Real-world evidence from Germany and the United States: Treatment initiation on low-efficacy versus high-efficacy therapies in patients with multiple sclerosis.

BACKGROUND: The hit-hard-and-early (HHAE) strategy where treatment is initiated with high-efficacy therapies opposed to low-efficacy therapies presents a potential paradigm shift in multiple sclerosis (MS) management. This study aimed to assess the adoption of the HHAE strategy in Germany and the United States (US) from 2020 to 2022 based on real-world data. METHODS: The analysis was based on longitudinal, patient-level data from Germany and the US. For Germany, data was extracted from the Permea platform covering approximately 44 % of all German community pharmacy dispensing. For the US, data from the Komodo Healthcare Map™ was utilized, covering medical benefit data from around 88 % of the US patient population. Patients ≥18 years old and who had at least 2 prescriptions for MS-related disease-modifying drugs (DMDs) between January 2020 and December 2022 were included. To approximate therapy beginners, a washout period of one year before treatment start was applied, excluding all patients who had an MS-related DMD prescription or claim in 2019. Cohort entry date was the day of the first MS-related DMD dispense or claim. DMDs were classified as high-efficacy and low-efficacy based on the Multiple Sclerosis Therapy Consensus Group (MSTCG). Group differences were assessed with two-sided χ2-square and t-tests. RESULTS: 29,604 MS therapy beginners were identified in the German and 49,791 MS therapy beginners were identified in the US dataset. 29.6 % of MS therapy beginners in Germany and 61.6 % in the US followed the HHAE strategy. Between 2020 and 2022, a significant 14 % increase in the HHAE strategy was observed in both countries (p < 0.0001). High-efficacy therapy beginners switched from their initially prescribed therapy less frequently than low-efficacy therapy beginners: 6.9 % of high-efficacy vs. 19.5 % of low-efficacy therapy beginners in Germany (p < 0.0001) and 5.5 % of high-efficacy vs. 25.0 % low-efficacy therapy beginners in the US (p < 0.0001) switched from their first prescribed DMD. CONCLUSION: Between 2020 and 2022, the adoption of the HHAE strategy increased in both countries, with the US exhibiting nearly double the adoption rates. High-efficacy therapy beginners were less likely to switch from their initially prescribed medication than low-efficacy therapy beginners. Real world evidence can provide valuable insights into rapidly changing treatment patterns in patients with MS.

Using machine learning algorithms to detect fear of falling in people with multiple sclerosis in standardized gait analysis.

INTRODUCTION: Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system. The progressive impairment of gait is one of the most important pathognomic symptoms which are associated with falls and fear of falling (FOF) in people with MS (pwMS). 60 % of pwMS show a FOF, which leads to restrictions in mobility as well as physical activity and reduces the quality of life in general. Therefore, early detection of FOF is crucial because it enables early implementation of rehabilitation strategies as well as clinical decision-making to reduce progression. Qualitative and quantitative evaluation of gait pattern is an essential aspect of disease assessment and can provide valuable insights for personalized treatment decisions in pwMS. Our objective was to identify the most appropriate clinical gait analysis methods to identify FOF in pwMS and to detect the optimal machine learning (ML) algorithms to predict FOF using the complex multidimensional data from gait analysis. METHODS: Data of 1240 pwMS was recorded at the MS Centre of the University Hospital Dresden between November 2020 and September 2021. Patients performed a multidimensional gait analysis with pressure and motion sensors, as well as patient-reported outcomes (PROs), according to a standardized protocol. A feature selection ensemble (FS-Ensemble) was developed to improve the classification performance. The FS-Ensemble consisted of four filtering methods: Chi-square test, information gain, minimum redundancy maximum relevance and ReliefF. Gaussian Naive Bayes, Decision Tree, k-Nearest Neighbor, and Support Vector Machines (SVM) were used to identify FOF. RESULTS: The descriptive analysis showed that 37 % of the 1240 pwMS had a FOF (n = 458; age: 51 ± 16 years, 76 % women, median EDSS: 4.0). The FS-Ensemble improved classification performance in most cases. The SVM showed the best performance of the four classification models in detecting FOF. The PROs showed the best F1 scores (Early Mobility Impairment Questionnaire F1 = 0.81 ± 0.00 and 12-item Multiple Sclerosis Scale F1 = 0.80 ± 0.00). CONCLUSION: FOF is an important psychological risk factor associated with an increased risk of falls. To integrate a functional early warning system for fall detection into MS management and progression monitoring, it is necessary to detect the relevant gait parameters as well as assessment methods. In this context, ML strategies allow the integration of gait parameters from clinical routine to support the initiation of early rehabilitation measures and adaptation of course-modifying therapeutics. The results of this study confirm that patients' self-assessments play an important role in disease management.

