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.

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.

Differential effects of selective versus unselective sphingosine 1-phosphate receptor modulators on T- and B-cell response to SARS-CoV-2 vaccination.

BACKGROUND: Sphingosine 1-phosphat receptor modulators (S1PRMs) have been linked to attenuated immune response to SARS-CoV-2 vaccines. OBJECTIVE: To characterize differences in the immune response to SARS-CoV-2 vaccines in patients on selective versus unselective S1PRMs. METHODS: Monocentric, longitudinal study on people with multiple sclerosis (pwMS) on fingolimod (FTY), siponimod (SIP), ozanimod (OZA), or without disease-modifying therapy (DMT) following primary and booster SARS-CoV-2 vaccination. Anti-SARS-CoV-2 antibodies and T-cell response was measured with electro-chemiluminescent immunoassay and interferon-γ release assay. RESULTS: Primary vaccination induced a significant antibody response in pwMS without DMT while S1PRM patients exhibited reduced antibody titers. The lowest antibodies were found in patients on FTY, whereas patients on OZA and SIP presented significantly higher levels. Booster vaccinations induced increased antibody levels in untreated patients and comparable titers in patients on OZA and SIP, but no increase in FTY-treated patients. While untreated pwMS developed a T-cell response, patients on S1PRMs presented a diminished/absent response. Patients undergoing SARS-CoV-2 vaccination before onset of S1PRMs presented a preserved, although attenuated humoral response, while T-cellular response was blunted. CONCLUSION: Our data confirm differential effects of selective versus unselective S1PRMs on T- and B-cell response to SARS-CoV-2 vaccination and suggest association with S1PRM selectivity rather than lymphocyte redistribution.

Long-Term Immune Response Profiles to SARS-CoV-2 Vaccination and Infection in People with Multiple Sclerosis on Anti-CD20 Therapy.

Our objective was to analyze longitudinal cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in people with multiple sclerosis (pwMS) on B-cell depleting treatment (BCDT) compared to pwMS without immunotherapy. We further evaluated the impact of COVID-19 infection and vaccination timing. PwMS (n = 439) on BCDT (ocrelizumab, rituximab, ofatumumab) or without immunotherapy were recruited for this prospective cohort study between June 2021 and June 2022. SARS-CoV-2 spike-specific antibodies and interferon-γ release of CD4 and CD8 T-cells upon stimulation with spike protein peptide pools were analyzed at different timepoints (after primary vaccination, 3 and 6 months after primary vaccination, after booster vaccination, 3 months after booster). Humoral response to SARS-CoV-2 was consistently lower whereas T-cell response was higher in patients with BCDT compared to controls. Cellular and humoral responses decreased over time after primary vaccination and increased again upon booster vaccination, with significantly higher antibody titers after booster than after primary vaccination in both untreated and B-cell-depleted pwMS. COVID-19 infection further led to a significant increase in SARS-CoV-2-specific responses. Despite attenuated B-cell responses, a third vaccination for patients with BCDT seems recommendable, since at least partial protection can be expected from the strong T-cell response. Moreover, our data show that an assessment of T-cell responses may be helpful in B-cell-depleted patients to evaluate the efficacy of SARS-CoV-2 vaccination.

NVX-CoV2373-induced T- and B-cellular immunity in immunosuppressed people with multiple sclerosis that failed to respond to mRNA and viral vector SARS-CoV-2 vaccines.

