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Background and Objectives: Relapse and MRI activity usually decline with aging but are replaced by progression independent of relapse activity (PIRA) in patients with multiple sclerosis (PwMS). However, several older PwMS continue to experience clinical relapses, and the impact on their disease remains undetermined. We aimed to determine the impact of an index relapse on disease outcomes in patients older than 50 years and to identify risk factors of disadvantageous outcomes., Methods: We performed a secondary analysis from 3 prospective cohorts in Germany. We evaluated all PwMS 50 years and older with a relapse ≤60 days before a baseline visit and at least 18 months of follow-up compared with a control cohort of PwMS without a relapse. Patients were stratified according to age ("50-54" vs "55-59" vs "60+") or disease outcomes ("stable" vs "active" vs "progressive," according to the Lublin criteria). We analyzed relapses, MRI activity, relapse-associated worsening, and PIRA. Regression analysis was performed to evaluate the association of specific baseline risk factors and treatment regimen changes with disease outcomes at month 18., Results: A total of 681 patients were included in the "relapse cohort" (50+: 361; 55+: 220; 60+: 100). The "control cohort" comprised 232 patients (50+: 117; 55+: 71; 60+: 44). Baseline epidemiologic parameters were balanced among cohorts and subgroups. We observed increased abundance of inflammatory activity and relapse-independent disability progression in the "relapse" vs "control" cohort. In the "relapse" cohort, we identified 273 patients as "stable" (59.7%), 114 patients as "active" (24.9%), and 70 patients as "progressive" (15.3%) during follow-up. Cardiovascular risk factors (CVRFs) and older age at baseline were identified as risk factors of progressive, whereas disease-modifying treatment (DMT) administration at baseline favored stable disease. DMT during follow-up was associated with stable over active, but not over progressive disease., Discussion: A relapse-suggesting underlying active disease-in PwMS older than 50 years was associated with continued disease activity and increased risk of PIRA. Presence of CVRF and absence of DMT at baseline appeared as risk factors of disadvantageous disease courses. An escalation of DMT switch was associated with stable over active but not progressive disease.

Introduction: The rapid roll-out of novel COVID-19 vaccines made near real-time post-marketing safety surveillance essential to identify rare and long-term adverse events following immunization (AEFIs). In light of the ongoing booster vaccination campaigns, it is key to monitor changes in observed safety patterns post-vaccination. The effect of sequential COVID-19 vaccinations, as well as heterologous vaccination sequences, on the observed post-vaccination safety pattern, remains largely unknown., Methods: The primary objective of this study was to describe the profile of spontaneously reported AEFIs following COVID-19 vaccination in the Netherlands, including the primary and booster series. Reports from consumers and healthcare professionals were collected via a COVID-19 vaccine-tailored online reporting form by the National Pharmacovigilance Centre Lareb (Lareb) between 6 January 2021 and 31 August 2022. The data were used to describe the most frequently reported AEFIs per vaccination moment, the consumer experienced burden per AEFI, and differences in AEFIs reported for homologous and heterologous vaccination sequences., Results: Lareb received 227,884 spontaneous reports over a period of twenty months. Overall, a high degree of similarity in local and systemic AEFIs per vaccination moment was observed, with no apparent change in the number of reports of serious adverse events after multiple COVID-19 vaccinations. No differences in the pattern of reported AEFIs per vaccination sequence was observed., Conclusion: Spontaneous reported AEFIs demonstrated a similar reporting pattern for homologous and heterologous primary and booster series of COVID-19 vaccination in the Netherlands., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background Typically defined as a thromboinflammatory disease, ischemic stroke features early and delayed inflammatory responses, which determine the extent of ischemia-related brain damage. T and natural killer cells have been implicated in neuronal cytotoxicity and inflammation, but the precise mechanisms of immune cell-mediated stroke progression remain poorly understood. The activating immunoreceptor NKG2D is expressed on both natural killer and T cells and may be critically involved. Methods and Results An anti-NKG2D blocking antibody alleviated stroke outcome in terms of infarct volume and functional deficits, coinciding with reduced immune cell infiltration into the brain and improved survival in the animal model of cerebral ischemia. Using transgenic knockout models devoid of certain immune cell types and immunodeficient mice supplemented with different immune cell subsets, we dissected the functional contribution of NKG2D signaling by different NKG2D-expressing cells in stroke pathophysiology. The observed effect of NKG2D signaling in stroke progression was shown to be predominantly mediated by natural killer and CD8 + T cells. Transfer of T cells with monovariant T-cell receptors into immunodeficient mice with and without pharmacological blockade of NKG2D revealed activation of CD8 + T cells irrespective of antigen specificity. Detection of the NKG2D receptor and its ligands in brain samples of patients with stroke strengthens the relevance of preclinical observations in human disease. Conclusions Our findings provide a mechanistic insight into NKG2D-dependent natural killer- and T-cell-mediated effects in stroke pathophysiology.

Autoimmune limbic encephalitis (ALE) presents with new-onset mesial temporal lobe seizures, progressive memory disturbance, and other behavioral and cognitive changes. CD8 T cells are considered to play a key role in those cases where autoantibodies (ABs) target intracellular antigens or no ABs were found. Assessment of such patients presents a clinical challenge, and novel noninvasive imaging biomarkers are urgently needed. Here, we demonstrate that visualization of the translocator protein (TSPO) with [ 18 F]DPA-714-PET-MRI reveals pronounced microglia activation and reactive gliosis in the hippocampus and amygdala of patients suspected with CD8 T cell ALE, which correlates with FLAIR-MRI and EEG alterations. Back-translation into a preclinical mouse model of neuronal antigen-specific CD8 T cell-mediated ALE allowed us to corroborate our preliminary clinical findings. These translational data underline the potential of [ 18 F]DPA-714-PET-MRI as a clinical molecular imaging method for the direct assessment of innate immunity in CD8 T cell-mediated ALE.

Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration.

Background and Objectives: B cell-depleting antibodies were proven as effective strategy for the treatment of relapsing multiple sclerosis (RMS). The monoclonal antibody ocrelizumab was approved in 2017 in the United States and in 2018 in the European Union, but despite proven efficacy in randomized, controlled clinical trials, its effectiveness in the real-world setting remains to be fully elucidated. In particular, most study patients were treatment naive or switched from injectable therapies, whereas oral substances or monoclonal antibodies made up >1% of previous treatments., Methods: We evaluated ocrelizumab-treated patients with RMS enrolled in the prospective cohorts at the University Hospitals Duesseldorf and Essen, Germany. Epidemiologic data at baseline were compared, and Cox proportional hazard models were applied to evaluate outcomes., Results: Two hundred eighty patients were included (median age: 37 years, 35% male patients). Compared with using ocrelizumab as a first-line treatment, its use as a third-line therapy increased hazard ratios (HRs) for relapse and disability progression, whereas differences between first- vs second-line and second- vs third-line remained smaller. We stratified patients according to their last previous disease-modifying treatment and here identified fingolimod (FTY) (45 patients, median age 40 years, 33% male patients) as a relevant risk factor for ongoing relapse activity despite 2nd-line (HR: 3.417 [1.007-11.600]) or 3rd-line (HR: 5.903 [2.489-13.999]) ocrelizumab treatment, disability worsening (2nd line: HR: 3.571 [1.013-12.589]; 3rd line: HR: 4.502 [1.728-11.729]), and occurrence of new/enlarging MRI lesions (2nd line: HR: 1.939 [0.604-6.228]; 3rd line: HR: 4.627 [1.982-10.802]). Effects were persistent throughout the whole follow-up. Neither peripheral B-cell repopulation nor immunoglobulin G levels were associated with rekindling disease activity., Discussion: Our prospectively collected observational data suggest suboptimal effectiveness of ocrelizumab in patients switching from FTY compared with those switching from other substances or having been treatment naive. These findings support previous studies indicating abated effectiveness of immune cell-depleting therapies following FTY treatment in patients with RMS., Classification of Evidence: This study provides Class IV evidence that for patients with RMS, previous treatment with FTY compared with previous treatment with other immunomodulating therapies decreases the effectiveness of ocrelizumab., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Neurological manifestations of autoimmune connective tissue diseases (CTD) are poorly understood and difficult to diagnose. We here aimed to address this shortcoming by studying immune cell compositions in CTD patients with and without neurological manifestation., Methods: Using flow cytometry, we retrospectively investigated paired cerebrospinal fluid (CSF) and blood samples of 28 CTD patients without neurological manifestation, 38 CTD patients with neurological manifestation (N-CTD), 38 non-inflammatory controls, and 38 multiple sclerosis (MS) patients, a paradigmatic primary neuroinflammatory disease., Results: We detected an expansion of plasma cells in the blood of both N-CTD and CTD compared to non-inflammatory controls and MS. Blood plasma cells alone distinguished the clinically similar entities N-CTD and MS with high discriminatory performance (AUC: 0.81). Classical blood monocytes indicated higher disease activity in systemic lupus erythematosus (SLE) patients. Surprisingly, immune cells in the CSF did not differ significantly between N-CTD and CTD, while CD4 + T cells and the CD4 + /CD8 + ratio were elevated in the blood of N-CTD compared to CTD. Several B cell-associated parameters partially overlapped in the CSF in MS and N-CTD. We built a machine learning model that distinguished N-CTD from MS with high discriminatory power using either blood or CSF., Conclusion: We here find that blood flow cytometry alone surprisingly suffices to distinguish CTD with neurological manifestations from clinically similar entities, suggesting that a rapid blood test could support clinicians in the differential diagnosis of N-CTD., (© 2023. The Author(s).)