Corticosteroid-depending effects on peripheral immune cell subsets vary according to disease modifying strategies in multiple sclerosis.

Background: The primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms through which corticosteroid treatment impacts acute neuroinflammation in people with MS (pwMS) remain not fully understood. In particular, the changes induced by glucocorticoids (GCs) on cells of the innate immune system and the differences between patients with distinct immunotherapies have received little attention to date. Methods: We conducted immunophenotyping using flow cytometry on peripheral blood mononuclear cells of pwMS who received IVMP treatment during a relapse. We compared the impact of an IVMP treatment on a broad variety of immune cell subsets within three groups: twelve patients who were treatment-naïve to disease modifying therapies (wDMT) to ten patients on platform therapies (PT) and eighteen patients on fingolimod therapy (FTY). Results: We observed pronounced interindividual short- and intermediate-term effects of IVMP on distinct immune cells subsets. In addition to the well-documented decrease in T-helper cells (Th cells), we detected significant alterations after the first IVMP infusion within the innate immune response among neutrophil, eosinophil and basophil granulocytes, monocytes and plasmacytoid dendritic cells (pDCs). When comparing patients wDMT to the PT and FTY cohorts, we found that IVMP had a similar impact on innate immune cells across all treatment groups. However, we did not observe a significant further decline in T lymphocyte counts during IVMP in patients with pre-existing lymphopenia under FTY treatment. Although T cell apoptosis is considered the main mechanism of action of GCs, patients with FTY still reported symptom improvement following IVMP treatment. Conclusion: In addition to T cell suppression, our data suggests that further immunoregulatory mechanisms of GC, particularly on cells of the innate immune response, are of greater significance than previously understood. Due to the regulation of the adaptive immune cells by DMTs, the impact of GC on these cells varies depending on the underlying DMT. Additional studies involving larger cohorts and cerebrospinal fluid samples are necessary to gain a deeper understanding of the immune response to GC in pwMS with different DMTs during relapse to define and explain differences in clinical response profiles.

SARS-CoV-2-Specific Immune Cytokine Profiles to mRNA, Viral Vector and Protein-Based Vaccines in Patients with Multiple Sclerosis: Beyond Interferon Gamma.

Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population.

Lymphopenia is Not the Primary Therapeutic Mechanism of Diroximel Fumarate in Relapsing-Remitting Multiple Sclerosis: Subgroup Analyses of the EVOLVE-MS-1 Study.

INTRODUCTION: In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. METHODS: EVOLVE-MS-1-an open-label, 96-week, phase 3 study-assessed DRF safety and exploratory efficacy in patients with relapsing-remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline). RESULTS: Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week 96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11-0.17) without lymphopenia and 0.12 (0.09-0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week 96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1-Q4), ARR at week 96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week 96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week 96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients. CONCLUSION: In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02634307.

The Association of Age, Sex, and BMI on Lower Limb Neuromuscular and Muscle Mechanical Function in People with Multiple Sclerosis.

(1) Background: The countermovement jump (CMJ) on a force plate could be a sensitive assessment for detecting early lower-limb muscle mechanical deficits in the early stages of multiple sclerosis (MS). CMJ performance is known to be influenced by various anthropometric, physiological, and biomechanical factors, mostly investigated in children and adult athletes. Our aim was to investigate the association of age, sex, and BMI with muscle mechanical function using CMJ to provide a comprehensive overview of lower-limb motor function in people with multiple sclerosis (pwMS). (2) Methods: A cross-sectional study was conducted with pwMS (N = 164) and healthy controls (N = 98). All participants performed three maximal CMJs on a force plate. Age, sex, and BMI were collected from all participants. (3) Results: Significant age, sex, and BMI effects were found for all performance parameters, flight time, and negative and positive power for pwMS and HC, but no significant interaction effects with the group (pwMS, HC) were detected. The highest significant effects were found for sex on flight time (η2 = 0.23), jump height (η2 = 0.23), and positive power (η2 = 0.13). PwMS showed significantly lower CMJ performance compared to HC in middle-aged (31-49 years), with normal weight to overweight and in both women and men. (4) Conclusions: This study showed that age, sex, and BMI are associated with muscle mechanical function in pwMS and HC. These results may be useful in developing reference values for CMJ. This is a crucial step in integrating CMJ into the diagnostic assessment of people with early MS and developing individualized and effective neurorehabilitative therapy.

