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.

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.

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.

[Current and innovative Approaches to Multiple Sclerosis Therapy]. / Neue Therapieansätze bei Multipler Sklerose inkl. Stellenwert älterer Präparate.

The landscape of immunotherapies in the management of Multiple Sclerosis (MS) is currently particularly dynamic. Over 21 immunotherapeutic options are approved by the European Meidcines Agency (EMA), Food and Drug Administration (FDA) and newer approaches are ongoing in clinical trials. With advancements in the understanding of MS pathophysiology and further development of diagnosis criteria, newer and more specific disease-modifying therapies (DMTs) have emerged in recent years. The selection and timing of proper therapeutic approaches is increasingly complex. We provide an overview of the available immunotherapies for a personalized MS treatment and discuss practical insights into their application. The importance of early intervention, distinction between escalation and induction approaches, and consideration of high-efficacy treatments for specific patient groups are in discussed. We emphasize the significance of a patient-centered approach, taking into account various factors such as comorbidities, family planning, administration preferences and potential side effects in treatment decision-making.

Management of multiple sclerosis fatigue in the digital age: from assessment to treatment.

Fatigue is one of the most disabling symptoms of Multiple Sclerosis (MS), affecting more than 80% of patients over the disease course. Nevertheless, it has a multi-faceted and complex nature, making its diagnosis, evaluation, and treatment extremely challenging in clinical practice. In the last years, digital supporting tools have emerged to support the care of people with MS. These include not only smartphone or table-based apps, but also wearable devices or novel techniques such as virtual reality. Furthermore, an additional effective and cost-efficient tool for the therapeutic management of people with fatigue is becoming increasingly available. Virtual reality and e-Health are viable and modern tools to both assess and treat fatigue, with a variety of applications and adaptability to patient needs and disability levels. Most importantly, they can be employed in the patient's home setting and can not only bridge clinic visits but also be complementary to the monitoring and treatment means for those MS patients who live far away from healthcare structures. In this narrative review, we discuss the current knowledge and future perspectives in the digital management of fatigue in MS. These may also serve as sources for research of novel digital biomarkers in the identification of disease activity and progression.

Influence of Pre-Analytic Conditions on Quantity of Lymphocytes.

Lymphocytes are key players in the pathogenesis of multiple sclerosis and a distinct target of several immunomodulatory treatment strategies. In this study, we aim to evaluate the effect of various pre-analytic conditions on immune cell counts to conclude the relevance for clinical implications. Twenty healthy donors were assessed for the effects of distinct storage temperatures and times after blood draws, different durations of tourniquet application, body positions and varying aspiration forces during blood draws. Immune cell frequencies were analyzed using multicolor flowcytometry. While storage for 24 h at 37 °C after blood draws was associated with significantly lower cell counts, different durations of tourniquet application, body positions and varying aspirations speeds did not have significant impacts on the immune cell counts. Our data suggest that immune cell counts are differently affected by pre-analytic conditions being more sensitive to storage temperature. Pre-analytic conditions should be carefully considered when interpreting the laboratory values of immune cell subpopulations.

Influence of exercise on quantity and deformability of immune cells in multiple sclerosis.

Objective: The study aimed to investigate the effect of exercise on immune cell count and cell mechanical properties in people with multiple sclerosis (pwMS) on different disease-modifying treatments (DMT) vs. healthy controls (HCs). Methods: A cohort of 16 HCs and 45 pwMS, including patients with lymphopenia (alemtuzumab and fingolimod) as well as increased lymphocyte counts (natalizumab), was evaluated for exercise-mediated effects on immune cell counts and lymphocyte deformability. As exercise paradigms, climbing stairs at normal speed or as fast as possible and cycling were used, while blood samples were collected before, immediately, and 20 as well as 60 min post-exercise. Immune cell subtypes and lymphocyte deformability were analyzed using multicolor flow cytometry and real-time deformability cytometry. Results: An increase in lymphocytes and selected subsets was observed following exercise in HCs and all pwMS on different DMTs. Patients with lymphopenia exhibited an increase in absolute lymphocyte counts and immune cell subsets till just below or into the reference range. An increase above the upper limit of the reference range was detected in patients on natalizumab. Exercise-induced alterations were observable even in low and more pronounced in high-intensity physical activities. Lymphocyte deformability was found to be only mildly affected by the investigated exercise regimes. Conclusion: People with multiple sclerosis (PwMS) treated with alemtuzumab, fingolimod, and natalizumab respond to acute exercise with a comparable temporal pattern characterized by the increase of immune cell subsets as HCs. The magnitude of response is influenced by exercise intensity. Exercise-mediated effects should be considered when interpreting laboratory values in patients on immunomodulatory therapy. The impact of exercise on biophysical properties should be further elucidated.

