures were considered: time to reach the Expanded Disability Status Scale (EDSS) scores 3.0/6.0/7.0, time to transition from relapsing-remitting to secondary progressive MS (SPMS) and meeting the no evidence of disease activity-3 criteria two years after diagnosis. We used a multivariable Cox proportional-hazards model with several covariates (e.g., sex, symptoms at MS onset) for the analysis. RESULTS:Overall, pwLOMS (N=814) showed a higher proportion of men and progressive MS, more frequent first motor symptoms and longer diagnostic delay, and reached the EDSS scores 3.0 and 6.0 faster than pwAOMS (N=5259). In pwLOMS, reaching EDSS=3.0 faster was more likely with initial motor/cerebellar/urinary tract system symptoms, while there was a lower risk of reaching the EDSS scores 3.0/6.0 with a delayed diagnosis. The risk of developing SPMS was higher in pwLOMS, which increased with the EDSS score within two years after disease onset. CONCLUSION:We found a markedly higher proportion of pwLOMS in the German population. The high proportion of progressive MS, faster achievement of EDSS milestones and higher conversion rate to SPMS indicate a relapse-independent disability pattern, suggesting a possible contribution of neurodegenerative mechanisms in LOMS.

BACKGROUND:People with severe multiple sclerosis (PsMS) have multidimensional, complex needs. COCOS-MS is an exploratory study of the effect of cross-sectoral care and case management (CCM) on these patients' quality of life, palliative care needs, and psychological distress, as well as caregivers' burden. METHODS:We conducted a randomized, controlled, phase II trial (DRKS00022771) with two parallel treatment arms: standard care versus CCM in addition to standard care over a 12-month period. A trial-specific CCM manual was used. The target variables were recorded in standardized fashion at baseline (T0) and every three months thereafter (T1 until the end of the intervention at T4, then T5 three months after the end of the intervention to determine sustainability). The primary endpoint was the change in the patients' quality of life (HALEMS) from baseline to month 12 in a group comparison. A modified intention-to-treat (mITT) was performed based on a mixed linear model with repeated measures over time (ARH1-structured covariance matrix). Values of p less than 0.05 were considered significant. RESULTS:80 PsMS were randomly assigned 1:1 to one of the two treatment arms (male: female 1:2, median age 55 years [IQR 49-62], EDSS 6.5 [6-7.5], dropout rate 10%). There was no significant improvement in HALEMS after one year (T4) in the group comparison (-0.08 [-0.31, 0.15], p = 0.503; NNT = 22). Secondary endpoints such as subjective health status, psychological distress, and palliative care needs showed a clear response at the end of the intervention. After the intervention ended, the values approached the baseline level. CONCLUSION:The primary endpoint did not reach significance in this health services research feasibility study. For further development of the study design, the focus will be on the psychological and palliative factors in which PsMS-a reference group for long-term neurological conditions-were found to benefit from the CCM.

The COVID-19 pandemic affected healthcare management for people with multiple sclerosis (PwMS), leading to alterations in disease-modifying therapies (DMTs) due to concerns about COVID-19 outcomes and vaccine efficacy. To compare DMT prescription patterns in PwMS before, during, and after the COVID-19 pandemic. PwMS from the German MS Register, between 2019 and 2024, either newly diagnosed (Cohort A) or who discontinued or switched DMT (Cohort B), were analyzed over a follow-up period of 3 months. Data from the pre-pandemic period were compared to early-, late-, and post-pandemic periods. DMTs were categorized as medium efficacy (meDMT) or high efficacy (heDMT). In Cohort A (n = 1810), pre-pandemic 46