Escalating to medium- versus high-efficacy disease modifying therapy after low-efficacy treatment in relapsing remitting multiple sclerosis.

BACKGROUND: In patients with relapsing remitting multiple sclerosis (RRMS) on low-efficacy disease modifying therapies (DMT), the optimal strategy on how to escalate treatment once needed, remains unknown. METHODS: We studied RRMS patients on low-efficacy DMTs listed in the Swiss National Treatment Registry, who underwent escalation to either medium- or high-efficacy DMTs. Propensity score-based matching was applied using 12 clinically relevant variables. Both groups were also separately matched with control subjects who did not escalate therapy. Time to relapse and to disability worsening were evaluated using Cox proportional hazard models. RESULTS: Of 1037 eligible patients, we 1:1 matched 450 MS patients who switched from low-efficacy to medium-efficacy (n = 225; 76.0% females, aged 42.4 ± 9.9 years [mean ± SD], median EDSS 3.0 [IQR 2-4]) or high-efficacy DMTs (n = 225; 72.4% females, aged 42.2 ± 10.6 years, median EDSS 3.0 [IQR 2-4]). Escalation to high-efficacy DMTs was associated with lower hazards of relapses than medium-efficacy DMTs (HR = 0.67, 95% CI 0.47-0.95, p = .027) or control subjects (HR = 0.61, 95% CI 0.44-0.84, p = .003). By contrast, escalation from low to medium-efficacy DMTs did not alter the hazard for relapses when compared to controls (i.e. patients on low-efficacy DMT who did not escalate DMT during follow-up) CONCLUSION: Our nationwide registry analysis suggests that, once escalation from a low-efficacy DMT is indicated, switching directly to a high-efficacy treatment is superior to a stepwise escalation starting with a moderate-efficacy treatment.

Neurofilaments as biomarkers in neurological disorders - towards clinical application.

Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.

Data on Ocrelizumab Treatment Collected by MS Patients in Germany Using Brisa App.

BACKGROUND: With a rising number of multiple sclerosis (MS) cases and increasing pressure on health systems, digital companion apps like Brisa, designed specifically for people with MS, can play an important role in the patient journey. These apps enable the collection of real-time longitudinal data that are critical to our understanding of the pathophysiology and progression of MS. METHODS: This retrospective, descriptive analysis consists of data from Brisa users who registered between 6 August 2021 and 8 September 2022. Of the unique users, 37.7% (n = 1593) fulfilled the inclusion criteria including information about medication and demographics and tracked one or more symptoms and/or patient-reported outcomes. Users were classified as moderate-efficacy treatment users, high-efficacy treatment users and ocrelizumab users, and the reporting frequency and scores of symptoms and patient-reported outcomes were analyzed. RESULTS: The largest cohort of Brisa users (405) reported treatment with ocrelizumab and were mostly diagnosed 2-5 years before the survey. The most reported MS symptoms were similar between OUs (ocrelizumab users), HETUs (high-efficacy treatment users) and METUs (moderate-efficacy treatment users). OUs on average reported symptoms and answered questionnaires more frequently. Baseline scores between HETUs and OUs were similar, whereas baseline scores of METUs were slightly lower in comparison. In a further analysis of OUs, disability scores increased with age; users aged 26-45 years had higher pain scores than 18-25-year-olds. No significant differences were found in quality of life, bowel control and vision between age groups. CONCLUSION: These findings show that the characteristics of the Brisa cohort are similar to the results of other studies and registries and can provide a representative overview of everyday disease management. Thereby, these results can bridge the gap between clinical research and real patient experience, but they also raise new questions, such as how often the hard-and-early therapy approach is already used and whether baseline characteristics and reasons for choosing a particular treatment contribute to the different outcomes over time. Answering these questions requires further research and analysis.

Comparison of time to clinically meaningful improvement in quality of life in neurological disorders in patients treated with natalizumab versus ocrelizumab.