Building a monitoring matrix for the management of multiple sclerosis.

Multiple sclerosis (MS) has a longitudinal and heterogeneous course, with an increasing number of therapy options and associated risk profiles, leading to a constant increase in the number of parameters to be monitored. Even though important clinical and subclinical data are being generated, treating neurologists may not always be able to use them adequately for MS management. In contrast to the monitoring of other diseases in different medical fields, no target-based approach for a standardized monitoring in MS has been established yet. Therefore, there is an urgent need for a standardized and structured monitoring as part of MS management that is adaptive, individualized, agile, and multimodal-integrative. We discuss the development of an MS monitoring matrix which can help facilitate data collection over time from different dimensions and perspectives to optimize the treatment of people with MS (pwMS). In doing so, we show how different measurement tools can combined to enhance MS treatment. We propose to apply the concept of patient pathways to disease and intervention monitoring, not losing track of their interrelation. We also discuss the use of artificial intelligence (AI) to improve the quality of processes, outcomes, and patient safety, as well as personalized and patient-centered care. Patient pathways allow us to track the patient's journey over time and can always change (e.g., when there is a switch in therapy). They therefore may assist us in the continuous improvement of monitoring in an iterative process. Improving the monitoring process means improving the care of pwMS.

The need for a strategic therapeutic approach: multiple sclerosis in check.

Multiple sclerosis (MS) is the most common chronic autoimmune neurological disease. Its therapeutic management has drastically evolved in the recent years with the development of specific disease-modifying therapies (DMTs). Together with the established injectables, oral and intravenous alternatives are now available for MS patients with significant benefits to modulate the disease course. Certain drugs present with a higher efficacy than the others, profiles and frequencies of adverse events differentiate as well. Thus due to the several and different treatment alternatives, the therapeutic approach adopted by neurologists requires a tactical focus for a targeted, timed, and meaningful treatment decision. An integration of rational and emotional control with proper communication skills is necessary for shared decision-making with patients. In this perspective paper, we reinforce the necessary concept of strategic MS treatment approach using all available therapies based on scientific evidence and current experience. We apply a didactic analogy to the strategic game chess. The opening with oriented attack (i.e. already in early disease stages as clinical isolated syndrome), a correct choice of chess pieces to move (i.e. among the several DMTs), a re-assessment reaction to different scenarios (e.g. sustained disease activity, adverse events, and family planning) and the advantage of real-world data are discussed to try the best approach to ultimately successfully approach the best personalized MS treatment.

Digital Biomarkers in Multiple Sclerosis.

For incurable diseases, such as multiple sclerosis (MS), the prevention of progression and the preservation of quality of life play a crucial role over the entire therapy period. In MS, patients tend to become ill at a younger age and are so variable in terms of their disease course that there is no standard therapy. Therefore, it is necessary to enable a therapy that is as personalized as possible and to respond promptly to any changes, whether with noticeable symptoms or symptomless. Here, measurable parameters of biological processes can be used, which provide good information with regard to prognostic and diagnostic aspects, disease activity and response to therapy, so-called biomarkers Increasing digitalization and the availability of easy-to-use devices and technology also enable healthcare professionals to use a new class of digital biomarkers-digital health technologies-to explain, influence and/or predict health-related outcomes. The technology and devices from which these digital biomarkers stem are quite broad, and range from wearables that collect patients' activity during digitalized functional tests (e.g., the Multiple Sclerosis Performance Test, dual-tasking performance and speech) to digitalized diagnostic procedures (e.g., optical coherence tomography) and software-supported magnetic resonance imaging evaluation. These technologies offer a timesaving way to collect valuable data on a regular basis over a long period of time, not only once or twice a year during patients' routine visit at the clinic. Therefore, they lead to real-life data acquisition, closer patient monitoring and thus a patient dataset useful for precision medicine. Despite the great benefit of such increasing digitalization, for now, the path to implementing digital biomarkers is widely unknown or inconsistent. Challenges around validation, infrastructure, evidence generation, consistent data collection and analysis still persist. In this narrative review, we explore existing and future opportunities to capture clinical digital biomarkers in the care of people with MS, which may lead to a digital twin of the patient. To do this, we searched published papers for existing opportunities to capture clinical digital biomarkers for different functional systems in the context of MS, and also gathered perspectives on digital biomarkers under development or already existing as a research approach.