Importance: Immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is important, especially in people with multiple sclerosis (pwMS) on immunosuppressive therapies. Objective: This study aims to determine whether adjuvanted protein-based vaccine NVX-CoV2373 is able to induce an immune response to SARS-CoV-2 in pwMS with inadequate responses to prior triple mRNA/viral vector vaccination. Design setting and participants: We conducted a single-center, prospective longitudinal cohort study at the MS Center in Dresden, Germany. In total, 65 participants were included in the study in accordance with the following eligibility criteria: age > 18 years, immunomodulatory treatment, and insufficient T-cellular and humoral response to prior vaccination with at least two doses of SARS-CoV-2 mRNA (BNT162b2, mRNA-1273) or viral vector vaccines (AZD1222, Ad26.COV2.S). Interventions: Intramuscular vaccination with two doses of NVX-CoV2373 at baseline and 3 weeks of follow-up. Main outcomes and measures: The development of SARS-CoV-2-specific antibodies and T-cell responses was evaluated. Results: For the final analysis, data from 47 patients on stable treatment with sphingosine-1-phosphate receptor (S1PR) modulators and 17 on ocrelizumab were available. The tolerability of the NVX-CoV2373 vaccination was overall good and comparable to the one reported for the general population. After the second NVX-CoV2373 vaccination, 59% of S1PR-modulated patients developed antispike IgG antibodies above the predefined cutoff of 200 binding antibody units (BAU)/ml (mean, 1,204.37 [95% CI, 693.15, 2,092.65] BAU/ml), whereas no clinically significant T-cell response was found. In the subgroup of the patients on ocrelizumab treatment, 23.5% developed antispike IgG > 200 BAU/ml (mean, 116.3 [95% CI, 47.04, 287.51] BAU/ml) and 53% showed positive spike-specific T-cellular responses (IFN-gamma release to antigen 1: mean, 0.2 [95% CI, 0.11, 0.31] IU/ml; antigen 2: mean, 0.24 [95% CI, 0.14, 0.37]) after the second vaccination. Conclusions: Vaccination with two doses of NVX-CoV2373 was able to elicit a SARS-CoV-2-specific immune response in pwMS lacking adequate immune responses to previous mRNA/viral vector vaccination. For patients receiving S1PR modulators, an increase in anti-SARS-CoV-2 IgG antibodies was detected after NVX-CoV2373 vaccination, whereas in ocrelizumab-treated patients, the increase of antiviral T-cell responses was more pronounced. Our data may impact clinical decision-making by influencing the preference for NVX-CoV2373 vaccination in pwMS receiving treatment with S1PR modulation or anti-CD20 treatment.

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.

S1P receptor modulators and the cardiovascular autonomic nervous system in multiple sclerosis: a narrative review.

Sphingosine 1-phosphate (S1P) receptor (S1PR) modulators have a complex mechanism of action, which are among the most efficient therapeutic options in multiple sclerosis (MS) and represent a promising approach for other immune-mediated diseases. The S1P signaling pathway involves the activation of five extracellular S1PR subtypes (S1PR1-S1PR5) that are ubiquitous and have a wide range of effects. Besides the immunomodulatory beneficial outcome in MS, S1P signaling regulates the cardiovascular function via S1PR1-S1PR3 subtypes, which reside on cardiac myocytes, endothelial, and vascular smooth muscle cells. In our review, we describe the mechanisms and clinical effects of S1PR modulators on the cardiovascular system. In the past, mostly short-term effects of S1PR modulators on the cardiovascular system have been studied, while data on long-term effects still need to be investigated. Immediate effects detected after treatment initiation are due to parasympathetic overactivation. In contrast, long-term effects may arise from a shift of the autonomic regulation toward sympathetic predominance along with S1PR1 downregulation. A mild increase in blood pressure has been reported in long-term studies, as well as decreased baroreflex sensitivity. In most studies, sustained hypertension was found to represent a significant adverse event related to treatment. The shift in the autonomic control and blood pressure values could not be just a consequence of disease progression but also related to S1PR modulation. Reduced cardiac autonomic activation and decreased heart rate variability during the long-term treatment with S1PR modulators may increase the risk for subsequent cardiac events. For second-generation S1PR modulators, this observation has to be confirmed in further studies with longer follow-ups. The periodic surveillance of cardiovascular function and detection of any cardiac autonomic dysfunction can help predict cardiac outcomes not only after the first dose but also throughout treatment. Plain Language Summary: What is the cardiovascular effect of S1P receptor modulator therapy in multiple sclerosis? Sphingosine 1-phosphate (S1P) receptor (S1PR) modulators are among the most efficient therapies for multiple sclerosis. As small molecules, they are not only acting on the immune but on cardiovascular and nervous systems as well. Short-term effects of S1PR modulators on the cardiovascular system have already been extensively described, while long-term effects are less known. Our review describes the mechanisms of action and the short- and long-term effects of these therapeutic agents on the cardiovascular system in different clinical trials. We systematically reviewed the literature that had been published by January 2022. One hundred seven articles were initially identified by title and abstract using targeted keywords, and thirty-nine articles with relevance to cardiovascular effects of S1PR therapy in multiple sclerosis patients were thereafter considered, including their references for further accurate clarification. Studies on fingolimod, the first S1PR modulator approved for treating multiple sclerosis, primarily support the safety profile of this therapeutic class. The second-generation therapeutic agents along with a different treatment initiation approach helped mitigate several of the cardiovascular adverse effects that had previously been observed at the start of treatment. The heart rate may decrease when initiating S1PR modulators and, less commonly, the atrioventricular conduction may be prolonged, requiring cardiac monitoring for the first 6 h of medication. Continuous therapy with S1PR modulators can increase blood pressure values; therefore, the presence of arterial hypertension should be checked during long-term treatment. Periodic surveillance of the cardiovascular and autonomic functions can help predict cardiac outcomes and prevent possible adverse events in S1PR modulators treatment. Further studies with longer follow-ups are needed, especially for the second-generation of S1PR modulators, to confirm the safety profile of this therapeutic class.