Aim: To assess time to improvement in Quality of Life in Neurological Disorders (Neuro-QoL) domains for patients treated with natalizumab versus ocrelizumab. Methods: Patients enrolled in the MS PATHS network who initiated treatment with either natalizumab or ocrelizumab rated the Neuro-QoL domains of physical function, symptoms, emotional health, cognitive function and social ability. Results: Time to clinically meaningful improvement was significantly shorter with natalizumab versus ocrelizumab for cognitive function (event time ratio [95% CI]: 0.37 [0.24-0.57]; p < 0.001), sleep disturbance (0.45 [0.28-0.72]; p = 0.001), social role participation (0.37 [0.21-0.66]; p = 0.001) and social role satisfaction (0.5 [0.31-0.8]; p = 0.004). Conclusion: Natalizumab had shorter time to clinically meaningful improvement in cognitive, sleep, and social role Neuro-QoL domains versus ocrelizumab.

Knowledge of treatment-related benefits associated with medication choices, including improvement of quality of life (QoL), are strong influential factors for patients to start and continue their therapies. Little is known about patient-reported time to onset of functional improvement upon the initiation of medications for multiple sclerosis (MS). The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network, a repository of collaborative international data on routine MS management, includes patient-reported information on the health-related QoL using the Quality of Life in Neurological Disorders (Neuro-QoL) measure. This study included data from 883 eligible patients enrolled in MS PATHS, with the aim of assessing and comparing the time to improvement in physical, mental and social health for patients treated with natalizumab versus ocrelizumab using Neuro-QoL. Natalizumab and ocrelizumab are both high-efficacy treatment options for relapsing forms of MS. The results demonstrated that, compared with ocrelizumab, natalizumab treatment led to faster effect on mental and social health, as well as quicker improvements in physical functioning in the arms and hands. Overall, it took shorter time for natalizumab-treated patients to achieve better QoL compared with ocrelizumab. These findings highlight the importance of QoL in disease management and provide a patient perspective for healthcare providers when making decisions about high-efficacy treatments for their patients with MS.

Consensus quality indicators for monitoring multiple sclerosis.

Multiple sclerosis (MS) as a chronic, degenerative autoimmune disease of the central nervous system has a longitudinal and heterogeneous course with increasing treatment options and risk profiles requiring constant monitoring of a growing number of parameters. Despite treatment guidelines, there is a lack of strategic and individualised monitoring pathways, including respective quality indicators (QIs). To address this, we systematically developed transparent, traceable, and measurable QIs for MS monitoring. Through literature review, expert discussions, and consensus-building, existing QIs were identified and refined. In a two-stage online Delphi process involving MS specialists (on average 53 years old and with 25 years of professional experience), the QIs were evaluated for content, clarity, and intelligibility, resulting in a set of 24 QIs and checklists to assess the quality of care. The final QIs provide a structured approach to document, monitor, and enhance the quality of care for people with MS across their treatment journey.

Sensitive Identification of Asymmetries and Neuromuscular Deficits in Lower Limb Function in Early Multiple Sclerosis.

BACKGROUND: In the early stages of multiple sclerosis (MS), there are no objective sensitive functional assessments to identify and quantify early subclinical neuromuscular deficits and lower limb strength asymmetries during complex movements. Single-countermovement jumps (SLCMJ), a maximum single leg vertical jump, on a force plate allow functional evaluation of unilateral lower limb performance in performance diagnostics and could therefore provide early results on asymmetries in MS. OBJECTIVE: Objective evaluation of early lower limb neuromuscular deficits and asymmetries in people with multiple sclerosis (pwMS) using SLCMJ on a force plate. METHODS: A study was conducted with pwMS (N = 126) and healthy controls (N = 97). All participants performed 3 maximal SLCMJs on a force plate. Temporal, kinetic, and power jump parameters were collected. The Expanded Disability Status Scale (EDSS) was performed on all participants. A repeated measures analysis of covariance (ANCOVA) with age, Body-Mass-Index, and gender as covariates was used. RESULTS: PwMS with normal muscle strength according to the manual muscle tests showed significantly reduced SLCMJ performance compared to HC. In both groups, jumping performance differed significantly between the dominant and non-dominant leg, with higher effect size for pwMS. A significant interaction effect between leg dominance and group was found for propulsive time, where the pwMS showed an even higher difference between the dominant and non-dominant leg compared to HC. Furthermore, there was a significant small correlation between leg asymmetries and EDSS in pwMS. CONCLUSION: The study shows that the SLCMJ on a force plate is suitable for the early detection of subclinical lower limb neuromuscular deficits and strength asymmetries in MS.