Introduction: Given the varying severity of coronavirus disease 2019 (COVID-19) and the rapid spread of Severe-Acute-Respiratory-Syndrome-Corona-Virus-2 (SARS-CoV-2), vaccine-mediated protection of particularly vulnerable individuals has gained increasing attention during the course of the pandemic., Methods: We performed a 1-year follow-up study of 51 ocrelizumab-treated patients with multiple sclerosis (OCR-pwMS) who received COVID-19 vaccination in 2021. We retrospectively identified 37 additional OCR-pwMS, 42 pwMS receiving natalizumab, 27 pwMS receiving sphingosine 1-phosphate receptor modulators, 59 pwMS without a disease-modifying therapy, and 61 controls without MS (HC). In OCR-pwMS, anti-SARS-CoV-2(S)-antibody titers were measured prior to the first and after the second, third, and fourth vaccine doses (pv2/3/4). The SARS-CoV-2-specific T cell response was analyzed pv2. SARS-CoV-2 infection status, COVID-19 disease severity, and vaccination-related adverse events were assessed in all pwMS and HC., Results: We found a pronounced and increasing anti-SARS-CoV-2(S)-antibody response after COVID-19 booster vaccinations in OCR-pwMS (pv2: 30.4%, pv3: 56.5%, and pv4 90.0% were antibody positive). More than one third of OCR-pwMS without detectable antibodies pv2 developed positive antibodies pv3. 23.5% of OCR-pwMS had a confirmed SARS-CoV-2 infection, of which 84.2% were symptomatic. Infection rates were comparable between OCR-pwMS and control groups. None of the pwMS had severe COVID-19. An attenuated humoral immune response was not associated with a higher risk of SARS-CoV-2 infection., Discussion: Additional COVID-19 vaccinations can boost the humoral immune response in OCR-pwMS and improve clinical protection against COVID-19. Vaccines effectively protect even OCR-pwMS without a detectable COVID-19 specific humoral immune response, indicating compensatory, e.g., T cell-mediated immunological mechanisms., Competing Interests: MR received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion, and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, and Merck. MK received travel grants from Merck Serono and Biogen, MB served on scientific advisory boards for Biogen, Novartis and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck and Novartis, HPH has received fees for consulting, speaking, and serving on steering committees from Bayer Healthcare, Biogen, GeNeuro, MedImmune, Merck, Novartis, Opexa, Receptos Celgene, Roche, Sanofi Genzyme, CSL Behring, Octapharma, and Teva, with approval from the Rector of Heinrich-Heine-University, OA received personal fees from Alexion, Bayer Healthcare, Biogen, Celgene, Merck Serono, MedImmune, Novartis, Roche, Teva, and Zambon, PA received compensation for serving on Scientific Advisory Boards and/or speaker honoraria and/or travel support from Novartis, Teva, Biogen, Bristol Meyers Squibb, Celgene, Janssen Cilag, Merz Pharmaceuticals, Ipsen, Allergan, Bayer Healthcare, Esai, UCB and Glaxo Smith Kline, Roche; he received research support from Novartis, Biogen, Celgene, Teva, Merz Pharmaceuticals, Ipsen, and Roche, TR reports grants and personal fees from Sanofi-Genzyme; personal fees from Biogen; personal fees and nonfinancial support from Merck Serono; personal fees from Roche; and personal fees from Teva, outside the submitted work. NM has received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharamceuticals, Fresenius Medical Care, Diamed, and BIAL, and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharmaceuticals, and Novartis Pharma. SGM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva, DK received travel grants from GeNeuro and Merck, refund of congress participation fees from GeNeuro, Merck and Servier, consulting fees from Grifols, payment for lectures from Grifols, support for research projects from Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Räuber, Willison, Korsen, Kölsche, Golombeck, Plaack, Schüller, Huntemann, Rolfes, Schroeter, Nelke, Regner-Nelke, Förster, Ringelstein, Barnett, Hartung, Aktas, Albrecht, Ruck, Melzer, Meuth and Kremer.)

Background: For treatment of relapsing-remitting multiple sclerosis (RRMS), a broad range of disease-modifying therapies (DMT) is available. However, few comparative effectiveness studies between different drugs have been performed., Objectives: This study aimed to compare the efficacy and treatment continuation of natalizumab and ocrelizumab in a real-world cohort of patients with relapsing-remitting multiple sclerosis (RRMS) from two German university hospitals., Methods: We performed a retrospective analysis of RRMS patients who initiated treatment with natalizumab or ocrelizumab between January 2016 and April 2019 at the German university hospitals of Mainz and Düsseldorf. Bayesian propensity score matching was conducted to correct for differences in baseline characteristics. Our primary outcome was no evidence of disease activity [NEDA-3: no relapses, no confirmed disability progression, and no magnetic resonance imaging (MRI) activity] and its subcomponents. Secondary outcomes included measurement of neurofilament light chain (NfL) in serum, analysis of premature discontinuation, and evidence of rebound activity in patients switching from natalizumab to ocrelizumab., Results: We identified 63 patients starting treatment with natalizumab and 76 patients starting with ocrelizumab. Binary logistic regression showed that treatment with natalizumab or a higher number of relapses in the previous year were independently associated with a higher risk for relapses. Patients receiving natalizumab had a higher probability of premature discontinuation of therapy ( p  = 0.002). After propensity score matching of the two treatment arms, 55 patients remained per group. NEDA-3 after 30 months of follow-up was reached by 53.1% in the ocrelizumab group and 36.1% in the natalizumab group ( p  = 0.177). Ocrelizumab was superior to natalizumab concerning the occurrence of relapses in log-rank test ( p  = 0.019). NfL levels in serum were low under both treatments. Patients who switched from natalizumab to ocrelizumab showed no increased rebound activity., Discussion: This study provides class IV evidence that treatment of RRMS patients with ocrelizumab and natalizumab show comparable effectiveness in combined endpoints, while ocrelizumab might be more effective in preventing the occurrence of relapses., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.P. reports no disclosures. L.R. received travel reimbursements from Merck Serono and Sanofi Genzyme, research support from Diamed, Merck Serono, and Novartis. Her research is funded by the Interdisciplinary Center for Clinical Studies (IZKF) Muenster. F.S. reports no disclosures. M.M. reports no disclosures. M.K. received honoraria for lecturing and travel expenses for attending meetings from Biogen, Merck Serono, and Novartis. Her research is funded by the German Multiple Sclerosis Society (DMSG) and Novartis. S.G.M. received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. F.Z. has recently received research grants and consultation funds from Biogen, Ministry of Education and Research (BMBF), Bristol Myers Squibb, Celgene, German Research Foundation (DFG), Janssen, Max Planck Society (MPG), Merck Serono, Novartis, Progressive MS Alliance (PMSA), Roche, Sanofi Genzyme, and Sandoz. S.B. has received honoria and compensation for travel from Biogen Idec, Bristol Myers Squibb, Merck Serono, Novartis, Sanofi Genzyme, Roche, and Teva., (© The Author(s), 2022.)