Timing of SARS-CoV-2 Vaccination Matters in People With Multiple Sclerosis on Pulsed Anti-CD20 Treatment.

BACKGROUND AND OBJECTIVES: Our objective was to investigate cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of people with multiple sclerosis (pwMS) on pulsed B-cell-depleting treatment (BCDT). In particular, we intended to evaluate a possible association between immune responses and the timing of vaccination under BCDT. METHODS: We conducted a cross-sectional study among pwMS on pulsed BCDT or without disease-modifying treatment after completed SARS-CoV-2 vaccination. Samples were collected during routine clinical visits at the Multiple Sclerosis Center Dresden, Germany, between June 2021 and September 2021. Blood was analyzed for SARS-CoV-2 spike protein-specific antibodies and interferon-γ release of CD4 and CD8 T cells on stimulation with spike protein peptide pools. Lymphocyte subpopulations and total immunoglobulin levels in the blood were measured as part of clinical routine. RESULTS: We included 160 pwMS in our analysis, comprising 133 pwMS on BCDT (n = 132 on ocrelizumab and n = 1 on rituximab) and 27 without disease-modifying treatment. Humoral and cellular anti-SARS-CoV-2 responses were reciprocally regulated by the time between the last BCDT cycle and vaccination. Although antibody responses increased with prolonged intervals between the last BCDT cycle and vaccination, CD4 and CD8 T-cell responses were higher in pwMS vaccinated at early time points after the last BCDT cycle compared with untreated pwMS. T-cellular vaccination responses correlated with total, CD3 CD4, and partly with CD3 CD8 lymphocyte counts. Humoral responses correlated with CD19 lymphocyte counts. Status post coronavirus disease 2019 infection led to significantly increased SARS-CoV-2-specific T-cell and antibody responses. DISCUSSION: Delaying BCDT is currently discussed as a strategy to optimize humoral responses to SARS-CoV-2 vaccination. However, T cells represent an important line of defense against SARS-CoV-2 infection as well, especially in light of emerging variants of concern. We observed enhanced CD4 and CD8 T-cellular responses in pwMS receiving vaccination at early time points after their last BCDT cycle. These data may influence clinical decision making with respect to vaccination strategies in patients receiving BCDT.

Transparent Quality Optimization for Machine Learning-Based Regression in Neurology.

