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BackgroundA high proportion of patients with relapsing remitting multiple sclerosis convert to secondary progressive multiple sclerosis (SPMS) characterized by irreversibly progressing disability and cognitive decline. Siponimod (Mayzent), a selective sphingosine-1-phosphate receptor modulator, was recently approved by the European Medicines Agency for the treatment of adult SPMS patients with active disease, as evidenced by relapses or magnetic resonance imaging features of ongoing inflammatory activity. Approval by the Food and Drug Administration covers a broader range of indications, comprising clinically isolated syndrome, relapsing remitting multiple sclerosis, and active SPMS. However, treatment effects of siponimod have not been assessed in a structured setting in clinical routine so far. ObjectiveThe objectives of AMASIA (impAct of Mayzent [siponimod] on secondAry progressive multiple Sclerosis patients in a long-term non-Interventional study in GermAny), a prospective noninterventional study, are to assess the long-term effectiveness and safety of siponimod in clinical routine and to evaluate the impact of disease burden on quality of life and socioeconomic conditions. Here, we report the study design of AMASIA. MethodsTreatment effects of siponimod will be evaluated in 1500 SPMS patients during a 3-year observational phase. According to the genetic polymorphism of CYP2C9, the initial dose will be titrated to the maintenance dose of 1 mg (CYP2C9*1*3 and *2*3) or 2 mg (all other polymorphisms of CYP2C9 except *3*3, which is contraindicated) taken orally once daily. Primary endpoint is the 6-month confirmed disability progression, as assessed by a functional composite endpoint comprising the Expanded Disability Status Scale and symbol digit modalities test to take appropriate account of cognitive changes and increase sensitivity. Further measures including multiple sclerosis activity data; assessments of functional domains; questionnaires addressing the patients’, physicians’, and relatives’ perspectives of disability progression; cognitive worsening; quality of life; and socioeconomic aspects will be documented using the multiple sclerosis documentation system MSDS3D. ResultsAMASIA is being conducted between February 2020 and February 2025 in up to 250 neurological centers in Germany. ConclusionsAMASIA will complement the pivotal phase III–derived efficacy and safety profile of siponimod with real-world data and will further evaluate several individual treatment aspects such as quality of life and socioeconomic conditions of patients and caregivers. It might help to establish siponimod as a promising option for the treatment of SPMS patients in clinical routine. International Registered Report Identifier (IRRID)DERR1-10.2196/19598

BackgroundThere is an unmet need for a tool that helps to evaluate patients who are at risk of progressing from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS). A new tool supporting the evaluation of early signs suggestive of progression in multiple sclerosis (MS) has been developed. In the initial stage, concepts relevant to progression were identified using a mixed method approach involving regression on data from a real-world observational study and qualitative research with patients and physicians. The tool was drafted in a questionnaire format to assess these variables. ObjectiveThis study aimed to develop the scoring algorithm for the tool, using both quantitative and qualitative research methods. MethodsThe draft scoring algorithm was developed using two approaches: quantitative analysis of real-world data and qualitative analysis based on physician interviews and ranking and weighting exercises. Variables that were included in the draft tool and regarded as most clinically relevant were selected for inclusion in a multiple logistic regression. The analyses were run using physician-reported data and patient-reported data. Subsequently, a ranking and weighting exercise was conducted with 8 experienced neurologists as part of semistructured interviews. Physicians were presented with the variables included in the draft tool and were asked to rank them in order of strength of contribution to progression and assign a weight by providing a percentage of the overall contribution. Physicians were also asked to explain their ranking and weighting choices. Concordance between physicians was explored. ResultsMultiple logistic regression identified age, MS disease activity, and Expanded Disability Status Scale score as the most significant physician-reported predictors of progression to SPMS. Patient age, mobility, and self-care were identified as the strongest patient-reported predictors of progression to SPMS. In physician interviews, the variables ranked and weighted as most important were stability or worsening of symptoms, intermittent or persistent symptoms, and presence of ambulatory and cognitive symptoms. Across all physicians, the level of concordance was 0.278 (P

BackgroundSurvey-based studies are frequently used to describe the economic impact of multiple sclerosis (MS). However, there is no validated health resource survey available, preventing comparison of study results and meaningful conclusions regarding the efficiency of long-term treatments. ObjectiveThe aim of this study was to develop and validate a tablet- and paper-based MS health resource utilization survey. MethodsWe developed and validated the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS), consisting of 24 cost items for paper and tablet users. Data for validation came from two large German observational studies. Survey practicability was assessed according to the response rate. Reliability was described using test-retest reliability as well as Guttman lambda. Construct validity was assessed as convergent and discriminant validity via correlations with associated patient-reported outcomes and known-group analyses. ResultsIn total, 2207 out of 2388 (response rate: 92.4%) patients completed the survey and were included to determine psychometric properties. The test-retest reliability had an intraclass correlation coefficient of 0.828 over a course of 3 months. Convergent validity analyses showed that total costs correlated positively with increased disability (r=0.411, P