Background: Dolutegravir (DTG) is an Integrase Strand Transfer Inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV infection. It is available in a number of pharmaceutical preparations including the fixed-dose combination (TLD) containing tenofovir (300 mg) + lamivudine (300 mg) + dolutegravir (50 mg). In 2018, Eswatini adopted TLD as the preferred first-line HIV treatment regimen for adults and adolescents as per WHO recommendations. From March 2019 to March 2020, the National Pharmacovigilance Center (NPC) in Eswatini received 8 reports of hyperglycaemia associated with the use of DTG. This study was conducted to investigate if Eswatini NPC database included cases suggestive of causality between dolutegravir and hyperglycaemia., Method: A qualitative synthesis of information from the Eswatini national pharmacovigilance database from March 2019 to March 2020 was conducted to investigate a casual association between hyperglycaemia and dolutegravir., Results: All reports with dolutegravir containing regimen and suspected Adverse Event of hyperglycaemia in the period of March 2019 to March 2020 were included in the study. Seven of the reports were serious (resulted in hospitalization and one case concerned optic neuritis, leading to blindness). Two patients had a medical history of diabetes while the rest of the patients had never experienced hyperglycaemia before starting dolutegravir. For all the reports, the time to onset of hyperglycaemia ranges from 2-5 months after the initiation of DTG. None of the patients discontinued the use of DTG. All the patients were treated with oral hypoglycaemic medication. In severe cases, patients were treated with intravenous normal saline and ringer lactate as well as rapid-acting insulins. All patients are currently stable on oral hypoglycaemic drugs., Conclusion: Cases that support causality between dolutegravir containing regimen and hyperglycaemia were found. These cases were mainly serious. Based on these findings it is recommended that healthcare professionals (HCPs) actively screen all patients for risk factors of hyperglycaemia before DTG initiation. In addition, it is important that HCPs are aware of the possible association between DTG and hyperglycaemia., (© 2022. The Author(s).)

Background: Cladribine is a synthetic purine analogue that interferes with DNA synthesis and repair next to disrupting cellular proliferation in actively dividing lymphocytes. The compound is approved for the treatment of multiple sclerosis (MS). Cladribine can cross the blood-brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. Here, we explored compartment-specific immunosuppressive as well as potential direct neuroprotective effects of oral cladribine treatment in experimental autoimmune encephalomyelitis (EAE) mice., Methods: In the current study, we compare immune cell frequencies and phenotypes in the periphery and CNS of EAE mice with distinct grey and white matter lesions (combined active and focal EAE) either orally treated with cladribine or vehicle, using flow cytometry. To evaluate potential direct neuroprotective effects, we assessed the integrity of the primary auditory cortex neuronal network by studying neuronal activity and spontaneous synaptic activity with electrophysiological techniques ex vivo., Results: Oral cladribine treatment significantly attenuated clinical deficits in EAE mice. Ex vivo flow cytometry showed that cladribine administration led to peripheral immune cell depletion in a compartment-specific manner and reduced immune cell infiltration into the CNS. Histological evaluations revealed no significant differences for inflammatory lesion load following cladribine treatment compared to vehicle control. Single cell electrophysiology in acute brain slices was performed and showed an impact of cladribine treatment on intrinsic cellular firing patterns and spontaneous synaptic transmission in neurons of the primary auditory cortex. Here, cladribine administration in vivo partially restored cortical neuronal network function, reducing action potential firing. Both, the effect on immune cells and neuronal activity were transient., Conclusions: Our results indicate that cladribine exerts a neuroprotective effect after crossing the blood-brain barrier independently of its peripheral immunosuppressant action., (© 2022. The Author(s).)

Background: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing-remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape., Methods: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions., Results: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy., Conclusion: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE., (© 2022. The Author(s).)

Objective: Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing., Methods: In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030)., Results: 42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes ("full/best" vs. "average" vs. "worse/none"). Upon discharge, the adjusted odds ratio for any treatment response ("full/best" + "average" vs. "worse/none") was 10.697 favouring immunoadsorption (p = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response ("full/best" vs. "average" + "worse/none") was 103.236 favouring IA patients (p = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors., Interpretation: Immunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement., (© 2022. The Author(s).)