Optical coherence tomography as a potential surrogate marker of dopaminergic modulation across the life span.

The retina has been considered a "window to the brain" and shares similar innervation by the dopaminergic system with the cortex in terms of an unequal distribution of D1 and D2 receptors. Here, we provide a comprehensive overview that Optical Coherence Tomography (OCT), a non-invasive imaging technique, which provides an "in vivo" representation of the retina, shows promise to be used as a surrogate marker of dopaminergic neuromodulation in cognition. Overall, most evidence supports reduced retinal thickness in individuals with dopaminergic dysregulation (e.g., patients with Parkinson's Disease, non-demented older adults) and with poor cognitive functioning. By using the theoretical framework of metacontrol, we derive hypotheses that retinal thinning associated to decreased dopamine (DA) levels affecting D1 families, might lead to a decrease in the signal-to-noise ratio (SNR) affecting cognitive persistence (depending on D1-modulated DA activity) but not cognitive flexibility (depending on D2-modulated DA activity). We argue that the use of OCT parameters might not only be an insightful for cognitive neuroscience research, but also a potentially effective tool for individualized medicine with a focus on cognition. As our society progressively ages in the forthcoming years and decades, the preservation of cognitive abilities and promoting healthy aging will hold of crucial significance. OCT has the potential to function as a swift, non-invasive, and economical method for promptly recognizing individuals with a heightened vulnerability to cognitive deterioration throughout all stages of life.

Building digital patient pathways for the management and treatment of multiple sclerosis.

Recent advances in the field of artificial intelligence (AI) could yield new insights into the potential causes of multiple sclerosis (MS) and factors influencing its course as the use of AI opens new possibilities regarding the interpretation and use of big data from not only a cross-sectional, but also a longitudinal perspective. For each patient with MS, there is a vast amount of multimodal data being accumulated over time. But for the application of AI and related technologies, these data need to be available in a machine-readable format and need to be collected in a standardized and structured manner. Through the use of mobile electronic devices and the internet it has also become possible to provide healthcare services from remote and collect information on a patient's state of health outside of regular check-ups on site. Against this background, we argue that the concept of pathways in healthcare now could be applied to structure the collection of information across multiple devices and stakeholders in the virtual sphere, enabling us to exploit the full potential of AI technology by e.g., building digital twins. By going digital and using pathways, we can virtually link patients and their caregivers. Stakeholders then could rely on digital pathways for evidence-based guidance in the sequence of procedures and selection of therapy options based on advanced analytics supported by AI as well as for communication and education purposes. As far as we aware of, however, pathway modelling with respect to MS management and treatment has not been thoroughly investigated yet and still needs to be discussed. In this paper, we thus present our ideas for a modular-integrative framework for the development of digital patient pathways for MS treatment.

Insights from Real-World Practice: The Dynamics of SARS-CoV-2 Infections and Vaccinations in a Large German Multiple Sclerosis Cohort.

The SARS-CoV-2 pandemic profoundly impacted people with multiple sclerosis (pwMS). Disease-related aspects and demographic factors may influence vaccination rates, infection susceptibility, and severity. Despite prior research, comprehensive real-world data obtained throughout the pandemic remain limited. We investigated SARS-CoV-2 vaccination and infection patterns in a large monocentric real-world cohort. We collected prospective data from medical visits at the MS Center Dresden, Germany, from the pandemic's beginning until 31 May 2022. Logistic regression and rank correlation analyses were used to explore associations between SARS-CoV-2 outcomes and patient characteristics. Of 2115 pwMS assessed (mean age 46.5, SD ± 12.9; median expanded disability status scale 2.5), 77.9% were under disease-modifying treatment (DMT), primarily B-cell depletion (25.4%). A total of 35.5% reported SARS-CoV-2 infections, and 77.4% were fully vaccinated. PwMS with increased disability, older age, and comorbidities were associated with higher vaccination rates, possibly due to the awareness of these populations regarding complications of SARS-CoV-2 infections. Infections were more common in younger females, people with a lower degree of disability, those with relapsing MS, and those who were not vaccinated. PwMS on B-cell depletion reported more infections than untreated pwMS and those receiving other types of disease-modifying therapy, despite higher vaccination rates. Most infections were mild, with no severity differences according to demographic or disease-related factors, except for gender. Notably, all fatal cases occurred in unvaccinated pwMS. Our studies suggest that demographic and disease-related factors, especially age and the use of B-cell depletion, significantly influenced SARS-CoV-2 vaccination and infection rates in our cohort. These factors may be considered in future preventive campaigns in further pandemics.