Drug and Neurofilament Levels in Serum and Breastmilk of Women With Multiple Sclerosis Exposed to Natalizumab During Pregnancy and Lactation.

Objective: To determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods. Methods: Eleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period. Results: The mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1). Conclusion: We determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis.

Natalizumab Pharmacokinetics and -Dynamics and Serum Neurofilament in Patients With Multiple Sclerosis.

Background: Natalizumab (NAT) is a high-efficacy treatment for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy that sometimes requires treatment cessation with a risk of returning disease activity. The aim of this study was to characterize the pharmacokinetics and -dynamics as well as neurodestruction marker serum neurofilament light chain (sNfL) in patients with RRMS and secondary progressive MS (SPMS) stopping NAT in correlation to clinical data. Methods: In this study, 50 RRMS and 9 SPMS patients after NAT cessation were included. Five RRMS patients on NAT treatment holiday were evaluated. Clinical and radiological disease activity were systemically assessed by frequent exams after NAT stop. Free NAT concentration, cell bound NAT, α4-integrin expression and α4-integrin-receptor saturation as well as immune cell frequencies were measured for up to 4 months after NAT withdrawal. Additionally, sNfL levels were observed up to 12 months in RRMS and up to 4 months in SPMS patients. Results: NAT cessation was associated with a return of disease activity in 38% of the RRMS and 33% of the SPMS patients within 12 and 7 months, respectively. Concentration of free and cell bound NAT as well as α4-integrin-receptor saturation decreased in the RRMS and SPMS patients whereas α4-integrin expression increased over time. NAT induced increase of lymphocytes and its subsets normalized and a non-significant drop of NK and Th17 T-cells counts could be detected. All RRMS patients showed physiological sNfL levels <8pg/ml 1 month after last NAT infusion. During follow-up period sNfL levels peaked up to 16-fold and were linked to return of disease activity in 19 of the 37 RRMS patients. Treatment holiday was also associated with a return of disease activity in 4 of 5 patients and with an increase of sNfL at an individual level. Conclusions: We demonstrate the reversibility of NAT pharmacodynamic and -kinetic markers. sNfL levels are associated with the recurrence of disease activity and can also serve as an early marker to predict present before onset of clinical or radiological disease activity on the individual level.

Digital Twins for Multiple Sclerosis.

An individualized innovative disease management is of great importance for people with multiple sclerosis (pwMS) to cope with the complexity of this chronic, multidimensional disease. However, an individual state of the art strategy, with precise adjustment to the patient's characteristics, is still far from being part of the everyday care of pwMS. The development of digital twins could decisively advance the necessary implementation of an individualized innovative management of MS. Through artificial intelligence-based analysis of several disease parameters - including clinical and para-clinical outcomes, multi-omics, biomarkers, patient-related data, information about the patient's life circumstances and plans, and medical procedures - a digital twin paired to the patient's characteristic can be created, enabling healthcare professionals to handle large amounts of patient data. This can contribute to a more personalized and effective care by integrating data from multiple sources in a standardized manner, implementing individualized clinical pathways, supporting physician-patient communication and facilitating a shared decision-making. With a clear display of pre-analyzed patient data on a dashboard, patient participation and individualized clinical decisions as well as the prediction of disease progression and treatment simulation could become possible. In this review, we focus on the advantages, challenges and practical aspects of digital twins in the management of MS. We discuss the use of digital twins for MS as a revolutionary tool to improve diagnosis, monitoring and therapy refining patients' well-being, saving economic costs, and enabling prevention of disease progression. Digital twins will help make precision medicine and patient-centered care a reality in everyday life.

[MSProDiscuss - Development of a Digital Anamnesis Tool to Identify Disease Progression in Multiple Sclerosis]. / MSProDiscuss ­ Entwicklung eines digitalen Tools zur standardisierten Patientenanamnese, um Progredienz bei Multipler Sklerose zu identifizieren.