Background: Vaccination has proven to be effective in preventing SARS-CoV-2 transmission and severe disease courses. However, immunocompromised patients have not been included in clinical trials and real-world clinical data point to an attenuated immune response to SARS-CoV-2 vaccines among patients with multiple sclerosis (MS) receiving immunomodulatory therapies., Methods: We performed a retrospective study including 59 ocrelizumab (OCR)-treated patients with MS who received SARS-CoV-2 vaccination. Anti-SARS-CoV-2-antibody titres, routine blood parameters and peripheral immune cell profiles were measured prior to the first (baseline) and at a median of 4 weeks after the second vaccine dose (follow-up). Moreover, the SARS-CoV-2-specific T cell response and peripheral B cell subsets were analysed at follow-up. Finally, vaccination-related adverse events were assessed., Results: After vaccination, we found anti-SARS-CoV-2(S) antibodies in 27.1% and a SARS-CoV-2-specific T cell response in 92.7% of MS cases. T cell-mediated interferon (IFN)-γ release was more pronounced in patients without anti-SARS-CoV-2(S) antibodies. Antibody titres positively correlated with peripheral B cell counts, time since last infusion and total IgM levels. They negatively correlated with the number of previous infusion cycles. Peripheral plasma cells were increased in antibody-positive patients. A positive correlation between T cell response and peripheral lymphocyte counts was observed. Moreover, IFN-γ release was negatively correlated with the time since the last infusion., Conclusion: In OCR-treated patients with MS, the humoral immune response to SARS-CoV-2 vaccination is attenuated while the T cell response is preserved. However, it is still unclear whether T or B cell-mediated immunity is required for effective clinical protection. Nonetheless, given the long-lasting clinical effects of OCR, monitoring of peripheral B cell counts could facilitate individualised treatment regimens and might be used to identify the optimal time to vaccinate., Competing Interests: Competing interests: MK received travel grants from Merck Serono and Biogen. LR received travel reimbursements from Merck Serono and Sanofi Genzyme. MP's research is funded by the German Multiple Sclerosis Society North Rhine-Westphalia (DMSG), Novartis and the programme "Innovative Medizinische Forschung" (IMF) of the Medical Faculty of the University of Muenster. MB served on scientific advisory boards for Biogen, Novartis and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck and Novartis. H-PH has received fees for consulting, speaking and serving on steering committees from Bayer Healthcare, Biogen, GeNeuro, MedImmune, Merck, Novartis, Opexa, Receptos Celgene, Roche, Sanofi Genzyme, CSL Behring, Octapharma and Teva, with approval from the Rector of Heinrich-Heine-University. OA received personal fees from Alexion, Bayer Healthcare, Biogen, Celgene, Merck Serono, MedImmune, Novartis, Roche, Teva and Zambon, and he received research support from the German Science Foundation (DFG) and the German Ministry of Education, Science, Research and Technology (BMBF), outside of the submitted work. PA received compensation for serving on Scientific Advisory Boards and/or speaker honoraria and/or travel support from Novartis, Teva, Biogen, Bristol Meyers Squibb, Celgene, Janssen Cilag, Merz Pharmaceuticals, Ipsen, Allergan, Bayer Healthcare, Esai, UCB and Glaxo Smith Kline, Roche; he received research support from Novartis, Biogen, Celgene, Teva, Merz Pharmaceuticals, Ipsen and Roche. NM has received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharamceuticals, Fresenius Medical Care, Diamed and BIAL, and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharmaceuticals and Novartis Pharma. TR reports grants from German Ministry of Education, Science, Research and Technology, during the conduct of the study; grants and personal fees from Sanofi-Genzyme; personal fees from Biogen; personal fees and non-financial support from Merck Serono; personal fees from Roche; and personal fees from Teva, outside the submitted work. SGM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche and Teva. DK received travel grants from GeNeuro and Merck, refund of congress participation fees from GeNeuro, Merck and Servier, consulting fees from Grifols, payment for lectures from Grifols, support for research projects from Teva and was funded by the Deutsche Forschungsgemeinschaft (DFG)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cladribine is a synthetic deoxyadenosine analogue approved for the treatment of highly active relapsing multiple sclerosis (RMS). Cladribine is considered to be a semi-selective immune-reconstitution therapy (IRT) that induces long-term remission following short course of treatment. Here, we evaluated the effect of cladribine on immune cell reduction and reconstitution during the first two years of treatment., Methods: We analyzed our longitudinal, prospective, real-world cohort of 80 cladribine-treated RMS patients from two tertiary centers in Germany. Laboratory testing was conducted monthly and included evaluation of cellular as well as soluble parameters. Laboratory outcomes were correlated with infectious adverse events (AEs) and clinical or paraclinical disease activity., Results: Selective alterations in immune cell populations occurred following cladribine treatment, with the most marked effects observed in year two of treatment. Specifically, a rapid reduction in CD56 + natural killer cells (nadir: month 1 (year 1) and 14 (year 2); -37 and -41% from baseline) was followed by a greater reduction in CD19 + B cells (nadir: month 2 and 14; -81 and -82%); a moderate effect on CD4 + (nadir: month 3 and 15; -48 and -61%) and CD8 + T cells (nadir: month 5 and 18; -40 and -48%). Despite the marked effect on B cells, immunoglobulin levels were unaffected. There was no or minimal effect on thrombocytes and innate immune cells. Clinical and paraclinical disease activity was unrelated to the observed immune alterations. Lymphopenia was the most commonly observed AE (86.3% of patients; grade III-IV lymphopenia: 38.8%). The cumulative incidence of infections was 55% with cladribine treatment, which were mostly mild or moderate. In total, 19 herpes infections developed in 8 (10%) cladribine-treated patients; all cases were dermatomal and 94.7% of the herpetic infections occurred during a period of lymphopenia., Conclusions: The immunophenotyping data obtained in our real-world setting are comparable to those demonstrated in pivotal clinical trials and provide further evidence that cladribine may represent a form of IRT. However, regarding the side-effect profile of cladribine, severe lymphopenia (exceeding grade II CTCAE) was more frequent, which may have prompted the development of herpes infections. Of note, lymphocyte dynamics did not correlate with clinical and paraclinical measures of disease activity in the two-year follow-up period., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The current range of disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has placed more importance on the accurate monitoring of disease progression for timely and appropriate treatment decisions. With a rising number of measurements for disease progression, it is currently unclear how well these measurements or combinations of them can monitor more mildly affected RRMS patients., Objectives: To investigate several composite measures for monitoring disease activity and their potential relation to the biomarker neurofilament light chain (NfL) in a clearly defined early RRMS patient cohort with a milder disease course., Methods: From a total of 301 RRMS patients, a subset of 46 patients being treated with a continuous first-line therapy was analyzed for loss of no evidence of disease activity (lo-NEDA-3) status, relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA), up to seven years after treatment initialization. Kaplan-Meier estimates were used for time-to-event analysis. Additionally, a Cox regression model was used to analyze the effect of NfL levels on outcome measures in this cohort., Results: In this mildly affected cohort, both lo-NEDA-3 and PIRA frequently occurred over a median observational period of 67.2 months and were observed in 39 (84.8%) and 23 (50.0%) patients, respectively. Additionally, 12 out of 26 PIRA manifestations (46.2%) were observed without a corresponding lo-NEDA-3 status. Jointly, either PIRA or lo-NEDA-3 showed disease activity in all patients followed-up for at least the median duration (67.2 months). NfL values demonstrated an association with the occurrence of relapses and RAW., Conclusion: The complementary use of different disease progression measures helps mirror ongoing disease activity in mildly affected early RRMS patients being treated with continuous first-line therapy., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials., (© 2022. The Author(s).)

Background: Real-world data from electronic health records (EHRs) represent a wealth of information for studying the benefits and risks of medical treatment. However, they are limited in scope and should be complemented by information from the patient perspective., Objective: The aim of this study is to develop an innovative research infrastructure that combines information from EHRs with patient experiences reported in questionnaires to monitor the risks and benefits of medical treatment., Methods: We focused on the treatment of overactive bladder (OAB) in general practice as a use case. To develop the Benefit, Risk, and Impact of Medication Monitor (BRIMM) infrastructure, we first performed a requirement analysis. BRIMM's starting point is routinely recorded general practice EHR data that are sent to the Dutch Nivel Primary Care Database weekly. Patients with OAB were flagged weekly on the basis of diagnoses and prescriptions. They were invited subsequently for participation by their general practitioner (GP), via a trusted third party. Patients received a series of questionnaires on disease status, pharmacological and nonpharmacological treatments, adverse drug reactions, drug adherence, and quality of life. The questionnaires and a dedicated feedback portal were developed in collaboration with a patient association for pelvic-related diseases, Bekkenbodem4All. Participating patients and GPs received feedback. An expert meeting was organized to assess the strengths, weaknesses, opportunities, and threats of the new research infrastructure., Results: The BRIMM infrastructure was developed and implemented. In the Nivel Primary Care Database, 2933 patients with OAB from 27 general practices were flagged. GPs selected 1636 (55.78%) patients who were eligible for the study, of whom 295 (18.0% of eligible patients) completed the first questionnaire. A total of 288 (97.6%) patients consented to the linkage of their questionnaire data with their EHR data. According to experts, the strengths of the infrastructure were the linkage of patient-reported outcomes with EHR data, comparison of pharmacological and nonpharmacological treatments, flexibility of the infrastructure, and low registration burden for GPs. Methodological weaknesses, such as susceptibility to bias, patient selection, and low participation rates among GPs and patients, were seen as weaknesses and threats. Opportunities represent usefulness for policy makers and health professionals, conditional approval of medication, data linkage to other data sources, and feedback to patients., Conclusions: The BRIMM research infrastructure has the potential to assess the benefits and safety of (medical) treatment in real-life situations using a unique combination of EHRs and patient-reported outcomes. As patient involvement is an important aspect of the treatment process, generating knowledge from clinical and patient perspectives is valuable for health care providers, patients, and policy makers. The developed methodology can easily be applied to other treatments and health problems., (©Karin Hek, Leàn Rolfes, Eugène P van Puijenbroek, Linda E Flinterman, Saskia Vorstenbosch, Liset van Dijk, Robert A Verheij. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 16.03.2022.)