The clinical monitoring of walking generates enormous amounts of data that contain extremely valuable information. Therefore, machine learning (ML) has rapidly entered the research arena to analyze and make predictions from large heterogeneous datasets. Such data-driven ML-based applications for various domains become increasingly applicable, and thus their software qualities are taken into focus. This work provides a proof of concept for applying state-of-the-art ML technology to predict the distance travelled of the 2-min walk test, an important neurological measurement which is an indicator of walking endurance. A transparent lean approach was emphasized to optimize the results in an explainable way and simultaneously meet the specified software requirements for a generic approach. It is a general-purpose strategy as a fractional−factorial design benchmark combined with standardized quality metrics based on a minimal technology build and a resulting optimized software prototype. Based on 400 training and 100 validation data, the achieved prediction yielded a relative error of 6.1% distributed over multiple experiments with an optimized configuration. The Adadelta algorithm (LR=0.000814, fModelSpread=5, nModelDepth=6, nepoch=1000) performed as the best model, with 90% of the predictions with an absolute error of <15 m. Factors such as gender, age, disease duration, or use of walking aids showed no effect on the relative error. For multiple sclerosis patients with high walking impairment (EDSS Ambulation Score ≥6), the relative difference was significant (n=30; 24.0%; p<0.050). The results show that it is possible to create a transparently working ML prototype for a given medical use case while meeting certain software qualities.

[The Multiple Sclerosis Health Resource Utilization Survey]. / Der Multiple Sclerosis Health Resource Utilization Survey.

BACKGROUND: In health economic studies, valid and reliable cost data are essential to reach meaningful conclusions. In the case of multiple sclerosis (MS), such studies are often based on primary data for which the underlying survey instruments have not been published. In addition, heterogeneous methods make the comparability and interpretation of such study results difficult. To standardize health economic studies in MS, the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS) was developed, validated and published in a freely accessible format. RESEARCH QUESTION: This review focuses on the MS-HRS. We report on the methodological background of studies on the assessment of cost of illness as well as MS-HRS-based results on the costs of disease dynamics in people with MS. METHODS: This article is based on a selective literature review on the MS-HRS as well as on health economic aspects of cost assessment. RESULTS: The MS-HRS provides a holistic assessment of direct medical, direct non-medical and indirect resource utilization. Within indirect costs, we considered absenteeism, either short term (sick leave) or long term (disability pension), but also presenteeism, which refers to impaired performance during work. Resources were valued at the societal opportunity cost or the best possible approximation. First analyses based on MS-HRS showed that, in addition to inpatient disease severity and clinical course, disease dynamics in form of relapses and progression have enormous socioeconomic implications. CONCLUSION: Valid cost data bring transparency to the economic consequences of diseases. In addition to clinical data, cost data can be used to determine cost-effectiveness and thus reveal opportunities for more efficient patient care. For the case of MS, a freely accessible tool is available for cost assessments.

Cost of illness in multiple sclerosis by disease characteristics - A review of reviews.

INTRODUCTION: In light of the increasing number of economic burden studies and heterogeneity in methodology and reporting standards, there is a need for robust evidence synthesis on an umbrella review level. AREAS COVERED: We performed the first review of reviews of cost-of-illness studies in multiple sclerosis. Focusing on disaggregated costs by disease characteristics (disability level, relapse, disease course), we also characterized the underlying methodological evidence base of individual (primary) studies. EXPERT COMMENTARY: We identified 17 reviews encompassing 111 unique primary studies, and a high degree of overlap across reviews. Costs were substantial, rising with disability level, relapse episodes, and disease progression. Disability was the key cost driver. Compared to mild disability, total costs for moderate disability were 1.4-2.3-fold higher and 1.8-2.9-fold higher for severe disability. With escalating disability, the share of costs outside the health system (indirect costs, informal care) increasingly outweighed the share of direct medical costs. Of all 111 primary studies, 72% gathered resource use/loss data by patient self-report. Associated costs were mostly reported by disability level (75%), followed by relapse (48%) and disease course (21%). In conclusion, although heterogeneity can make in-depth comparisons of costs across studies impossible, important patterns are broadly apparent.

Automated Analysis of the Two-Minute Walk Test in Clinical Practice Using Accelerometer Data.