During the course of Multiple Sclerosis (MS), most patients with relapsing remitting MS (RRMS) convert to secondary progressive MS (SPMS), an MS-phenotype associated with a steady deterioration of functional ability independent from relapses and worsened prognosis. Due to the heterogeneity of this conversion, SPMS-diagnosis is often challenging and made retrospectively with a delay of several years. In this review, we first discuss advantages and limitations of screening tools for early SPMS-detection such as the SPMS nomogram, the MS prediction score, and the best SPMS definition approach. These screening tools might help to shorten the phase of diagnostic uncertainty. We then focus on the development of MSProDiscuss, a novel web-based tool that helps the treating neurologist to systematically assesses parameters highly relevant for SPMS-conversion during routine anamnesis. These parameters involve disease activity, symptoms, and impacts of the patient's overall symptoms. In a recent validation study, MSProDiscuss demonstrated high sensitivity, specificity, and interrater reliability. MSProDiscuss does not impose an additional time burden on the treating neurologist and its results are easy to interpret by a simple traffic light system. In first usability tests, it was therefore assessed as a helpful tool for the clinical routine. The early detection of clinically significant progression by diagnostic tools such as MSProDiscuss could open a time-window for therapeutic interventions.

A focus on secondary progressive multiple sclerosis (SPMS): challenges in diagnosis and definition.

Secondary progressive multiple sclerosis (SPMS) is the second most common form of multiple sclerosis (MS). One in two relapse remitting multiple sclerosis (RRMS) patients will develop SPMS within 15 years and up to two-thirds after 30 years, leading to a progressive decrease of neurological function and limitation of daily activities. Nevertheless, the SPMS diagnosis is often established retrospectively and delayed up to 3 years due to several patient- and clinician-related factors. Definitive clinical diagnostic criteria are lacking and research is currently ongoing to identify imaging and biochemical biomarkers. As new therapies are introduced, early SPMS diagnosis may represent a window of opportunity for intervention. New approaches, endpoints or technologies could help physicians establishing a diagnosis. Here, we review SPMS in relation to its diagnostic and definition challenges and current screening techniques and tools.

The Dresden Protocol for Multidimensional Walking Assessment (DMWA) in Clinical Practice.

Walking impairments represent one of the most debilitating symptom areas for people with multiple sclerosis (MS). It is important to detect even slightest walking impairments in order to start and optimize necessary interventions in time to counteract further progression of the disability. For this reason, a regular monitoring through gait analysis is highly necessary. At advanced stages of MS with significant walking impairment, this assessment is also necessary to optimize symptomatic treatment, choose the most suitable walking aid and plan individualized rehabilitation. In clinical practice, walking impairment is only assessed at higher levels of the disease using e.g., the Expanded Disability Status Scale (EDSS). In contrast to the EDSS, standardized functional tests such as walking speed, walking endurance and balance as well as walking quality and gait-related patient-reported outcomes allow a more holistic and sensitive assessment of walking impairment. In recent years, the MS Center Dresden has established a standardized monitoring procedure for the routine multidimensional assessment of gait and balance disorders. In the following protocol, we present the techniques and procedures for the analysis of gait and balance of people with MS at the MS Center Dresden. Patients are assessed with a multidimensional gait analysis at least once a year. This enables long-term monitoring of walking impairment, which allows early active intervention regarding further progression of disease and improves the current standard clinical practice.

No Impact of Long-Term Fingolimod Treatment on Fecal Secretory Immunoglobulin A Levels in Patients With Multiple Sclerosis.

BACKGROUND: Fingolimod (FTY) is a sphingosine 1 phosphate (S1P) agonist with significant effects on immune cell distribution used as an effective disease modifying therapy in multiple sclerosis (MS) patients. Animal studies have demonstrated that a dysregulation of egress of murine secretory Immunglobulin A (sIgA)+ plasmablasts from Peyer's patches in FTY-treated mice reduced fecal sIgA levels. Alterations in intestinal levels of sIgA could modify the gut microbiome and homeostasis in humans. We analyzed the effect of FTY on the fecal and salivary sIgA levels as marker of the humoral immune system in the gut. METHODS: Twenty five people with confirmed MS diagnosis according to 2010 revised McDonald's criteria and on long-term continuous treatment at the MS Center in Dresden, Germany were enrolled in this exploratory cross-sectional study. Fecal and salivary sIgA were analyzed after at least 12 months of treatment with FTY or Glatiramer acetate (GA). RESULTS: Fifteen MS patients on FTY and 10 on GA participated in this study. The mean fecal sIgA concentration of both groups was not decreased compared to reference values and did not demonstrate significant differences between them (FTY 3323.13 µg/g +/- 2094.72; GA 2040.65 µg/g +/- 1709.07). A similar pattern was seen in the salivary sIgA and serum immunoglobulins levels. CONCLUSION: In this pilot study, we could not confirm the decrease of fecal sIgA after a long-term treatment with FTY. Further longitudinal studies should evaluate the effects of MS treatments on the gut immune system in more detail.