Background: Alemtuzumab is an anti-CD52 antibody approved for the treatment of relapsing remitting multiple sclerosis (RRMS). The summary of product characteristics (SmPC) provides recommendations on the administration of alemtuzumab to prevent or reduce the risk of serious side effects associated with alemtuzumab infusion, including myocardial ischemia, hemorrhagic stroke, arterial dissection, and pulmonary alveolar hemorrhage. However, real-world implementation of alemtuzumab infusion management recommendations has not been previously assessed., Methods: Here we provide a large-scale multi-center (in- and outpatient) observational study on alemtuzumab infusion management in daily clinical care in Germany (ALEMLL08025; INFUSE-MS; NIS-no. 364). Parameters of infusion management - including infusion administration, clinical and laboratory monitoring - were assessed, compared between study centers and the occurrence of infusion-associated reactions (IARs) was documented. Moreover, the TSQM and MSIS-29 questionnaires were used to quantify patient satisfaction and health-related quality of life., Results: 140 RRMS patients were enrolled in this study. Alemtuzumab infusion regimes (treatment course 1 and 2) were comparable between infusion sites and in accordance with recommendations by the SmPC. Standardization of infusion management was associated with a satisfactory safety profile. IARs were usually mild, headache (13.6%), rash (10.7%), and pyrexia (6.4%) being the most common ones. TSQM and MSIS-29 scores denoted high patient satisfaction and health-related quality of life among RRMS patients treated with alemtuzumab., Conclusion: In conclusion, our results indicate that infusion management of alemtuzumab is highly standardized and in line with the SmPC. Alemtuzumab treatment and implementation of infusion management recommendations are associated with a satisfactory safety profile regarding the occurrence of IARs, a high patient satisfaction and health-related quality of life as important indicators for the quality of MS care., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To explore factors that are associated with reactogenicity in general and systemic after the first dose of COVID-19 vaccine in the Netherlands., Design: A web-based prospective cohort design using patient reported outcomes (PROs)., Setting: Any person who has been vaccinated with any brand of COVID-19 vaccine in the Dutch COVID immunization programme., Participants: 22,184 participants. Of these, 13,959 (62.9%) experienced reactogenicity in general and 11,979 (54.0%) systemic reactogenicity within 7 days after vaccination., Main Outcome Measures: Factors that are associated with the occurrence of reactogenicity after COVID-19 vaccination., Results: Compared to the Comirnaty® vaccine, the highest odds ratio (OR) for developing reactogenicity was for the Vaxzevria® vaccine (OR 5.18) followed by Spikevax® (OR 2.16), and Janssen (OR 1.65). Participants with a history of COVID-19 disease had a 3.10 increased odds for reactogenicity. Women had a 2.08 increased odds compared to men. Older participants experienced less reactogenicity. Compared to the age group < 50, the ORs for the age groups 50-60, 61-79, and ≥80 were 0.36, 0.15, and 0.10 respectively. The use of an antipyretic drug, or a drug for nervous system disorders gave an increased odds of 1.34 and 1.16 respectively. A body mass index of 25.0-29.9 and over 30 was negatively associated with reactogenicity (OR 0.87 and OR 0.72 respectively). Comorbidities that were associated with reactogenicity were cardiac disorders (OR 1.26), respiratory disorders (OR 1.31), psychiatric disorders (1.37), reproductive disorders (OR 1.54), and eye disorders (OR 1.55). The factors associated with systemic reactogenicity were mostly comparable, but there were differences for comorbidities, drug use, and the strength of the regression coefficient., Conclusions: This extensive study with over 22,000 vaccine recipients in the Netherlands demonstrated that, taken into account all factors in the model, the Comirnaty® vaccine gave the least and the Vaxzevria® vaccine the most reactogenicity in general and systemic after the first dose. Also a person with a history of COVID-19 disease, female sex and younger age had an increased odds for experiencing reactogenicity after vaccination., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rag1 -/- mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1 -/- mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1 null IL2rg null (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1 -/- and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1 -/- NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1 -/- were comparable in number and function to those in WT mice. Rag1 -/- mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1 -/- controls. Our results indicate that NK cells from Rag1 -/- mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke., (© 2021. The Author(s).)

Background: Oral cladribine has been approved for the treatment of relapsing multiple sclerosis (MS) yet real-world evidence regarding its effectiveness and safety remains scarce., Objective: To evaluate efficacy and safety outcomes of MS patients following induction of cladribine., Methods: We evaluated our prospective cohort of cladribine-treated MS patients from two tertiary centres in Germany. Relapses, disability worsening and occurrence of new or enlarging T2-hyperintense magnetic resonance imaging (MRI) lesions were assessed as well as lymphocyte counts and herpes virus infections., Results: Among 270 patients treated with cladribine, we observed a profound reduction of both relapses and new or enlarging MRI lesions. Treatment appeared more efficacious, especially in patients without previous therapy or following platform substances. Patients switching from natalizumab were prone to re-emerging disease activity. Among patients following dimethyl fumarate pre-treatment, severe lymphopenia was common and associated with increased rates of herpes virus manifestations., Conclusion: Overall, we observed an efficacy and safety profile of cladribine consistent with data from the phase 3 clinical trial. However, patients switching from natalizumab experienced suboptimal disease control beyond rebound activity following cessation of natalizumab. Furthermore, dimethyl fumarate pre-treatment was associated with a profound risk of developing severe lymphopenia and subsequent herpes virus infections.

It remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca 2+ ) is the most important second messenger, for which the potassium channel K 2P 18.1 is a relevant regulator. Here, we identify K 2P 18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-κB-mediated K 2P 18.1 upregulation in tTreg progenitors. K 2P 18.1 provided the driving force for sustained Ca 2+ influx that facilitated NF-κB- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K 2P 18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K 2P 18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K 2P 18.1 variant that is associated with poor clinical outcomes indicate that K 2P 18.1 also plays a role in human Treg development. Pharmacological modulation of K 2P 18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K 2P 18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K 2P 18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders., (© 2021. The Author(s).)

Background & Aims: The 2-pore potassium channel subfamily K member 9 (KCNK9) regulates intracellular calcium concentration and thus modulates cell survival and inflammatory signaling pathways. It also was recognized as a risk allele for inflammatory bowel disease. However, it remains unclear whether KCNK9 modulates inflammatory bowel disease via its impact on immune cell function or whether its influence on calcium homeostasis also is relevant in intestinal epithelial cells., Methods: Kcnk9 -/- mice were challenged with 3% dextran sulfate sodium (DSS) to induce experimental acute colitis. Primary cultures of intestinal epithelial cells were generated, and expression of potassium channels as well as cytosolic calcium levels and susceptibility to apoptosis were evaluated. Furthermore, we evaluated whether KCNK9 deficiency was compensated by the closely related 2-pore potassium channel KCNK3 in vivo or in vitro., Results: Compared with controls, KCNK9 deficiency or its pharmacologic blockade were associated with aggravated DSS-induced colitis compared with wild-type animals. In the absence of KCNK9, intestinal epithelial cells showed increased intracellular calcium levels and were more prone to mitochondrial damage and caspase-9-dependent apoptosis. We found that expression of KCNK3 was increased in Kcnk9 -/- mice but did not prevent apoptosis after DSS exposure. Conversely, increased levels of KCNK9 in Kcnk3 -/- mice were associated with an ameliorated course of DSS-induced colitis., Conclusions: KCNK9 enhances mitochondrial stability, reduces apoptosis, und thus supports epithelial cell survival after DSS exposure in vivo and in vitro. Conversely, its increased expression in Kcnk3 -/- resulted in less mitochondrial damage and apoptosis and was associated with beneficial outcomes in DSS-induced colitis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Although CSF analysis routinely enables the diagnosis of neurological diseases, it is mainly used for the gross distinction between infectious, autoimmune inflammatory, and degenerative disorders of the CNS. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analysed 546 patients with autoimmune neuroinflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters that were altered across all autoimmune neuroinflammatory CNS diseases and differentiated them from other neurological conditions and inter-autoimmunity classifiers that subdifferentiate variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist the classification of neurological patients. Overall, we showed that the integrated analysis of blood and CSF parameters improves the differential diagnosis of neurological diseases, thereby facilitating early treatment decisions., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: In MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation., Methods: To evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85)., Results: Analysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS. However, HDs displayed a strong age-dependent decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells, whereas this age-dependent reduction was completely abrogated in patients with MS. An age-dependent increase in the expression of the costimulatory molecule CD226 on memory CD8 T cells was absent in patients with MS. CD226 expression correlated with disability in younger (≤50 years) patients with MS. CSF analysis revealed a significant age-dependent decline in various immune cell populations in PPMS but not RRMS, suggesting a differential effect of aging on the intrathecal compartment in PPMS., Discussion: Our data illustrate that aging in MS is associated with a dysbalance between costimulatory and immunoregulatory signals provided by CD8 T cells favoring a proinflammatory phenotype and, more importantly, a pattern of premature immune aging in the CD8 T-cell compartment of young patients with MS with potential implications for disease severity., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) cells, capable of pro-inflammatory as well as regulatory effects, might be of interest for the pathophysiologic understanding of PA in IIM., Methods: To extend our understanding of immunological alterations in IIM patients with PA, we compared the signatures of NK cells in peripheral blood using multi-color flow cytometry in IIM patients with ( n = 12, of which anti-synthetase syndrome = 8 and dermatomyositis = 4) or without PA ( n = 12)., Results: We did not observe any significant differences for B cells, CD4, and CD8 T cells, while total NK cell numbers in IIM patients with PA were reduced compared to non-PA patients. NK cell alterations were driven by a particular decrease of CD56 dim NK cells, while CD56 bright NK cells remained unchanged. Comparisons of the cell surface expression of a large panel of NK receptors revealed an increased mean fluorescence intensity of NKG2D + on NK cells from patients with PA compared with non-PA patients, especially on the CD56 dim subset. NKG2D + and NKp46 + cell surface levels were associated with reduced vital capacity, serving as a surrogate marker for clinical severity of PA., Conclusion: Our data illustrate that PA in IIM is associated with alterations of the NK cell repertoire, suggesting a relevant contribution of NK cells in certain IIMs, which might pave the way for NK cell-targeted therapeutic approaches.