One of the core problems for people with multiple sclerosis (pwMS) is the impairment of their ability to walk, which can be severely restrictive in everyday life. Therefore, monitoring of ambulatory function is of great importance to be able to effectively counteract disease progression. An extensive gait analysis, such as the Dresden protocol for multidimensional walking assessment, covers several facets of walking impairment including a 2-min walk test, in which the distance taken by the patient in two minutes is measured by an odometer. Using this approach, it is questionable how precise the measuring methods are at recording the distance traveled. In this project, we investigate whether the current measurement can be replaced by a digital measurement method based on accelerometers (six Opal sensors from the Mobility Lab system) that are attached to the patient's body. We developed two algorithms using these data and compared the validity of these approaches using the results from 2-min walk tests from 562 pwMS that were collected with a gold-standard odometer. In 48.4% of pwMS, we detected an average relative measurement error of less than 5%, while results from 25.8% of the pwMS showed a relative measurement error of up to 10%. The algorithm had difficulties correctly calculating the walking distances in another 25.8% of pwMS; these results showed a measurement error of more than 20%. A main reason for this moderate performance was the variety of pathologically altered gait patterns in pwMS that may complicate the step detection. Overall, both algorithms achieved favorable levels of agreement (r = 0.884 and r = 0.980) with the odometer. Finally, we present suggestions for improvement of the measurement system to be implemented in the future.

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.

Using Machine Learning Algorithms for Identifying Gait Parameters Suitable to Evaluate Subtle Changes in Gait in People with Multiple Sclerosis.

In multiple sclerosis (MS), gait impairment is one of the most prominent symptoms. For a sensitive assessment of pathological gait patterns, a comprehensive analysis and processing of several gait analysis systems is necessary. The objective of this work was to determine the best diagnostic gait system (DIERS pedogait, GAITRite system, and Mobility Lab) using six machine learning algorithms for the differentiation between people with multiple sclerosis (pwMS) and healthy controls, between pwMS with and without fatigue and between pwMS with mild and moderate impairment. The data of the three gait systems were assessed on 54 pwMS and 38 healthy controls. Gaussian Naive Bayes, Decision Tree, k-Nearest Neighbor, and Support Vector Machines (SVM) with linear, radial basis function (rbf) and polynomial kernel were applied for the detection of subtle walking changes. The best performance for a healthy-sick classification was achieved on the DIERS data with a SVM rbf kernel (κ = 0.49 ± 0.11). For differentiating between pwMS with mild and moderate disability, the GAITRite data with the SVM linear kernel (κ = 0.61 ± 0.06) showed the best performance. This study demonstrates that machine learning methods are suitable for identifying pathologic gait patterns in early MS.

Profiles of eHealth Adoption in Persons with Multiple Sclerosis and Their Caregivers.

(1) Background: Persons with multiple sclerosis (pwMS) are often characterized as ideal adopters of new digital healthcare trends, but it is worth thinking about whether and which pwMS will be targeted and served by a particular eHealth service like a patient portal. With our study, we wanted to explore needs and barriers for subgroups of pwMS and their caregivers when interacting with eHealth services in care and daily living. (2) Methods: This study comprises results from two surveys: one collecting data from pwMS and their relatives (as informal caregivers) and another one providing information on the opinions and attitudes of healthcare professionals (HCPs). Data were analyzed descriptively and via generalized linear models. (3) Results: 185 pwMS, 25 informal caregivers, and 24 HCPs in the field of MS participated. Nine out of ten pwMS used information technology on a daily base. Individual impairments like in vision and cognition resulted in individual needs like the desire to actively monitor their disease course or communicate with their physician in person. HCPs reported that a complete medication overview, additional medication information, overview of future visits and a reminder of medication intake would be very helpful eHealth features for pwMS, while they themselves preferred features organizing and enriching future visits. (4) Conclusions: A closer look at the various profiles of eHealth adoption in pwMS and their caregivers indicated that there is a broad and robust enthusiasm across several subgroups that does not exclude anyone in general, but constitutes specific areas of interest. For pwMS, the focus was on eHealth services that connect previously collected information and make them easily accessible and understandable.

Improving Digital Patient Care: Lessons Learned from Patient-Reported and Expert-Reported Experience Measures for the Clinical Practice of Multidimensional Walking Assessment.