Magnetic resonance imaging (MRI) is a critical diagnostic tool and monitoring modality for multiple sclerosis (MS), frequently employing gadolinium-based contrast agents (Gd). However, concerns regarding the accumulation of Gd have prompted international guidelines (MAGNIMS-CMSC-NAIMS, 2021) to advocate for the limitation of Gd utilization. Consequently, we assessed of the impact of the 2021 guidelines on the use of Gd in MRI in MS patients in Germany by conducting a retrospective analysis of MRI data from 12,833 MS patients in the German MS Register (2019–2024). Generalized additive models were employed to analyze Gd use trends over time by MRI type (cranial, spinal, combined). From 2020 to 2024, a significant decline in Gd use was observed, with percentages dropping from 74.2 to 41.2

Hintergrund: Neu, zugelassene Therapien haben meist noch unbekannte Nebenwirkungen, obwohl die klinischen Studien, die zur Zulassung führten, bereits Sicherheit und Wirksamkeit analysierten. Ein Grund dafür ist, dass die Ein- und Ausschlusskriterien der Studien das meist heterogenere Patientenkollektiv in der klinischen Routineversorgung oft nicht komplett abbilden. Fragestellung: In dieser Studie wurden die Auswirkungen der Übertragbarkeit von Phase-III Ein- und Ausschlusskriterien auf MS-Patienten in der klinischen Praxis analysiert, die mit DMDs behandelt werden. Dabei wurden die demografischen und klinischen Merkmale bei Therapiebeginn zwischen Patienten verglichen, die alle Kriterien erfüllt hätten, und solchen, die mindestens eines nicht erfüllt hätten. Zudem wurden Unterschiede in der Häufigkeit von (schwerewiegenden) unerwünschten Ereignissen ((S)UEs) zwischen den beiden Gruppen untersucht. Methoden: Datenbasis bildeten zwei nationale, prospektive, beobachtende, klinische, multizentrische Register, das REGIMS-Register und das MS-Register der DMSG. Folgende Ein- Ausschlusskriterien wurden angewandt: Alter, klinischer Verlauf der RRMS, Schübe, EDSS-Score, Medikationsgeschichte. Für kategoriale Vergleiche wurde der Chi-Quadrat-Test durchgeführt und für kontinuierliche Variablen der t-Test. Um den Unterschied in den Daten zur (S)UEs zu untersuchen, wurden logistische Regressionsmodelle berechnet. Ein p-Wert von <0,05 wurde als statistisch signifikant angesehen. Ergebnisse: 28% der Patienten des REGIMS-Registers und 5% der Patienten des MS-Registers haben die 4 vordefinierten Einschlusskriterien erfüllt und wären somit in eine Phase-III-Zulassungsstudie der entsprechenden Substanz aufgenommen worden. MS-Register-Patienten, die das Kriterium Alter und das Kriterium EDSS-Score nicht erfüllt hätten, hatten eine höhere Wahrscheinlichkeit, dass UEs auftreten. Schlussfolgerung: Unsere Ergebnisse zeigen eine deutliche Patientenselektion durch spezifische Einschlusskriterien in klinischen Studien von MS-Therapeutika, verglichen mit dem Patientenkollektiv, das nach Zulassung diese Therapie erhält. Diese Selektion geht allerdings nicht mit einem höheren Risiko in Bezug auf SUEs für diejenigen Patienten einher, die nicht in die entsprechende klinische Phase-III-Studie eingeschlossen worden wären. Background: Newly approved therapies usually still have unknown adverse events, although the clinical trials that led to approval had already analysed safety and efficacy. One reason for this is that the inclusion and exclusion criteria of the trials often do not fully reflect the usually heterogeneous patient population in routine clinical care. Research question: The aim of the study was to analyse the extent to which patients with multiple sclerosis (MS) from routine clinical care fulfil the inclusion and exclusion criteria for the corresponding clinical phase III trial of the respective drug. Methods: Sociodemographic and clinical characteristics as well as (serious) adverse events ((S) AEs) were compared. Data were based on two national, prospective, observational, clinical, multicentre registries, the REGIMS registry and the DMSG MS registry. Results: 28% of the patients in the REGIMS registry and 5% of the patients in the MS registry fulfilled the 4 predefined inclusion criteria and would therefore have been included in a phase III registration trial of the corresponding substance. MS registry patients who would not have met the age and EDSS score criteria were more likely to experience AEs. Conclusion: Our results show a clear selection of patients by specific inclusion criteria in clinical trials of MS therapeutics compared to the patient population receiving this therapy after approval. However, this selection is not associated with a higher risk of AEs for those patients who would not have been included in the corresponding phase III clinical trial.