Objectives: Alemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified., Methods: We retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity., Results: The regression analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; p<0.001)) and for the time to worsening of disability (HR 7.676, 95% CI 2.870 to 20.534; p<0.001). Additionally, patients pretreated with fingolimod were more likely to experience spinal relapses (55% vs 10% among previously naïve patients; p<0.001) and had an increased risk of secondary autoimmunity (HR 5.875, 95% CI 2.126 to 16.27; p<0.001)., Conclusion: In the real-world setting, we demonstrated suboptimal disease control and increased risk of secondary autoimmunity following alemtuzumab, among patients previously treated with fingolimod. These data can provide guidance for improving MS therapeutic management., Competing Interests: Competing interests: SP: received travel grants from Sanofi Genzyme and Merck Serono, lecturing honoraria from Sanofi Genzyme, Mylan Healthcare, and Biogen, and research support from Diamed, Merck Serono, and the German Multiple Sclerosis Society Northrhine-Westphalia. TR: received travel grants and financial research support from Genzyme and Novartis and received honoraria for lecturing from Roche, Merck, Genzyme, Biogen and Teva. RP: received honoraria for lecturing and travel expenses for attending meetings from Alexion, Bayer Health Care, Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi-Genzyme, and Teva; has received research funding from Novartis. LR: received travel grants from Merck Serono and Sanofi-Genzyme. MP: received speaker honoraria and travel reimbursements from Novartis. CK: received travel grants from TEVA, compensation for serving on Scientific Advisory Boards for Novartis, and speaker honoraria from Biogen, Genzyme, and Merck Serono. BW: received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck Serono, Sanofi Genzyme, Novartis pharmaceuticals, and personal fees from Bayer, Biogen, Teva Pharma. LK: received compensation for serving on Scientific Advisory Boards for Genzyme, Janssen, Novartis, and Roche. She received speaker honoraria and travel support from Biogen, Genzyme, Merck Serono, Novartis, Roche and TEVA. She receives research support from the German Ministry for Education and Research, the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Novartis, and Merck Serono. CK: received honoraria for lecturing and travel expenses for attending meetings from Almirall, Merck Serono, Desitin, Sanofi-Genzyme, Biogen, Teva, Bayer, Novartis, Boehringer Ingelheim, Pfizer, Bristol Myers-Squibb, Daiichi Sankyo, Siemens, Eisai, Biotronik, Roche, Stago, Ever Pharma, CSL Behring, Mylan, MedDay Pharmaceuticals, Amgen. HW: received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Sanofi Genzyme, Merck Serono, and Novartis. He received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck Serono, Omniamed, Novartis, and Sanofi Aventis. He received compensation as a consultant from Biogen Idec, Merck Serono, Novartis, Roche, and Sanofi-Genzyme. HW also received research support from Bayer Healthcare, Bayer Vital, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Sanofi US and Teva. SGM: received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

While posterior reversible encephalopathy syndrome (PRES) is often characterized by an inflammatory cerebrospinal-fluid (CSF) profile, knowledge of immune cell patterns in PRES is lacking. Thus, we retrospectively characterized CSF and peripheral blood (PB) from 15 PRES patients, which we analyzed by multidimensional flow cytometry (FC). Results were compared to 72 controls, as well as to 9 patients with progressive multifocal leukoencephalopathy (PML, as a relevant differential diagnosis) and 15 multiple sclerosis patients (MS, as a classical neuroinflammatory disorder), respectively. Total protein level in CSF from PRES patients was elevated compared to that in controls, but not to MS and PML. In-depth FC analysis revealed no differences for adaptive immune cells (B cells, plasma cells, CD4 + , and CD8 + T cells) in PB or CSF of PRES compared to controls. In contrast, we observed alterations of the adaptive immune response in CSF of PML and MS compared to PRES, indicating that the adaptive immune response is not a driver of disease in PRES. Indeed, PRES was characterized by an innate immune response with CD14 ++ /CD16 + (intermediate) monocytes elevated in PB and CSF, while CD14 ++ /CD16 - (classical) monocytes were decreased in PB from PRES patients as compared to controls. Levels of CD14 ++ /CD16 + monocytes correlated with the duration of hospital stay as a surrogate marker for disease severity in PRES patients. Our findings argue for a role of innate rather than adaptive immunity in the pathophysiology of PRES. The observed shift in monocyte subsets might provide valuable diagnostic clues for the clinical management of these patients., (© 2021. The Author(s).)