BACKGROUND: Walking assessment (WA) enables meaningful patient mobility assessment. In this context, patient satisfaction with WA can influence assessment compliance and indirectly affect outcomes. One opportunity to assess patient satisfaction is patient-reported and expert-reported experience measures (PREM). Research on PREMs and WA in daily clinical multiple sclerosis (MS) practice does not exist yet. METHODS: We surveyed people with MS about their experience and assessed healthcare professionals' experience via an interview after patients completed WA. RESULTS: Gait parameters were related to perceived difficulty and strain during performance. Less impaired patients perceived the WA to be less difficult and exhausting but were less likely to use WA results for themselves. Men and patients with higher impairment would perform WA more frequently. A good workflow, a fully performed WA with standardized testing, fully functional measurement systems, support and safeguarding by staff in case of falls, direct feedback after the testing, and patients' motivation are identified by the experts as necessary factors for a successful WA. CONCLUSIONS: As patients' experience has an impact on patients' outcomes, long-term monitoring of PREMs should become an integral part of the healthcare service to identify and avoid problems early.

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.

Tolerability and Efficacy of Clindamycin/Tretinoin versus Adapalene/Benzoyl Peroxide in the Treatment of Acne Vulgaris.

Acne vulgaris is the most common dermatological disorder worldwide, causing significant physical and psychological morbidity. Topical combination therapy has shown superior efficacy compared to monotherapy, especially when combined with retinoids. Few studies have directly compared combined formulations. This evaluator-blinded pilot study compared the efficacy and tolerability of two marketed topical combination acne gels, clindamycin 1%-tretinoin 0.025% (CT) and benzoyl peroxide 2.5%-adapalene 0.1% (BA) in 20 patients with mild to moderate acne vulgaris. Gels were applied daily on opposite sides of the face for 21 days. The primary outcome was difference in transepidermal water loss (TEWL) at the end of treatment. Secondary endpoints were skin moisture content measurement, Investigators' Global Assessment, subject self-assessments (SSA) of burning/stinging, itching, erythema, and dryness/scaling, and Comparative Participant Satisfaction Questionnaire (CPSQ). Efficacy was assessed by inflammatory and non- inflammatory acne efflorescences counts. TEWL increased significantly for both CT and BA (+57.74%, P=0.002; +58.77%, P<0.001); skin moisture content significantly decreased only for BA (-16.47%, P=0.02). Only BA showed a significant increase in erythema and dryness/scaling (P=0.027 and P=0.014) and in SSA burning/stinging (P=0.04). Patient satisfaction evaluation also reflected the strong BA irritation. Although CT and BA both reduced acne lesions (P<0.001) and more patients preferred to continue with CT, subject perception of acne improvement was higher for BA. These findings suggest that CT and BA have similar efficacy in the treatment of mild to moderate papulopustular acne. However, CT was better tolerated than BA by both medical and subject evaluation. CT is an effective and tolerated treatment option.J Drugs Dermatol. 2021;20(3):295-301. doi:10.36849/JDD.2021.5641.

Electronic Health Interventions in the Case of Multiple Sclerosis: From Theory to Practice.

(1) Background: eHealth interventions play a growing role in shaping the future healthcare system. The integration of eHealth interventions can enhance the efficiency and quality of patient management and optimize the course of treatment for chronically ill patients. In this integrative review, we discuss different types of interventions, standards and advantages of quality eHealth approaches especially for people with multiple sclerosis (pwMS). (2) Methods: The electronic databases PubMed, Cochrane and Web of Science were searched to identify potential articles for eHealth interventions in pwMS; based on 62 articles, we consider different ways of implementing health information technology with various designs. (3) Results: There already exist some eHealth interventions for single users with a single-use case, interventions with a social setting, as well as eHealth interventions that integrate various single and social interventions and even those that may be used additionally for complex use cases. A key determinant of consumer acceptance is a high-quality user-centric design for healthcare practitioners and pwMS. In pwMS, the different neurological disabilities should be considered, and particular attention must be paid to the course of the treatment and the safety processes of each treatment option. (4) Conclusion: Depending on the field of application and the respective users, interventions are designed for single, social, integrated or complex use. In order to be accepted by their target group, interventions must be beneficial and easy to use.