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.

Although the detailed pathogenesis of multiple sclerosis (MS) is not completely understood, a broad range of disease-modifying therapies (DMTs) are available. A common side effect of nearly every MS therapeutic agent is lymphopenia, which can be both beneficial and, in some cases, treatment-limiting. A sound knowledge of the underlying mechanism of action of the selected agent is required in order to understand treatment-associated changes in white blood cell counts, as well as monitoring consequences. This review is a comprehensive summary of the currently available DMTs with regard to their effects on lymphocyte count. In the first part, we describe important general information about the role of lymphocytes in the course of MS and the essentials of lymphopenic states. In the second part, we introduce the different DMTs according to their underlying mechanism of action, summarizing recommendations for lymphocyte monitoring and definitions of lymphocyte thresholds for different therapeutic regimens.

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.

Introduction: For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real-world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. Areas covered: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high-quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment-specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. Expert opinion: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process.

The measurement of serum neurofilament light chain (sNfL) is of growing importance in the field of neurology. In the management of multiple sclerosis, it can serve as a useful marker to assess disease activity and treatment response. This paper compares two available methods, namely the Single Molecule Array (Simoa) and the Ella microfluid platform, to measure longitudinal sNfL levels of 42 highly active multiple sclerosis patients treated with alemtuzumab over a period of 36 months. In order to assess the methods agreement, Bland–Altman plots and Passing–Bablok regression were analyzed. Here, we show that despite the fact that Ella measures around 24% higher values than Simoa, both are equally suitable for longitudinal sNfL monitoring.

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.