Several studies suggest a role for the peripheral immune system in the pathophysiology of amyotrophic lateral sclerosis. However, comprehensive studies investigating the intrathecal immune system in amyotrophic lateral sclerosis are rare. To elucidate whether compartment-specific inflammation contributes to amyotrophic lateral sclerosis pathophysiology, we here investigated intrathecal and peripheral immune profiles in amyotrophic lateral sclerosis patients and compared them with controls free of neurological disorders (controls) and patients with dementia or primary progressive multiple sclerosis. Routine CSF parameters were examined in 308 patients, including 132 amyotrophic lateral sclerosis patients. In a subgroup of 41 amyotrophic lateral sclerosis patients, extensive flow-cytometric immune cell profiling in peripheral blood and CSF was performed and compared with data from 26 controls, 25 dementia and 21 multiple sclerosis patients. Amyotrophic lateral sclerosis patients presented with significantly altered proportions of monocyte subsets in peripheral blood and increased frequencies of CD4 + and CD8 + T cells expressing the activation marker HLA-DR in peripheral blood (CD8 + ) and CSF (CD4 + and CD8 + ) compared with controls. While dementia and multiple sclerosis patients exhibited a comparable increase in intrathecal CD8 + T-cell activation, CD8 + T-cell activation in the peripheral blood in amyotrophic lateral sclerosis was higher than in multiple sclerosis patients. Furthermore, intrathecal CD4 + T-cell activation in amyotrophic lateral sclerosis surpassed levels in dementia patients. Intrathecal T-cell activation resulted from in situ activation rather than transmigration of activated T cells from the blood. While T-cell activation did not correlate with amyotrophic lateral sclerosis progression, patients with rapid disease progression showed reduced intrathecal levels of immune-regulatory CD56 bright natural killer cells. The integration of these parameters into a composite score facilitated the differentiation of amyotrophic lateral sclerosis patients from patients of all other cohorts. To conclude, alterations in peripheral monocyte subsets, as well as increased peripheral and intrathecal activation of CD4 + and CD8 + T cells concomitant with diminished immune regulation by CD56 bright natural killer cells, suggest an involvement of these immune cells in amyotrophic lateral sclerosis pathophysiology., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic., Methods: In our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020)., Results: Three hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09-13.07] weeks). Three months after the last ocrelizumab infusion, 182 (90.1%) patients following SID and 105 (90.5%) EID patients remained relapse free ( p = 0.903). Three-month confirmed progression of disability was observed in 18 SID patients (8.9%) and 11 EID patients (9.5%, p = 0.433). MRI progression was documented in 9 SID patients (4.5%) and 8 EID patients (6.9%) at 3-month follow-up ( p = 0.232). Multivariate logistic regression showed no association between treatment regimen and no evidence of disease activity status at follow-up (OR: 1.266 [95% CI: 0.695-2.305]; p = 0.441). Clinical stability was accompanied by persistent peripheral CD19 + B-cell depletion in both groups (SID vs EID: 82.6% vs 83.3%, p = 0.463). Disease activity in our cohort was not associated with CD19 + B-cell repopulation., Conclusion: Our data support EID of ocrelizumab as potential risk mitigation strategy in times of the COVID-19 pandemic., Classification of Evidence: This study provides Class IV evidence that for patients with RRMS, an EID of at least 4 weeks does not diminish effectiveness of ocrelizumab., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

In the recent past, a plethora of drugs have been approved for the treatment of multiple sclerosis (MS). These therapeutics are mainly confined to immunomodulatory or immunosuppressive strategies but do not sufficiently address remyelination and neuroprotection. However, several neuroregenerative agents have shown potential in pre-clinical research and entered Phase I to III clinical trials. Although none of these compounds have yet proceeded to approval, understanding the causes of failure can broaden our knowledge about neuroprotection and neuroregeneration in MS. Moreover, most of the investigated approaches are characterised by consistent mechanisms of action and proved convincing efficacy in animal studies. Therefore, learning from their failure will help us to enforce the translation of findings acquired in pre-clinical studies into clinical application. Here, we summarise trials on MS treatment published since 2015 that have either failed or were interrupted due to a lack of efficacy, adverse events, or for other reasons. We further outline the rationale underlying these drugs and analyse the background of failure to gather new insights into MS pathophysiology and optimise future study designs. For conciseness, this review focuses on agents promoting remyelination and medications with primarily neuroprotective properties or unconventional approaches. Failed clinical trials that pursue immunomodulation are presented in a separate article.

Background and Purpose: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are demyelinating disorders that typically affect the optic nerves and the spinal cord. However, recent studies have demonstrated various forms of brain involvement indicating encephalitic syndromes, which consequently are included in the diagnostic criteria for both. Swallowing is processed in a distributed brain network and is therefore disturbed in many neurological diseases. The aim of this study was to investigate the occurrence of oropharyngeal dysphagia in NMOSD and MOGAD using flexible endoscopic evaluation of swallowing (FEES) as a surrogate parameter of brain involvement., Methods: Thirteen patients with NMOSD and MOGAD (mean age 54.2 ± 18.6 years, six men) who received FEES during clinical routine were retrospectively reviewed. Their extent of oropharyngeal dysphagia was rated using an ordinal dysphagia severity scale. FEES results were compared to a control group of healthy individuals. Dysphagia severity was correlated with the presence of clinical and radiological signs of brain involvement, the Expanded Disability Status Scale (EDSS) and the occurrence of pneumonia., Results: Oropharyngeal dysphagia was present in 8/13 patients, including six patients without other clinical indication of brain involvement. Clinical or subclinical swallowing impairment was significantly more severe in patients with NMOSD and MOGAD compared to the healthy individuals (p = 0.009) and correlated with clinical signs of brain involvement (p = 0.038), higher EDSS (p = 0.006) and pneumonia (p = 0.038)., Conclusion: Oropharyngeal dysphagia can occur in NMOSD and MOGAD and might be associated with pneumonia and disability. FEES may help to detect subclinical brain involvement., (© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of NeurologyEuropean Academy of Neurology.)

Objective: To report 77 patients with multiple sclerosis (MS) who developed skin-related adverse events (AEs) following treatment with cladribine., Methods: We evaluated our prospective bicentric cladribine cohort. Cladribine-treated patients with a skin AE were identified., Results: Two hundred thirty-nine cladribine-treated patients with MS were evaluated. Seventy-seven patients (32%) showed at least 1 skin AE at median 1 month after cladribine initiation (range: 1-12). Within first 3 months following last cladribine exposition, hair thinning (n = 28, 12%), skin rash (n = 20; 8%), mucositis (n = 13, 5%), and pruritus (n = 6, 3%) were observed. Furthermore, 35 patients (15%) developed herpes virus infections (time since last cladribine exposition: median 83 [range: 10-305]). In 15 patients, herpes zoster infection was severe (CTCAE grade ≥ 3) and required hospitalization. Delayed skin AEs (≥3 months after a cladribine treatment cycle) involved 1 case of leukocytoclastic vasculitis and 2 cases of alopecia areata. Finally, 2 patients presented with in total 3 isolated precancerous lesions (1 leukoplakia simplex and 2 actinic keratosis) and 1 patient developed a squamous cell carcinoma., Conclusion: Skin AEs are common in patients with MS treated with cladribine. Until risk management plans have been adjusted to include these phenomena, clinicians should perform a thorough clinical follow-up and in suspicious cases seek early interdisciplinary support. In light of the observed delayed skin reactions, we further emphasize the necessity of careful clinical surveillance of cladribine-treated patients for yet undescribed secondary autoimmune events., Classification of Evidence: This study provides Class IV evidence that skin-related AEs are frequent in patients with MS following cladribine in a real-world setting., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare condition defined by encephalopathy with acute or subacute onset, the presence of serum anti-thyroid antibodies, and reasonable exclusion of alternative causes. Despite having strong response towards corticosteroid treatment, some patients exhibit a chronic-relapsing course and require long-term immunosuppression. Markers for early identification of those patients are still absent. Thus, we aimed to characterise clinical as well as laboratory parameters of our local SREAT cohort., Methods: We retrospectively evaluated a cohort of 22 SREAT patients treated in our hospital from January 2014., Results: A total of 14 patients with a monophasic disease course and eight patients with multiple relapses were identified. Neither baseline characteristics nor routine cerebrospinal fluid (CSF) parameters were able to distinguish between those patient groups. Flow cytometry following initial relapse therapy showed treatment-resistant sequestration of activated CD4+ T cells in patients with a relapsing disease course, whereas other lymphocyte subsets showed uniform changes. Such changes were also present in long-term follow-up CSF examination., Conclusion: Our findings indicate a potential biomarker for risk stratification in patients with SREAT. Currently, it remains unclear whether the observed two phenotypes are different spectra of SREAT or represent separate diseases in terms of pathophysiology., (© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Aims: Various attempts have been made to support recovery following optic neuritis (ON), but the respective trials have mostly been negative. The aim of this study was to determine whether disease-modifying treatment (DMT) following ON as first manifestation of relapsing-remitting multiple sclerosis influences long-term outcomes., Methods: A total of 79 patients with ON were identified and evaluated at relapse, DMT induction, and 12 months following treatment induction with either glatiramer acetate (GLAT), interferon-beta (IFN), or teriflunomide (TRF). Low-contrast letter acuity (LCLA) and full-field visual-evoked potentials (FF-VEP) were compared between treatment groups using multivariable regression models. The impact of TRF treatment induction compared with IFN or GLAT following relapses outside the optic nerves was evaluated in an independent cohort of 122 patients. Magnetic resonance imaging (MRI) outcomes and rates of confirmed improvement of relapse-related disability were evaluated., Results: TRF-treated patients exhibited higher LCLA and lower relative P100 latencies normalized to the fellow-eye. Findings were significant following covariate-adjustment by multivariable analyses. Cranial MRI lesion load as well as disability progression rates were not significantly different between groups. The cohort of patients following relapses other than ON showed no differences in confirmed improvement of disability., Conclusion: TRF treatment is associated with favorable outcomes regarding functional optic nerve recovery following ON in early multiple sclerosis., Competing Interests: Conflict of interest statement: Steffen Pfeuffer: received travel grants from Sanofi Genzyme and Merck Serono, lecturing honoraria from Sanofi Genzyme, Mylan Healthcare, and Biogen, and research support from Diamed, Merck Serono, and the German Multiple Sclerosis Society Northrhine-Westphalia. Laura Kerschke: declares no conflicts of interest Tobias Ruck: received travel grants and financial research support from Genzyme and Novartis and received honoraria for lecturing from Roche, Merck, Genzyme, Biogen, and Teva. Leoni Rolfes: received travel grants from Merck Serono and Sanofi-Genzyme. Marc Pawlitzki: received speaker honoraria and travel reimbursements from Novartis. Philipp Albrecht: received compensation for serving on Scientific Advisory Boards for Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. He received speaker honoraria and travel support from Allergan, Bayer Vital GmbH, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, Roche. Philipp Albrecht received research support from Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. Heinz Wiendl: received compensation for serving on Scientific Advisory Boards/Steering Committees for Bayer Healthcare, Biogen Idec, Sanofi Genzyme, Merck Serono, and Novartis. He received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck Serono, Omniamed, Novartis, and Sanofi Aventis. He received compensation as a consultant from Biogen Idec, Merck Serono, Novartis, Roche, and Sanofi-Genzyme. Heinz Wiendl also received research support from Bayer Healthcare, Bayer Vital, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Sanofi US, and Teva. Sven G. Meuth: received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. The current work was conducted outside of third-party funding., (© The Author(s), 2021.)