Toward mechanistic medical digital twins: some use cases in immunology.

A fundamental challenge for personalized medicine is to capture enough of the complexity of an individual patient to determine an optimal way to keep them healthy or restore their health. This will require personalized computational models of sufficient resolution and with enough mechanistic information to provide actionable information to the clinician. Such personalized models are increasingly referred to as medical digital twins. Digital twin technology for health applications is still in its infancy, and extensive research and development is required. This article focuses on several projects in different stages of development that can lead to specific-and practical-medical digital twins or digital twin modeling platforms. It emerged from a two-day forum on problems related to medical digital twins, particularly those involving an immune system component. Open access video recordings of the forum discussions are available.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Shifting from the treat-to-target to the early highly effective treatment approach in patients with multiple sclerosis - real-world evidence from Germany.

Background: While evidence highlights the effectiveness of initiating disease-modifying therapy with a high-efficacy medication for multiple sclerosis (MS) patients with poor prognostic factors, it remains unclear whether this approach has been adopted by a broad range of MS providers in Germany yet. Objective: To assess the adoption of the early highly effective treatment (EHT) compared to the treat-to-target treatment approach with the option of escalating treatment efficacy over time in Germany based on real-world evidence data. Design: Patient-level pharmacy dispensing data from the Permea platform were analysed from 2020 to 2022. Methods: In total, 29,529 therapy beginners (>18 years) were included to analyse shifts in treatment approaches over time and switching behaviour. Medication classification adhered to the German Society of Neurology guidelines and designated fumarates, glatiramer acetate, teriflunomide and interferons as low-efficacy category 1 medications; cladribine and S1P-modulators as medium-efficacy category 2 medications; and alemtuzumab, natalizumab, ocrelizumab, ofatumumab and rituximab (off-label) as high-efficacy category 3 medications. Results: Our results show that 70.0% of patients redeemed their first prescription for category 1 medication, 16.3% for category 2 and 13.7% for category 3 medications. The proportion of prescriptions filled shifted from 2020 to 2022 with a decrease of 14.7% for category 1 drugs and an increase of 12.5% for category 3 drugs. 93.2% of patients stayed on their initially prescribed medication category. 3.2% of category 1 and 3.7% of category 2 therapy beginners escalated to category 3 medication. 3.4% of category 3 medication users de-escalated their treatment to category 1 or category 2. Conclusion: While most individuals started their treatment according to the treat-to-target approach and remained on their initially prescribed medication category, there has been a steadily increasing shift towards the EHT approach since 2020. These insights demonstrate that, while not officially recommended by German guidelines, MS providers increasingly adopt the EHT approach.

Preferences, Adherence, and Satisfaction: Three Years of Treatment Experiences of People with Multiple Sclerosis.

Background: To reduce the risk of long-term disability in people with Multiple Sclerosis (pwMS), an increasing number of disease-modifying immune therapies (DMT) are available, involving diverse mechanisms of action, levels of efficacy, treatment risks, and tolerability aspects. Including patient preferences and expectations in shared decision-making may improve treatment satisfaction, adherence, and persistence. Purpose: To investigate long-term alignment of individual preferences and expectations of pwMS with their actual DMT and its effect on treatment satisfaction, health-related quality of life (HRQoL), adherence, and treatment discontinuation. Methods: A total of 401 pwMS beginning a new DMT were enrolled from 2015 to 2018 in a non-interventional study at three German MS centres. Patient preferences regarding DMT, TSQM-9, SF36, and self-reported adherence as well as relapses and EDSS were recorded at baseline and every 3 to 6 months for up to 3 years. Results: Efficacy and tolerability were the highest-ranking preferences at baseline. Actual selection of DMT corresponded more closely to safety than efficacy, tolerability, or convenience preferences. Participants reported excellent adherence throughout the study. DMT persistence was 69.0%, with earlier discontinuation for injectable vs oral or infusion therapies. Breakthrough disease, rather than patient-reported outcomes, was the main driver of DMT discontinuation. For all routes of administration, global treatment satisfaction increased over time despite lower satisfaction with convenience. Several patterns of changing preferences were observed. Conclusion: This study provides insight into the interaction of DMT preferences of pwMS with their actual treatment experience. Treatment decisions should be aligned with long-term expectations of pwMS to promote continuous adherence.