BackgroundDefining the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) can be challenging and delayed. A digital tool (MSProDiscuss) was developed to facilitate physician-patient discussion in evaluating early, subtle signs of multiple sclerosis (MS) disease progression representing this transition. ObjectiveThis study aimed to determine cut-off values and corresponding sensitivity and specificity for predefined scoring algorithms, with or without including Expanded Disability Status Scale (EDSS) scores, to differentiate between RRMS and SPMS patients and to evaluate psychometric properties. MethodsExperienced neurologists completed the tool for patients with confirmed RRMS or SPMS and those suspected to be transitioning to SPMS. In addition to age and EDSS score, each patient’s current disease status (disease activity, symptoms, and its impacts on daily life) was collected while completing the draft tool. Receiver operating characteristic (ROC) curves determined optimal cut-off values (sensitivity and specificity) for the classification of RRMS and SPMS. ResultsTwenty neurologists completed the draft tool for 198 patients. Mean scores for patients with RRMS (n=89), transitioning to SPMS (n=47), and SPMS (n=62) were 38.1 (SD 12.5), 55.2 (SD 11.1), and 69.6 (SD 12.0), respectively (P

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

BackgroundThe number of multiple sclerosis (MS) information websites, online communities, and Web-based health education programs has been increasing. However, MS patients’ willingness to use new ways of communication, such as websites, mobile phone application, short message service, or email with their physician, remains unknown. ObjectivesWe designed a questionnaire to evaluate the a priori use of electronic communication methods by MS patients and to assess their acceptance of such tools for communication with their health care providers. MethodsWe received complete data from 586 MS patients aged between 17 and 73 years. Respondents were surveyed in outpatient clinics across Germany using a novel paper-and-pencil questionnaire. In addition to demographics, the survey items queried frequency of use of, familiarity with, and comfort with using computers, websites, email, and mobile phones. ResultsAbout 90% of all MS patients used a personal computer (534/586) and the Internet (527/586) at least once a week, 87.0% (510/586) communicated by email, and 85.6% (488/570) communicated by mobile phone. When asked about their comfort with using electronic communication methods for communication with health care providers, 20.5% (120/586) accepted communication by mobile Internet application or short message service via mobile phone, 41.0% (240/586) by websites, 54.3% (318/586) by email service, and 67.8% (397/586) by at least one type of electronic communication. The level of a priori use was the best predictor for the acceptance of electronic communication with health care providers. Patients who reported already searching online for health information (odds ratio 2.4, P < .001) and who had already communicated with a physician through a website (odds ratio 3.3, P = .03) reported higher acceptance for Web-based communication. Patients who already scheduled appointments with their mobile phones (odds ratio 2.1, P = .002) were more likely to accept the use of mobile phone applications or short message service for communicating with their physician. ConclusionsThe majority of MS patients seen at specialist centers already use modern communication technology regularly. New forms of electronic communication appear to have high levels of acceptance for exchanging information about MS between patients and health care providers. Such methods should be integrated into eHealth services such as electronic health records and patient relationship management systems.

ObjectiveThis study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).BackgroundPrevious post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.Design/methodsIn this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup.ResultsHigh versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p

Background: Best supportive care (BSC) measures are an essential component for the management of primary progressive multiple sclerosis (PPMS). Objectives: RETRO PPMS (ML39631) is the first study to systematically analyze the therapeutic journey and standard of BSC of patients with PPMS in Germany. Design: This multicenter, non-interventional study retrospectively analyzed patient charts. Methods: Data were recorded up until the first infusion of ocrelizumab (July 2018 to October 2021). Medical history, disease status, disease activity and treatments were assessed from 12 months before PPMS diagnosis until study start. Acute interventions, BSC parameters and rehabilitation measures from the past 27 months were assessed. Results: The core analysis population (N = 462) had a mean age (range) of 57.4 (27–85) years and mean disease duration of 13.7 (0.3–55.2) years. The most frequently reported symptoms were muscle spasticity, bladder disorder, ataxia, gait disturbance and fatigue. The most commonly used treatment was physical/occupational therapy (66.5% of patients); 47.2% received off-label treatment with corticosteroids/disease-modifying therapies. BSC measures for many symptoms were strikingly rare – especially for fatigue and cognitive impairment. Conclusion: This analysis uncovers severe BSC deficits for many debilitating PPMS symptoms. There is still a large unmet need for innovative multidisciplinary care concepts and improvements in neurological primary and secondary care. [ABSTRACT FROM AUTHOR]