Flow stagnation of peri-ischemic capillaries due to dynamic leukocyte stalls has been described to be a contributor to ongoing penumbral injury in transient brain ischemia, but has not been investigated in permanent experimental stroke so far. Moreover, it is discussed that obstructing neutrophils are involved in this process; however, their contribution has not yet been proven. Here, we characterize the dynamics of neutrophil granulocytes in two models of permanent stroke (photothrombosis and permanent middle cerebral artery occlusion) using intravital two-photon fluorescence microscopy. Different to previous studies on LysM-eGFP + cells we additionally apply a transgenic mouse model with tdTomato-expressing neutrophils to avoid interference from additional immune cell subsets. We identify repetitively occurring capillary stalls of varying duration promoted by neutrophils in both models of permanent cerebral ischemia, validating the suitability of our new transgenic mouse model in determining neutrophil occlusion formation in vivo. Flow cytometric analysis of peripheral blood (PB) and brain tissue from mice subjected to photothrombosis reveal an increase in the total proportion of neutrophils, with selective upregulation of endothelial adherence markers in the PB. In conclusion, the dynamic microcirculatory stall phenomenon that is described after transient ischemia followed by reperfusion also occurs after permanent small- or large-vessel stroke and is clearly attributable to neutrophils., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The immunological synapse is a transient junction that occurs when the plasma membrane of a T cell comes in close contact with an APC after recognizing a peptide from the antigen-MHC. The interaction starts when CRAC channels embedded in the T cell membrane open, flowing calcium ions into the cell. To counterbalance the ion influx and subsequent depolarization, K v 1.3 and KCa3.1 channels are recruited to the immunological synapse, increasing the extracellular K + concentration. These processes are crucial as they initiate gene expression that drives T cell activation and proliferation. The T cell-specific function of the K 2P channel family member TASK2 channels and their role in autoimmune processes remains unclear. Using mass spectrometry analysis together with epifluorescence and super-resolution single-molecule localization microscopy, we identified TASK2 channels as novel players recruited to the immunological synapse upon stimulation. TASK2 localizes at the immunological synapse, upon stimulation with CD3 antibodies, likely interacting with these molecules. Our findings suggest that, together with K v 1.3 and KCa3.1 channels, TASK2 channels contribute to the proper functioning of the immunological synapse, and represent an interesting treatment target for T cell-mediated autoimmune disorders., (© 2020 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Purpose: The primary aim of this study was to gain insight in the safety profile of the new antidiabetic agents glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in daily practice. The secondary aim was to compare reported adverse drug reactions (ADRs) with information described in the Summary of Product Characteristics (SPC) and to generate knowledge about characteristics, like time to onset and outcome of ADRs. This knowledge is important for drug regulators and clinical practice to understand and manage ADRs better., Methods: A prospective, observational web-based cohort event monitoring study among first-time users of GLP-1 agonists and DPP-4 inhibitors. Patients were recruited through community pharmacies from 2008 to 2016. Participants were invited to complete six web-based questionnaires over a 1-year periods after start of the antidiabetic agent. Questions were posed about patient characteristics, drug use, and ADRs. Data were analyzed using descriptive statistics., Results: Then, 743 patients were included. Also 62% of all GLP-1 agonist users (total n = 119) and 33% of DPP-4 inhibitor users (total n = 624) experienced an ADR. Of the 10 most reported ADRs, for GLP-1 agonist all, and for DPP-4 inhibitors 8 were described in the drug's SPC. For 45 (91%) ADRs, the patients recovered without discontinuation of the GLP-1 agonist and 79 (73%) ADRs without discontinuation of the DPP-4 inhibitor therapy., Conclusions: This study gives insight in the safety profile and ADR characteristics of the new antidiabetic agents. This study provides important knowledge for healthcare professionals in managing ADRs and can be directly applied in consultations in daily practice., (© 2020 John Wiley & Sons Ltd.)

In the past decades, multiple sclerosis (MS) treatment has experienced vast changes resulting from major advances in disease-modifying therapies (DMT). Looking at the overall number of studies, investigations with therapeutic advantages and encouraging results are exceeded by studies of promising compounds that failed due to either negative or inconclusive results or have been interrupted for other reasons. Importantly, these failed clinical trials are informative experiments that can help us to understand the pathophysiological mechanisms underlying MS. In several trials, concepts taken from experimental models were not translatable to humans, although they did not lack a well-considered pathophysiological rationale. The lessons learned from these discrepancies may benefit future studies and reduce the risks for patients. This review summarizes trials on MS since 2015 that have either failed or have been interrupted for various reasons. We identify potential causes of failure or inconclusiveness, looking at the path from basic animal experiments to clinical trials, and discuss the implications for our current view on MS pathogenesis, clinical practice, and future study designs. We focus on anti-inflammatory treatment strategies, without including studies on already approved and effective DMT. Clinical trials addressing neuroprotective and alternative treatment strategies are presented in a separate article.

Immunosuppression and immunomodulation are valuable therapeutic approaches for managing neuroimmunological diseases. In times of the Coronavirus disease 2019 (COVID-19) pandemic, clinicians must deal with the question of whether immunotherapy should currently be initiated or discontinued in neurological patients. Uncertainty exists especially because different national medical associations publish different recommendations on the extent to which immunotherapies must be continued, monitored, or possibly switched during the current pandemic. Based on the most recently available data both about the novel coronavirus and the approved immunotherapies for neurological diseases, we provide an updated overview that includes current treatment strategies and the associated COVID-19 risk, but also the potential of immunotherapies to treat COVID-19., (Copyright © 2020. Published by Elsevier B.V.)