Newly approved therapies usually have unknown adverse events, although the clinical trials that led to approval had already tested them for safety and efficacy. One reason for this is that the inclusion and exclusion criteria of the trials often do not fully reflect the usually heterogeneous patient population in routine clinical care.The aim of the study was to analyse the extent to which patients with multiple sclerosis (MS) in routine clinical care fulfil the inclusion and exclusion criteria for the corresponding clinical phase III trial of the respective drug.Sociodemographic and clinical characteristics as well as (serious) adverse events ((S) AEs) were compared. Data were based on two national, prospective, observational, clinical, multicentre registries, the REGIMS registry and the DMSG MS registry.Patients (28%) in the REGIMS registry and 5% of the patients in the MS registry fulfilled the 4 predefined inclusion criteria and would therefore have been included in a phase III registration trial of the corresponding substance.Our results show a clear selection of patients by specific inclusion criteria in clinical trials of MS therapeutics compared to the patient population receiving this therapy after approval. However, this selection is not associated with a higher risk of AEs for those patients who would not have been included in the corresponding phase III clinical trial.

High efficacy therapies (HET) play a crucial role in multiple sclerosis (MS) management. HET discontinuation/de-escalation is a critical decision, especially in different age groups, due to potential changes in relapse rates. We aimed at evaluating the impact of HET discontinuation on annualized relapse rates (ARRs) in people with MS (pwMS) aged ≥ 50 or < 50 years. We retrospectively analyzed data of 1,091 pwMS (German MS Register). ARR before and 12 months after the HET washout period were compared between older and younger patients for switching from HET to HET (H–H), HET to mild/moderate efficacy therapies (H-M) or HET to discontinuation (H–D). Reasons for therapy switches were assessed for all subgroups. Most treatment switches continued with another HET (H–H n = 786), while de-escalation (H-M n = 86) or discontinuation (H–D n = 219) occurred less frequently. The minority within each switching group were ≥ 50 years of age (H–H 29

INTRODUCTION:Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system affecting 2.9 million people worldwide. MS symptom variety can have a significant impact on the economic and occupational participation of people with MS (pwMS). The objective of this study was to investigate the trends in the employment (EMP) status change of pwMS over a 2-year period and to identify the associated sociodemographic, clinical and symptom-specific factors. METHODS:The present longitudinal observational study analysed real-world registry data from pwMS characterised by ≥1 documented data set during 2014-2023, an age of 18-60 years, ≥2 data sets during a 2-year period (±2 months) and a documented EMP status change. The transition from EMP to non-employment (NEMP) or vice versa within a 2-year period was investigated during two visits: baseline (pre-transition) and follow-up (post-transition). Univariable and multivariable logistic regression models were utilised to identify associated variables. RESULTS:The study population (N = 940) was classified into NEMP-to-EMP patients (n = 269) and EMP-to-NEMP patients (n = 671). EMP-to-NEMP patients were found to be older in median (45.6 vs. 39.3 years) and more likely to have chronic progressive MS at baseline (14.2% vs. 4.8%) than NEMP-to-EMP patients. Moderate/severe disability level emerged as the most robust predictor of EMP-to-NEMP switches (odds ratio [OR] = 1.89, p = 0.005). Pain (baseline: OR = 1.96, p = 0.017; follow-up: OR = 5.57, p = 0.025) and cognitive impairment (baseline: OR = 1.78, p = 0.048; follow-up: OR = 10.47, p = 0.005) were significant symptomatic predictors of EMP-to-NEMP transitions. CONCLUSION:The results emphasise the particular importance of pain and cognitive impairment as independent symptomatic predictors, whose impact on work ability may be underestimated.

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.