Purpose: Understanding the long-term safety of disease-modifying therapies for multiple sclerosis (MS) in routine clinical practice can be undertaken through registry-based studies. However, variability of data quality across such sources poses the challenge of data fit for regulatory decision-making. CLARION, a non-interventional cohort safety study of cladribine tablets, combines aggregated data from MS registries/data sources, except in Germany (which utilizes primary data collection). We describe the application of key data quality indicators (DQIs) within CLARION to evaluate data quality over time, as recommended by the European Medicines Agency (EMA) guideline on registry-based studies. Methods: DQIs were defined with participating registries/sources; they were used to assess data quality according to the EMA Data Quality Framework, addressing consistency, accuracy, completeness, and study representativeness. DQIs were associated with potential remedial measures if data quality was not met. DQIs were summarized overall and for individual MS registries/data sources to November 1, 2022. Results: A total of 28 DQIs were analyzed using data from 5069 patients arising from eight MS registries/data sources and 14 countries. The Representativeness DQIs showed that 72.0% of patients were female, median age at MS diagnosis was 29.0 to 43.3 years, and 93.5% had relapsing-remitting MS. Consistency DQIs showed a total of 2899 patients had achieved at least two years of follow-up; 6.9% did not have any recorded visits during this timeframe. Discrepant values were assessed as part of Accuracy DQIs, and improvements over time were noted for recorded dates of MS onset and diagnosis. Regarding Completeness DQIs, 191/5069 (3.8%) patients were lost to follow-up. Conclusion: The application of 28 DQIs within the CLARION study has helped with understanding, not only intrinsic and question-specific determinants of data quality, but also tracking the quality of post-authorization safety data obtained from MS registries/data sources, thereby providing a foundation for the regulatory decision-making process. [ABSTRACT FROM AUTHOR]

Use of techniques derived from generative artificial intelligence (AI), specifically large language models (LLMs), offer a transformative potential on the management of multiple sclerosis (MS). Recent LLMs have exhibited remarkable skills in producing and understanding human-like texts. The integration of AI in imaging applications and the deployment of foundation models for the classification and prognosis of disease course, including disability progression and even therapy response, have received considerable attention. However, the use of LLMs within the context of MS remains relatively underexplored. LLMs have the potential to support several activities related to MS management. Clinical decision support systems could help selecting proper disease-modifying therapies; AI-based tools could leverage unstructured real-world data for research or virtual tutors may provide adaptive education materials for neurologists and people with MS in the foreseeable future. In this focused review, we explore practical applications of LLMs across the continuum of MS management as an initial scope for future analyses, reflecting on regulatory hurdles and the indispensable role of human supervision. [ABSTRACT FROM AUTHOR]

Background: Siponimod, a second-generation, selective sphingosine 1- phosphate receptor (S1PR) 1 and 5 modulator, represents an important therapeutic choice for active secondary progressive multiple sclerosis (SPMS). Besides the beneficial immunomodulatory effects, siponimod impacts cardiovascular function through S1PR1 modulation. Short-term vagomimetic effects on cardiac activity have proved to be mitigated by dose titration. However, long-term consequences are less known. Objectives: This study aimed to investigate the long-term impact of siponimod on cardiac autonomic modulation in people with SPMS (pwSPMS). Methods: Heart rate variability (HRV) and vascular hemodynamic parameters were evaluated using Multiple Trigonometric Regressive Spectral analysis in 47 pwSPMS before siponimod therapy and after one, three, six and 12 months of treatment. Autonomic activation tests (tilt test for the sympathetic and deep breathing test for the parasympathetic cardiac modulation) were performed at each examination. Results: pwSPMS preserved regular cardiovascular modulation responses during the autonomic tests reflected in the variation of several HRV parameters, such as RMSSD, pNN50, total power of HRV, high-frequency and low-frequency bands of the spectral domain or hemodynamic vascular parameters (Cwk, Zao, TPR, MAP) and baroreflex sensitivity (BRS). In the long-term follow-up, RMSSD, pNN50, total power, BRS and CwK presented a significant decrease, underlining a reduction of the parasympathetic and a shift towards sympathetic predominance in cardiac autonomic modulation that tends to stabilise after 1 year of treatment. Conclusion: Due to dose titration, the short-term effects of siponimod on cardiac autonomic modulation are mitigated. The long-term impact on cardiac autonomic modulation is similar to fingolimod. The autonomic activation tests showed normal cardiovascular responses during 1-year followup in pwSPMS, confirming the safety profile of siponimod. Further research on autonomic function could reveal whether the observed sympathetic activation is a compensatory response to S1P signaling intervention or a feature of the disease, while also shedding light on the role of S1PR modulation in MS. [ABSTRACT FROM AUTHOR]

Summary: Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long‐term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow‐up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non‐effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non‐effective treatment group showed a significant increase of age‐adjusted percentile of serum neurofilament light chain levels at follow‐up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non‐effective treatment group. Longitudinal changes of age‐adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea‐related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences. [ABSTRACT FROM AUTHOR]